200 (ref. 24). TROP2 expression levels were low (H-score ≤200) in 52.5% and 19.0%, and high (H-score >200) in 47.5% and 69.8% of the patients in cohorts 1A and 1B, respectively (Table 1). There was a trend toward an inverse correlation between PD-L1 and TROP2 expression (r = −0.14, P = 0.18) (Extended Data Fig. 2c). No significant association was found between PD-L1 TPS (%) and clinical response (Extended Data Fig. 2d,e), although patients with a PD-L1 TPS of ≥50% tended to have a higher response rate in cohort 1B (78.3%) (Extended Data Fig. 3a,b). Similarly, no significant association was detected between TROP2 expression and objective response (Extended Data Figs. 2f,g and 3c,d). Further exploratory analysis of the combined impact of the TROP2 and PD-L1 categories indicated that PD-L1 expression levels appeared to be positively correlated with treatment response in the TROP2 high-expression subgroup but not in the TROP2 low-expression subgroup (Extended Data Table 1). Efficacy by subgroups Post hoc subgroup analysis by clinicopathological characteristics showed that the efficacy of sac-TMT with tagitanlimab was consistent across subgroups in both cohorts (Extended Data Fig. 4). Detailed subgroup analyses of cohorts 1A and 1B revealed that combination therapy was effective in patients with different levels of PD-L1 and TROP2 expression and those with squamous cell or nonsquamous cell histology (Extended Data Table 2). Clinically meaningful responses to sac-TMT and tagitanlimab were observed across various PD-L1 levels in both cohorts. Specifically, patients with a PD-L1 TPS of <1% had an ORR of 41.7% in cohort 1A and 57.1% in cohort 1B. Those with a PD-L1 TPS between 1% and 49% experienced an ORR of 38.5% in cohort 1A and 63.2% in cohort 1B. For patients with a PD-L1 TPS ≥50%, ORR was 40.0% in cohort 1A and 78.3% in cohort 1B (Extended Data Fig. 5 and Extended Data Table 2). ORR in TROP2-low patients was 42.9% in cohort 1A and 83.3% in cohort 1B. ORR in TROP2-high patients was 36.8% in cohort 1A and 68.2% in cohort 1B (Extended Data Fig. 6 and Extended Data Table 2). Patients with nonsquamous carcinoma and squamous carcinoma exhibited similar responses to the combination of sac-TMT and tagitanlimab. In cohort 1A, the ORR was 44.4% for nonsquamous carcinoma and 36.4% for squamous carcinoma. In cohort 1B, the ORR was 64.7% for nonsquamous carcinoma and 69.0% for squamous carcinoma (Extended Data Fig. 7 and Extended Data Table 2). Safety of sac-TMT combined with tagitanlimab A total of 40 patients in cohort 1A and 63 patients in cohort 1B were included in the safety set for safety assessment. The median dose intensity for sac-TMT in cohort 1A and cohort 1B was 1.6 mg per kg per week and 2.1 mg per kg per week, respectively. The median dose intensity for tagitanlimab in cohort 1A and cohort 1B was 387.7 mg per week and 418.8 mg per week, respectively. In cohort 1A, 38 of 40 (95.0%) patients reported at least one treatment-related adverse event (TRAE), compared to 61 of 63 (96.8%) patients in cohort 1B. Grade 3 or higher TRAEs were observed in 42.5% of patients (17 of 40) in cohort 1A and 58.7% (37 of 63) in cohort 1B (Table 3). TRAEs led to treatment interruption in 27.5% (11 of 40) of the patients in cohort 1A and 54.0% (34 of 63) of the patients in cohort 1B. sac-TMT dose reduction because of TRAEs was required in 17.5% (7 of 40) of the patients in cohort 1A and 42.9% (27 of 63) in cohort 1B. Treatment discontinuation of any drug because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 6.3% (4 of 63) of the patients in cohort 1B. Discontinuation of sac-TMT occurred in two patients in cohort 1B (one because of drug hypersensitivity and one because of an infusion-related reaction), whereas no patient experienced TRAEs leading to sac-TMT discontinuation in cohort 1A. Treatment discontinuation of tagitanlimab because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 3.2% (2 of 63) of the patients in cohort 1B. Treatment-related serious adverse events occurred in 10.0% (4 of 40) and 20.6% (13 of 63) of the patients in cohort 1A and cohort 1B, respectively. No treatment-related deaths were reported. Table 3 Overall safety summary Full size table The most common TRAEs of any grade (occurring in ≥20% of patients) included anemia (80.0% and 79.4%), decreased neutrophil count (62.5% and 66.7%), decreased white blood cell count (50.0% and 54.0%), alopecia (45.0% and 49.2%), rash (40.0% and 38.1%), nausea (27.5% and 36.5%), decreased appetite (25.0% and 28.6%), increased alanine transaminase (ALT) (22.5% and 27.0%) and stomatitis (22.5% and 55.6%) in cohorts 1A and 1B, respectively (Table 4). The most common grade ≥3 TRAEs in cohorts 1A and 1B were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%), anemia (5.0% and 19.0%), rash (5.0% and 7.9%), stomatitis (0% and 9.5%) and drug eruption (7.5% and 0%) (Table 4). Interstitial lung disease (ILD) occurred in one patient in cohort 1B (grade 2), with no grade ≥3 pneumonitis or ILD reported. Table 4 Most common TRAEs (occurring in ≥20% of patients) and grade 3–5 TRAEs (occurring in ≥5% of patients) Full size table Immune-related adverse events (irAEs) were reported in 25.0% of patients (10 of 40) in cohort 1A and 39.7% (25 of 63) in cohort 1B. Grade 3 or higher irAEs occurred in 7.5% of cohort 1A (3 of 40) and 12.7% of cohort 1B (8 of 63) (Extended Data Table 3). The most common irAEs in cohorts 1A and 1B included rash (12.5% and 14.3%), increased alanine aminotransferase (ALT) (0% and 11.1%), hypothyroidism (2.5% and 7.9%), increased aspartate aminotransferase (AST) (0% and 6.3%) and hyperthyroidism (0% and 6.3%). Discussion In this phase 2 study, the combination of sac-TMT and tagitanlimab exhibited encouraging efficacy and a manageable safety profile in patients with advanced or metastatic NSCLC in the first-line setting. The observed ORR of 40.0% in cohort 1A and 66.7% in cohort 1B, together with the substantial depth and duration of response, underscore the potential of this combination strategy. Notably, the treatment response was consistent across diverse NSCLC subgroups, irrespective of PD-L1 expression status, TROP2 expression levels or histological subtype (squamous versus nonsquamous). These findings provide a rationale for further investigation of sac-TMT plus immunotherapy in a broad spectrum of patients with NSCLC, as evidenced by the increasing number of phase 3 studies evaluating this combination therapy. The ORR observed with biweekly (every 2 weeks (Q2W)) administration of sac-TMT and tagitanlimab is promising and suggests a potential improvement over the historical ORR of 48.0% to 57.9% achieved with conventional platinum-based chemotherapy plus an anti-PD-1 or anti-PD-L1 antibody for patients with NSCLC2,5. Moreover, the toxicity profile associated with the Q2W regimen was manageable. Therefore, sac-TMT administered Q2W has been adopted in most ongoing phase 3 trials for further investigation. ADCs have been shown to potentiate the effectiveness of anti-PD-1 or anti-PD-L1 therapies through a multifaceted mechanism of action. These include Fc-mediated effector functions, induction of immunogenic cell death, maturation of dendritic cells, increased T cell infiltration, boosted immunological memory and upregulation of immunomodulatory proteins, including PD-L1 and major histocompatibility complex21,22,23,25,26. Empirical evidence indicates a pronounced immunomodulatory effect of ADCs in immunocompetent animal models compared with their immunodeficient counterparts, highlighting the important role of ADCs in modulating the tumor microenvironment27,28. Collectively, these mechanisms underpin the potentially enhanced therapeutic outcomes observed with the combination of sac-TMT and tagitanlimab. In particular, in the subset of patients with a PD-L1 TPS value of 50% or greater, the ORR was 78.3% in cohort 1B. This rate is approximately twice that observed with pembrolizumab alone29 and surpasses by nearly 20% the ORR achieved with pembrolizumab plus platinum-based chemotherapy4,5. In light of these findings, randomized controlled trials are encouraged to explore whether sac-TMT plus pembrolizumab could further improve patient outcomes in people with high PD-L1 expression (NCT06170788) or positive PD-L1 expression (NCT06448312) compared with pembrolizumab alone. Another TROP2-targeting ADC, datopotamab deruxtecan, is also being evaluated in combination with pembrolizumab, with or without chemotherapy, in the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) studies. The results of these randomized trials are awaited given the early efficacy signal noted in the current study. Our study indicated that sac-TMT plus tagitanlimab is active in squamous NSCLC, a subtype with a high unmet medical need30. Specifically, patients with squamous carcinoma demonstrated an ORR of 36.4% in cohort 1A and 69.0% in cohort 1B. These results are comparable with those observed in patients with nonsquamous lung cancer, who demonstrated ORR of 44.4% in cohort 1A and 64.7% in cohort 1B. Further research is being conducted to evaluate the potential benefits of sac-TMT in patients with squamous NSCLC. A phase 3 clinical trial (NCT06422143) has been initiated to investigate this potential. This study was designed to compare the outcomes of pembrolizumab with or without maintenance therapy with sac-TMT, following induction treatment with pembrolizumab plus carboplatin and taxane, in patients with metastatic squamous NSCLC. Although not designed for comprehensive translational research, the current study focused on exploring the impact of two key biomarkers, TROP2 and PD-L1, on the efficacy of sac-TMT plus tagitanlimab therapy. Consistent with the known mechanisms of ICIs, we observed potentially enhanced treatment responses in patients with PD-L1 TPS ≥50% in cohort 1B. TROP2 expression levels showed no clear correlation with efficacy, a finding aligned with previous TROP2-directed ADC monotherapy studies31,32. This suggests that TROP2 membrane expression alone may not reliably predict the response to TROP2-directed ADC combined with immunotherapy. Accordingly, several ongoing phase 3 studies of first-line NSCLC have been initiated to further investigate the efficacy of sac-TMT plus pembrolizumab based on different PD-L1 expression levels (for example, with PD-L1 TPS ≥1% (NCT06448312), ≥50% (NCT06170788) and <1% (NCT06711900)), without TROP2-based patient selection. Intriguingly, our exploratory analysis indicated a trend toward a positive correlation between PD-L1 expression and treatment response, specifically in the TROP2 high-expression subgroup, but not in the TROP2 low-expression subgroup (Extended Data Table 1). These preliminary findings suggest a complex interplay between TROP2 and PD-L1 biomarkers, although validation requires in-depth translational studies in the future. In terms of safety, the combination of sac-TMT and tagitanlimab is generally manageable and consistent with the known profiles of individual agents, with no new safety signals19,33. Hematological toxicities, the most common TRAEs, were in the expected range and could be addressed with standard care. Although patients in cohort 1B experienced a higher incidence of grade 3 or higher hematological adverse events compared with those in cohort 1A, these events were manageable in both groups. Stomatitis also occurred more frequently in cohort 1B; however, the majority of cases were in grades 1 and 2. Of note, ILD, a concerning adverse event linked to irinotecan and other ADCs (for example, DS-8201) is rare with sac-TMT and tagitanlimab. We reported a single case of grade 2 ILD in cohort 1B. The most common irAEs reported were rash, elevations in ALT and AST levels, hypothyroidism and hyperthyroidism, consistent with the known safety profile of tagitanlimab33. Some 17.5% of patients in cohort 1A and 42.9% of patients in cohort 1B experienced dose reduction of sac-TMT. However, discontinuation of any investigational drug because of TRAEs was rare (2.5% in cohort 1A and 6.3% in cohort 1B). No treatment-related deaths were reported. Our study has several limitations. First, this was an open-label study without a comparator arm. Therefore, the benefits of sac-TMT plus tagitanlimab over traditional platinum-based chemotherapy plus immunotherapy remain to be elucidated. Second, the modest cohort size and lack of formal hypothesis testing precluded definitive statistical inferences. Third, the relatively short follow-up period in cohort 1B rendered the PFS outcomes and DOR data preliminary. Future efforts will focus on reporting long-term toxicity and efficacy data. Furthermore, the relationship between TROP2 and PD-L1 expression and treatment response remains unclear because of the limited sample size. Further biomarker-driven studies that focus on tumor microenvironment and dynamic changes in blood biomarkers are necessary to better identify patients who are more likely to benefit from sac-TMT plus anti-PD-1 or anti-PD-L1 immunotherapy. Limitations aside, the OptiTROP-Lung01 study established the safety, tolerability and preliminary efficacy of sac-TMT with tagitanlimab in patients with advanced NSCLC lacking actionable genomic alterations. These results support ongoing studies that aim to validate our findings and delineate the therapeutic potential of combining TROP2-directed ADC with immunotherapy in various disease scenarios. Methods Study design, participants and ethics The OptiTROP-Lung01 trial (NCT05351788) is an ongoing, open-label, multicohort, multicenter, phase 2 study of sac-TMT plus tagitanlimab (KL-A167) with or without carboplatin or cisplatin, in patients with advanced NSCLC. Cohort 1 enrolled patients with locally advanced or metastatic NSCLC harboring wild-type EGFR and negative anaplastic lymphoma kinase (ALK) fusion gene, with no known actionable alterations in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic tyrosine receptor kinase (NTRK) or v-raf murine sarcoma viral oncogene homolog B (BRAF), with no known driver gene alterations targetable by other approved therapies. Eligible patients should not have received prior ICI therapy and have no prior or at most one prior line of systemic therapy. Cohort 1 is further divided into cohorts 1A and 1B. Patients in cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks (Q3W)) + tagitanlimab (1,200 mg, Q3W) in each 3-week cycle, and patients in cohort 1B were treated with sac-TMT (5 mg kg−1, every 2 weeks (Q2W)) + tagitanlimab (900 mg, Q2W) in each 4-week cycle. These two cohorts were initiated sequentially to assess tolerability and optimize dosing regimens to inform subsequent phase 3 study design. Here, we presented the initial safety and efficacy data from both cohort 1A and cohort 1B. The dosing strategies for cohorts 1A and 1B were determined based on phase 1 studies that suggested optimal efficacy and safety profiles (details are provided in Supplementary Information). Specifically, in the phase 1–2, dose escalation–expansion, global first-in-human study of sac-TMT (ClinicalTrials.gov identifier: NCT04152499), the maximum tolerated dose was 5.5 mg kg−1 Q2W and the recommended doses for expansion were 4 mg kg−1 Q2W and 5 mg kg−1 Q2W. Similarly, in the phase 1 study of tagitanlimab (ChinaTRugtrials.org identifier: CTR20181198), 900 mg Q2W and 1,200 mg Q3W were both selected as the recommended doses for tagitanlimab based on their similar efficacy and exposure levels. Given these findings, we chose to explore the combination of sac-TMT and tagitanlimab at two different dosing frequencies: Q2W and Q3W. The Q2W dosing strategy was selected based on the recommended dose of each agent, whereas the Q3W dosing strategy was explored to align with the more common dose interval for anti-PD-1 or anti-PD-L1 therapy in clinical practice. Cohort 1A also was designed to establish initial safety with a lower dose intensity of sac-TMT (5 mg kg−1 Q3W), whereas cohort 1B explored a higher dose intensity of sac-TMT (5 mg kg−1 Q2W) to evaluate potential efficacy gains. All enrolled patients received continuous treatment until intolerable toxicity, no further clinical benefit as assessed by the investigator (based on a comprehensive assessment of imaging and clinical condition), or the patient’s request for discontinuation of treatment, whichever occurs first; the maximum duration of treatment with tagitanlimab is 24 months. Further details of key inclusion and exclusion criteria are provided below and in Supplementary Information. Key inclusion criteria were: (1) Male or female patients ≥18 and ≤75 years of age at the time of signing the informed consent form (2) Histologically and cytologically confirmed NSCLC, locally advanced (stage IIIB and IIIC) or metastatic (stage IV) NSCLC not amenable to radical surgery and/or radical radiotherapy (regardless of concurrent chemotherapy) (according to the 8th edition of TNM Staging of Lung Cancer published by the International Union Against Cancer and American Joint Committee on Cancer)34 (3) For patients with nonsquamous NSCLC, prior tissue-based EGFR and ALK reports must be available, otherwise tumor tissue samples (archival or fresh, primary or metastatic) must be collected for assessment of EGFR and ALK status (either in a local laboratory or in a central laboratory). For patients with squamous NSCLC, if the prior EGFR and ALK statuses are unknown, the corresponding tests would not be required for study enrollment, and the EGFR and ALK status of these patients would be considered negative. (4) Patients with locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion gene, no known ROS1, NTRK, BRAF gene alterations, or no known driver gene alterations that can also be targeted by other approved therapies, no prior ICI therapy, and no prior or at most one prior line of systemic therapy. Prior adjuvant, neoadjuvant or radical chemoradiotherapy may be considered first-line therapy if there is disease progression during the treatment or within 6 months after completion of treatment. (5) Be able to provide fresh or archival tumor tissue for biomarker testing and analysis (PD-L1 and TROP2 expression level) (6) Patients with at least one measurable lesion per RECIST v.1.1 criteria (7) Patients with an ECOG performance status of 0 to 1 with an expected survival of ≥12 weeks (8) Adequate organ and bone marrow function (no blood transfusion, recombinant human thrombopoietin or colony-stimulating factor therapy within 2 weeks before first dose) (9) Patients must recover from all toxicities (≤grade 1 or the inclusion criterion specified in the protocol based on Common Terminology Criteria for Adverse Events v.5.0 assessment) due to prior treatment, except for alopecia and vitiligo (10) Female patients of childbearing potential and male patients with partners of childbearing potential who use effective medical contraception during the study treatment period and for 6 months after the end of dosing (see Supplementary Information for specific contraceptive measures) (11) Each patient must voluntarily agree to participate in the study, sign the informed consent form and comply with the protocol-specified visits and relevant procedures. Key exclusion criteria were: (1) Presence of small cell lung carcinoma components in histological pathology (2) History of other malignancies, except locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, or other solid tumors curatively treated with no evidence of disease for ≥3 years (3) Presence of metastases to the brainstem, meninges and spinal cord, or spinal cord compression (4) Patients with active brain metastases (5) Patients who have received any chemotherapy, immunotherapy, biotherapy and so on within 4 weeks before the first dose of study treatment, or received small molecule tyrosine kinase inhibitors, antitumor hormone therapy, systemic immune stimulators (including but not limited to interferon, interleukin-2), radiotherapy or herbal products preparations for approved antitumor indications within 2 weeks before the first dose of study treatment (6) Patients who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of the study treatment, or received more than 30 Gy of radiation for lung lesions within 6 months before the first dose of the study treatment (7) Patients who required the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks before the first dose of the study treatment and during the study (concomitant use of strong inhibitors or inducers of CYP3A4 are not allowed in this study, and the representative drugs for known strong CYP3A4 inhibitors or inducers are listed in Supplementary Information) (8) Patients who have received systemic corticosteroids (>10 mg d−1 prednisone or equivalent, or low-dose corticosteroids, such as ≤10 mg d−1 prednisone or equivalent, are allowed if the dose is stable for 4 weeks), or other immunosuppressive therapy within 2 weeks before the first dose. Steroids are allowed as prophylaxis for hypersensitivity reactions. (9) Received any live vaccine 4 weeks before the first dose of study treatment (10) With active infections requiring systemic treatment within 2 weeks before the first dose of study treatment (11) With Grade 2 or above peripheral neuropathy (12) History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment (13) Arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy that have resolved as judged by the investigator) and pulmonary embolism within 6 months before the first dose of study treatment (14) Active or previous clear history of inflammatory bowel disease (for example, Crohn’s disease, ulcerative colitis, or chronic diarrhea) (15) Prior TROP2-targeted therapy (16) Serious or uncontrolled cardiac disease or clinical symptoms requiring treatment, including any of the following: (i) New York Heart Association Grade 3 or 4 congestive heart failure within 6 months before the first dose of study treatment (ii) Unstable angina pectoris uncontrolled by medication within 6 months before the first dose of study treatment (iii) History of myocardial infarction (iv) Serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia) within 6 months before the first dose of study treatment (v) Corrected QT interval >480 ms at baseline (17) History of (noninfectious) ILD or noninfectious pneumonitis requiring steroid therapy and current ILD or noninfectious pneumonitis, or suspected ILD or noninfectious pneumonitis at screening that cannot be excluded by imaging (18) Uncontrolled systemic disease as judged by the investigator (19) Active autoimmune disease requiring systemic treatment within the past 2 years (hormone replacement therapy is not considered a systemic therapy), such as type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenal or pituitary insufficiency requiring only physiologic doses of glucocorticoid replacement therapy (20) Certain viral infections including active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥500 IU ml−1 or upper limit of normal, which is higher) or hepatitis C (hepatitis C antibody positive, and HCV-RNA above the upper limit of normal); known history of positive human immunodeficiency virus test or known acquired immunodeficiency syndrome, or known active syphilis infection (21) Known active tuberculosis (22) Known hypersensitivity to the study drug or any of its components, or severe allergic reactions to other monoclonal antibodies (23) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation (24) Pregnant or lactating women (25) Any patient whose condition deteriorates rapidly during the screening process before the first dose, such as severe changes in performance status and so on (26) Other circumstances that, in the opinion of the investigator, are not appropriate for participation in this study. The study was conducted at 17 sites in China following the moral, ethical and scientific principles outlined in the Declaration of Helsinki and the Good Clinical Practice. Approvals for the study protocol, any amendments and informed consent were obtained from independent ethics committees of each participating site and central approval was obtained from the Sun Yat-sen University Cancer Center institutional review board before study initiation. All patients provided written informed consent. Any amendment to the protocol must be reviewed and approved by the ethics committee before implementation. Clinical trial objectives The primary objectives were to assess the safety, tolerability and antitumor activity of sac-TMT in combination with tagitanlimab in patients with advanced or metastatic NSCLC. The secondary objectives were to assess the efficacy, pharmacokinetics and immunogenicity of sac-TMT in combination with tagitanlimab. Other objectives were to assess the correlation between the expression level of TROP2 in tumor tissue and antitumor activity and the correlation between the expression level of PD-L1 in tumor tissue and antitumor activity. Clinical endpoint and assessments The primary endpoints included the safety endpoint measured by the incidence and severity of adverse events and the efficacy endpoint, namely ORR as assessed by the investigator according to RECIST v.1.1. The secondary endpoints included efficacy, namely PFS, DOR and DCR assessed by the investigator according to RECIST v.1.1. Other endpoints include the correlation between antitumor activity and the expression level of TROP2 and PD-L1 in tumor tissue. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. The severity of each adverse event was also recorded. An irAE refers to an adverse event related to tagitanlimab injection and is considered to be caused by an immune-mediated mechanism, and may require corticosteroid hormone, other immunosuppressants or hormone replacement therapy. Tumor response assessments based on RECIST v.1.1 were performed every 6 weeks by investigators. Immunohistochemistry and biomarker analysis Patients should provide approximately ten tumor tissue slides at or after diagnosis of locally advanced or metastatic tumor for TROP2 and PD-L1 protein assessment (five slides for TROP2 and five for PD-L1 detection, respectively). TROP2 and PD-L1 expression levels in formalin-fixed tumor samples were assessed using immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd). In detail, TROP2 expression was stained and assessed with anti-TROP2 monoclonal antibody (1:3,000; Abcam, cat. no. EPR20043). For PD-L1 expression, we used the ready-to-use companion diagnostic assay PD-L1 IHC 22C3 pharmDx (Agilent), which is approved by the US Food and Drug Administration and National Medical Products Administration, and is prevalidated for clinical use. All the areas in each tissue section were evaluated for TROP2 or PD-L1 expression. H-score refers to the product of tumor cell staining intensity and the percentage of stained cells at a given intensity in the membrane compartment, which was calculated as ‘(1 × % cells with weak intensity staining) + (2 × % cells with moderate intensity staining) + (3 × % cells with strong intensity staining)’. TROP2 expression level was divided into two subgroups: low expression with an H-score of ≤200, and high expression with an H-score of >200. PD-L1 expression was documented as TPS, with scores of 0–1% being defined as negative expression, 1–49% as low expression and ≥50% as high expression. Statistical analyses The statistical analyses of cohorts 1A and 1B were mainly descriptive and focused on safety and efficacy estimates, without formal hypothesis testing. Thus, no statistical power calculations were performed to determine the sample sizes for cohorts 1A and 1B. Based on regulatory guidance, a minimum of 30 patients per cohort was required. To adequately characterize the safety profile and preliminary efficacy, each cohort was planned to enroll between 30 and 60 patients. If not otherwise specified, the data were summarized using descriptive statistical methods according to the following general principles. The descriptive statistics for continuous variables were presented using number, mean, s.d., maximum, minimum and median, and the descriptive statistics for categorical variables were presented using incidence and frequency or number and percentage of patients. Safety was assessed on the safety set, defined as all patients who have received at least one dose of the investigational product and have safety evaluation data. The biomarker analysis set included all patients who received at least one dose of the study drugs and had pretreatment specimens for TROP2 and/or PD-L1 assessment. Median follow-up time was calculated based on the reverse Kaplan–Meier method. The primary endpoint of investigator-assessed ORR was based on the FAS, and the 95% CI of ORR was estimated using the Clopper–Pearson method. Analysis of the secondary endpoint of DCR was based on the FAS, and the 95% CI of DCR was estimated using the Clopper–Pearson method. The secondary endpoint of investigator-assessed PFS was based on the FAS population, and the median values of the two groups were estimated using the Kaplan–Meier method, and their 95% CI values were calculated using the Brookmeyer–Crowley method. At the time of primary analysis, for patients without disease progression or death, PFS was censored at the date of the last valid imaging examination. For patients without postbaseline tumor assessments, PFS was censored at the time of administration. For patients whose date of first disease progression or death was more than two assessment cycles away from the date of the previous imaging, the date of PFS was censored to the date of the last valid imaging before progression. DOR as assessed by the investigator was defined as the time from the date of the first obtained complete response (CR) or PR to disease progression or death due to any cause, whichever occurs first. Analysis of DOR was based on patients with CR and PR in the FAS, the median values of each group was estimated using the Kaplan–Meier method, and the corresponding 95% CI was calculated using the Brookmeyer–Crowley method. For patients without progression or death, DOR was censored at the date of the last valid imaging examination. No imputation for missing values was conducted for ORR and DCR. Comparisons of biomarker levels between groups were performed using Dunn’s test for multiple comparisons. The chi-squared test was used for categorical variables. Pearson test was used to determine the correlation between the TROP2 expression level (H-score) and PD-L1 TPS level in cohorts 1A and 1B. Statistical significance was defined as a two-sided P value < 0.05. Data were collected using an electronic data capture system (Clinflash EDC, v.2024.3.0). Statistical analyses and graph drawing were conducted using the SAS v.9.4 and R v.4.1.3. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to fangwf@sysucc.org.cn, zhangli@sysucc.org.cn or mict@kelun.com. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by the corresponding authors, the SYSUCC institutional review board, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. to evaluate the merit of the research proposed, the availability of the data, the intended use of the data and the presence of conflict of interests. A signed data access agreement with the sponsors is required before data sharing. The study protocol and the remaining data are available in the Article or Supplementary Information. References Bray, F. et al. 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Oncol. 35, 2790–2797 (2017). Article CAS PubMed Google Scholar Shi, Y. et al. Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. Lancet Reg. Health West. Pac. 31, 100617 (2023). PubMed Google Scholar Lababede, O. & Meziane, M.A. The eighth edition of TNM staging of lung cancer: reference chart and diagrams. Oncologist 23, 844–848 (2018). Article PubMed PubMed Central Google Scholar Download references Acknowledgements The study was sponsored by Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. The sponsor provided the investigated drug and worked with investigators on the trial design, data collection, data analyses and results interpretation. This study was also supported, in part by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2024ZD0519700 awarded to L.Z.; grant nos 2024ZD0520200 and 2024ZD0520205 awarded to S. Hong), National Natural Science Foundation of China (grant nos 82272789 and 82241232 awarded to L.Z., grant nos 82373262 and 82173101 awarded to W.F., grant no. 82172713 awarded to S. Hong), Natural Science Foundation of Guangdong Province (grant no. 2023B1515020008 awarded to S. Hong) and Guangzhou Science and Technology Program (grant no. 2024A04J6485 awarded to S. Hong). We thank all the patients who volunteered to participate in the OptiTROP-Lung01 study and their families for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and their devoted team members for participating in the OptiTROP-Lung01 study. Author information Author notes These authors contributed equally: Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu. Authors and Affiliations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China Shaodong Hong, Li Zhang & Wenfeng Fang The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China Qiming Wang Henan Cancer Hospital, Zhengzhou, China Qiming Wang Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China Qiming Wang Jilin Cancer Hospital, Changchun, China Ying Cheng Hunan Cancer Hospital, Changsha, China Yongzhong Luo & Lin Wu The First Hospital of China Medical University, Shenyang, China Xiujuan Qu Shanxi Cancer Hospital, Taiyuan, China Haibo Zhu West China Hospital of Sichuan University, Chengdu, China Zhenyu Ding The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Xingya Li Harbin Medical University Cancer Hospital, Harbin, China Yan Wang Hubei Cancer Hospital, Wuhan, China Sheng Hu Chongqing University Cancer Hospital, Chongqing, China Enwen Wang The Second Affiliated Hospital of Nanchang University, Nanchang, China Anwen Liu Shandong Cancer Hospital, Jinan, China Yuping Sun Zhejiang Cancer Hospital, Hangzhou, China Yun Fan The First Affiliated Hospital of Xiamen University, Xiamen, China Feng Ye Jiangsu Province Hospital, Nanjing, China Kaihua Lu Beijing Cancer Hospital, Beijing, China Jian Fang Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China Yuping Shen, Xiaoping Jin & Junyou Ge National Engineering Research Center of Targeted Biologics, Chengdu, China Junyou Ge Contributions S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. conceived and designed the study. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. provided study materials and recruited participants. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. collected and assembled the data. S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. analyzed and interpreted the data. All authors were involved in writing, reviewing and editing of the paper, and in final approval of the paper. All authors are accountable for all aspects of the work. Corresponding authors Correspondence to Li Zhang or Wenfeng Fang. Ethics declarations Competing interests Y. Shen, X.J. and J.G. are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma, and consulting for MSD, Beigene and Xiansheng Pharma. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks Melissa Johnson, Maiying Kong and Shengxiang Ren for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Efficacy in the full analysis set population. a, b, Spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in cohort 1 A (a) and cohort 1B (b). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). c, d, Kaplan-Meier survival curves of progression-free survival for cohort 1 A (c) and cohort 1B (d), respectively. Solid step lines represent Kaplan-Meier estimates of PFS probability, where vertical drops indicate events; shaded bands depict pointwise 95% confidence intervals around that estimate using the Brookmeyer–Crowley method; marks (+) denote censored data points. PFS, progression-free survival; CI, confidence interval; N.E., not estimable. Extended Data Fig. 2 The correlation between PD-L1 expression, TROP2 expression and treatment response. a, b, Expression of PD-L1 (tumor proportion score, TPS) (a) and TROP2 (b) in cohort 1A and cohort 1B. c, scatter plot of PD-L1 versus TROP2 expression in patients with both biomarkers available. Correlation was assessed using a two-sided Pearson test (no adjustment for multiple comparisons); the gray shaded area represents 95% confidence bands for the linear regression fit. d, e, Association between PD-L1 expression and confirmed best overall response in cohort 1 A (d) and cohort 1B (e). f, g, Association between TROP2 expression and response in cohort 1 A (f) and cohort 1B (g). Box plots in panels a, b, d–g depict the median (center line), first quartile (Q1; box bottom), and third quartile (Q3; box top). Whiskers encompass 1.5 times the interquartile range (IQR), with points beyond whiskers representing outliers. Group comparisons were performed using a two-sided Dunn’s test for multiple comparisons (d–g). TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 3 Tumor response distribution by PD-L1 expression and TROP2 expression categories. a, b, the difference of tumor response among three PD-L1 TPS categories was compared in cohort 1 A (a) and cohort 1B (b). c, d, according to the cutoff of the H-score of 200, patients were divided into two groups: low TROP2 expression and high TROP2 expression, and the difference of tumor response between two TROP2 expression groups was compared in cohort 1 A (c) and cohort 1B (d). Statistical significance was determined using Chi-squared test. TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 4 Forrest plots for confirmed overall response rate in different patient subgroups. a, cohort 1 A; b, cohort 1B. Subgroup with sample size ≥ 10 were shown. The central mark on each horizontal error bar represents the point estimate of the cORR for the respective subgroup. The horizontal error bar represents the 95% confidence interval for each cORR value. cORR, confirmed objective response rate; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 5 Depth and duration of response by PD-L1 expression. a, b, c, waterfall plot depicting the maximum change from baseline in target lesion size in patients with PD-L1 TPS of < 1% (a), between 1 and 49% (b) and ≥ 50% (c); d, e, f, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with PD-L1 TPS of < 1% (d), between 1 and 49% (e), and ≥ 50% (f). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 6 Depth and duration of response by TROP2 expression. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with TROP2 H-score of ≤ 200 (a) and TROP2 H-score of > 200 (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with TROP2 H-score of ≤ 200 (c) and TROP2 H-score of > 200 (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Fig. 7 Depth and duration of response by histology subgroup. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with non-squamous carcinoma (a) and squamous carcinoma (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with non-squamous carcinoma (c) and squamous carcinoma (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Table 1 Subgroup efficacy in cohort 1A and cohort 1B grouped by PD-L1 expression among TROP2 low or high-expression population Full size table Extended Data Table 2 Subgroup efficacy analysis by PD-L1/TROP2 expression and histology Full size table Extended Data Table 3 Immune-related adverse events (irAEs) (occurring in ≥ 2% of patients) and grade 3-5 irAEs (occurring in at least one patient) Full size table Supplementary information Supplementary Information Redacted study protocol (v.3.0, 2023.01.01). Reporting Summary Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Hong, S., Wang, Q., Cheng, Y. et al. First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial. Nat Med 31, 3654–3661 (2025). https://doi.org/10.1038/s41591-025-03883-5 Download citation Received 16 August 2024 Accepted 03 July 2025 Published 19 August 2025 Version of record 19 August 2025 Issue date November 2025 DOI https://doi.org/10.1038/s41591-025-03883-5 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer immunotherapy Non-small-cell lung cancer This article is cited by Perioperative Immunotherapy for Non-Small Cell Lung Cancer (NSCLC) Sarafina Urenna OtisGiuseppe Luigi BannaAkash Maniam Current Oncology Reports (2025) You have full access to this article via Sun Yat-sen University. Download PDF Sections Figures References Abstract Main Results Discussion Methods Data availability References Acknowledgements Author information Ethics declarations Peer review Additional information Extended data Supplementary information Rights and permissions About this article This article is cited by Advertisement Nature Medicine (Nat Med) ISSN 1546-170X (online) ISSN 1078-8956 (print) nature.com sitemap About Nature Portfolio About us Press releases Press office Contact us Discover content Journals A-Z Articles by subject protocols.io Nature Index Publishing policies Nature portfolio policies Open access Author & Researcher services Reprints & permissions Research data Language editing Scientific editing Nature Masterclasses Research Solutions Libraries & institutions Librarian service & tools Librarian portal Open research Recommend to library Advertising & partnerships Advertising Partnerships & Services Media kits Branded content Professional development Nature Awards Nature Careers Nature Conferences Regional websites Nature Africa Nature China Nature India Nature Japan Nature Middle East Privacy Policy Use of cookies Your privacy choices/Manage cookies Legal notice Accessibility statement Terms & Conditions Your US state privacy rights Springer Nature © 2025 Springer Nature Limited CloseNature Briefing Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Email address e.g. jo.smith@university.ac.uk Sign up I agree my information will be processed in accordance with the Nature and Springer Nature Limited Privacy Policy.". An AI-generated interactive educational simulation created by Anonymous on MyPopku."> 200 (ref. 24). TROP2 expression levels were low (H-score ≤200) in 52.5% and 19.0%, and high (H-score >200) in 47.5% and 69.8% of the patients in cohorts 1A and 1B, respectively (Table 1). There was a trend toward an inverse correlation between PD-L1 and TROP2 expression (r = −0.14, P = 0.18) (Extended Data Fig. 2c). No significant association was found between PD-L1 TPS (%) and clinical response (Extended Data Fig. 2d,e), although patients with a PD-L1 TPS of ≥50% tended to have a higher response rate in cohort 1B (78.3%) (Extended Data Fig. 3a,b). Similarly, no significant association was detected between TROP2 expression and objective response (Extended Data Figs. 2f,g and 3c,d). Further exploratory analysis of the combined impact of the TROP2 and PD-L1 categories indicated that PD-L1 expression levels appeared to be positively correlated with treatment response in the TROP2 high-expression subgroup but not in the TROP2 low-expression subgroup (Extended Data Table 1). Efficacy by subgroups Post hoc subgroup analysis by clinicopathological characteristics showed that the efficacy of sac-TMT with tagitanlimab was consistent across subgroups in both cohorts (Extended Data Fig. 4). Detailed subgroup analyses of cohorts 1A and 1B revealed that combination therapy was effective in patients with different levels of PD-L1 and TROP2 expression and those with squamous cell or nonsquamous cell histology (Extended Data Table 2). Clinically meaningful responses to sac-TMT and tagitanlimab were observed across various PD-L1 levels in both cohorts. Specifically, patients with a PD-L1 TPS of <1% had an ORR of 41.7% in cohort 1A and 57.1% in cohort 1B. Those with a PD-L1 TPS between 1% and 49% experienced an ORR of 38.5% in cohort 1A and 63.2% in cohort 1B. For patients with a PD-L1 TPS ≥50%, ORR was 40.0% in cohort 1A and 78.3% in cohort 1B (Extended Data Fig. 5 and Extended Data Table 2). ORR in TROP2-low patients was 42.9% in cohort 1A and 83.3% in cohort 1B. ORR in TROP2-high patients was 36.8% in cohort 1A and 68.2% in cohort 1B (Extended Data Fig. 6 and Extended Data Table 2). Patients with nonsquamous carcinoma and squamous carcinoma exhibited similar responses to the combination of sac-TMT and tagitanlimab. In cohort 1A, the ORR was 44.4% for nonsquamous carcinoma and 36.4% for squamous carcinoma. In cohort 1B, the ORR was 64.7% for nonsquamous carcinoma and 69.0% for squamous carcinoma (Extended Data Fig. 7 and Extended Data Table 2). Safety of sac-TMT combined with tagitanlimab A total of 40 patients in cohort 1A and 63 patients in cohort 1B were included in the safety set for safety assessment. The median dose intensity for sac-TMT in cohort 1A and cohort 1B was 1.6 mg per kg per week and 2.1 mg per kg per week, respectively. The median dose intensity for tagitanlimab in cohort 1A and cohort 1B was 387.7 mg per week and 418.8 mg per week, respectively. In cohort 1A, 38 of 40 (95.0%) patients reported at least one treatment-related adverse event (TRAE), compared to 61 of 63 (96.8%) patients in cohort 1B. Grade 3 or higher TRAEs were observed in 42.5% of patients (17 of 40) in cohort 1A and 58.7% (37 of 63) in cohort 1B (Table 3). TRAEs led to treatment interruption in 27.5% (11 of 40) of the patients in cohort 1A and 54.0% (34 of 63) of the patients in cohort 1B. sac-TMT dose reduction because of TRAEs was required in 17.5% (7 of 40) of the patients in cohort 1A and 42.9% (27 of 63) in cohort 1B. Treatment discontinuation of any drug because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 6.3% (4 of 63) of the patients in cohort 1B. Discontinuation of sac-TMT occurred in two patients in cohort 1B (one because of drug hypersensitivity and one because of an infusion-related reaction), whereas no patient experienced TRAEs leading to sac-TMT discontinuation in cohort 1A. Treatment discontinuation of tagitanlimab because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 3.2% (2 of 63) of the patients in cohort 1B. Treatment-related serious adverse events occurred in 10.0% (4 of 40) and 20.6% (13 of 63) of the patients in cohort 1A and cohort 1B, respectively. No treatment-related deaths were reported. Table 3 Overall safety summary Full size table The most common TRAEs of any grade (occurring in ≥20% of patients) included anemia (80.0% and 79.4%), decreased neutrophil count (62.5% and 66.7%), decreased white blood cell count (50.0% and 54.0%), alopecia (45.0% and 49.2%), rash (40.0% and 38.1%), nausea (27.5% and 36.5%), decreased appetite (25.0% and 28.6%), increased alanine transaminase (ALT) (22.5% and 27.0%) and stomatitis (22.5% and 55.6%) in cohorts 1A and 1B, respectively (Table 4). The most common grade ≥3 TRAEs in cohorts 1A and 1B were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%), anemia (5.0% and 19.0%), rash (5.0% and 7.9%), stomatitis (0% and 9.5%) and drug eruption (7.5% and 0%) (Table 4). Interstitial lung disease (ILD) occurred in one patient in cohort 1B (grade 2), with no grade ≥3 pneumonitis or ILD reported. Table 4 Most common TRAEs (occurring in ≥20% of patients) and grade 3–5 TRAEs (occurring in ≥5% of patients) Full size table Immune-related adverse events (irAEs) were reported in 25.0% of patients (10 of 40) in cohort 1A and 39.7% (25 of 63) in cohort 1B. Grade 3 or higher irAEs occurred in 7.5% of cohort 1A (3 of 40) and 12.7% of cohort 1B (8 of 63) (Extended Data Table 3). The most common irAEs in cohorts 1A and 1B included rash (12.5% and 14.3%), increased alanine aminotransferase (ALT) (0% and 11.1%), hypothyroidism (2.5% and 7.9%), increased aspartate aminotransferase (AST) (0% and 6.3%) and hyperthyroidism (0% and 6.3%). Discussion In this phase 2 study, the combination of sac-TMT and tagitanlimab exhibited encouraging efficacy and a manageable safety profile in patients with advanced or metastatic NSCLC in the first-line setting. The observed ORR of 40.0% in cohort 1A and 66.7% in cohort 1B, together with the substantial depth and duration of response, underscore the potential of this combination strategy. Notably, the treatment response was consistent across diverse NSCLC subgroups, irrespective of PD-L1 expression status, TROP2 expression levels or histological subtype (squamous versus nonsquamous). These findings provide a rationale for further investigation of sac-TMT plus immunotherapy in a broad spectrum of patients with NSCLC, as evidenced by the increasing number of phase 3 studies evaluating this combination therapy. The ORR observed with biweekly (every 2 weeks (Q2W)) administration of sac-TMT and tagitanlimab is promising and suggests a potential improvement over the historical ORR of 48.0% to 57.9% achieved with conventional platinum-based chemotherapy plus an anti-PD-1 or anti-PD-L1 antibody for patients with NSCLC2,5. Moreover, the toxicity profile associated with the Q2W regimen was manageable. Therefore, sac-TMT administered Q2W has been adopted in most ongoing phase 3 trials for further investigation. ADCs have been shown to potentiate the effectiveness of anti-PD-1 or anti-PD-L1 therapies through a multifaceted mechanism of action. These include Fc-mediated effector functions, induction of immunogenic cell death, maturation of dendritic cells, increased T cell infiltration, boosted immunological memory and upregulation of immunomodulatory proteins, including PD-L1 and major histocompatibility complex21,22,23,25,26. Empirical evidence indicates a pronounced immunomodulatory effect of ADCs in immunocompetent animal models compared with their immunodeficient counterparts, highlighting the important role of ADCs in modulating the tumor microenvironment27,28. Collectively, these mechanisms underpin the potentially enhanced therapeutic outcomes observed with the combination of sac-TMT and tagitanlimab. In particular, in the subset of patients with a PD-L1 TPS value of 50% or greater, the ORR was 78.3% in cohort 1B. This rate is approximately twice that observed with pembrolizumab alone29 and surpasses by nearly 20% the ORR achieved with pembrolizumab plus platinum-based chemotherapy4,5. In light of these findings, randomized controlled trials are encouraged to explore whether sac-TMT plus pembrolizumab could further improve patient outcomes in people with high PD-L1 expression (NCT06170788) or positive PD-L1 expression (NCT06448312) compared with pembrolizumab alone. Another TROP2-targeting ADC, datopotamab deruxtecan, is also being evaluated in combination with pembrolizumab, with or without chemotherapy, in the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) studies. The results of these randomized trials are awaited given the early efficacy signal noted in the current study. Our study indicated that sac-TMT plus tagitanlimab is active in squamous NSCLC, a subtype with a high unmet medical need30. Specifically, patients with squamous carcinoma demonstrated an ORR of 36.4% in cohort 1A and 69.0% in cohort 1B. These results are comparable with those observed in patients with nonsquamous lung cancer, who demonstrated ORR of 44.4% in cohort 1A and 64.7% in cohort 1B. Further research is being conducted to evaluate the potential benefits of sac-TMT in patients with squamous NSCLC. A phase 3 clinical trial (NCT06422143) has been initiated to investigate this potential. This study was designed to compare the outcomes of pembrolizumab with or without maintenance therapy with sac-TMT, following induction treatment with pembrolizumab plus carboplatin and taxane, in patients with metastatic squamous NSCLC. Although not designed for comprehensive translational research, the current study focused on exploring the impact of two key biomarkers, TROP2 and PD-L1, on the efficacy of sac-TMT plus tagitanlimab therapy. Consistent with the known mechanisms of ICIs, we observed potentially enhanced treatment responses in patients with PD-L1 TPS ≥50% in cohort 1B. TROP2 expression levels showed no clear correlation with efficacy, a finding aligned with previous TROP2-directed ADC monotherapy studies31,32. This suggests that TROP2 membrane expression alone may not reliably predict the response to TROP2-directed ADC combined with immunotherapy. Accordingly, several ongoing phase 3 studies of first-line NSCLC have been initiated to further investigate the efficacy of sac-TMT plus pembrolizumab based on different PD-L1 expression levels (for example, with PD-L1 TPS ≥1% (NCT06448312), ≥50% (NCT06170788) and <1% (NCT06711900)), without TROP2-based patient selection. Intriguingly, our exploratory analysis indicated a trend toward a positive correlation between PD-L1 expression and treatment response, specifically in the TROP2 high-expression subgroup, but not in the TROP2 low-expression subgroup (Extended Data Table 1). These preliminary findings suggest a complex interplay between TROP2 and PD-L1 biomarkers, although validation requires in-depth translational studies in the future. In terms of safety, the combination of sac-TMT and tagitanlimab is generally manageable and consistent with the known profiles of individual agents, with no new safety signals19,33. Hematological toxicities, the most common TRAEs, were in the expected range and could be addressed with standard care. Although patients in cohort 1B experienced a higher incidence of grade 3 or higher hematological adverse events compared with those in cohort 1A, these events were manageable in both groups. Stomatitis also occurred more frequently in cohort 1B; however, the majority of cases were in grades 1 and 2. Of note, ILD, a concerning adverse event linked to irinotecan and other ADCs (for example, DS-8201) is rare with sac-TMT and tagitanlimab. We reported a single case of grade 2 ILD in cohort 1B. The most common irAEs reported were rash, elevations in ALT and AST levels, hypothyroidism and hyperthyroidism, consistent with the known safety profile of tagitanlimab33. Some 17.5% of patients in cohort 1A and 42.9% of patients in cohort 1B experienced dose reduction of sac-TMT. However, discontinuation of any investigational drug because of TRAEs was rare (2.5% in cohort 1A and 6.3% in cohort 1B). No treatment-related deaths were reported. Our study has several limitations. First, this was an open-label study without a comparator arm. Therefore, the benefits of sac-TMT plus tagitanlimab over traditional platinum-based chemotherapy plus immunotherapy remain to be elucidated. Second, the modest cohort size and lack of formal hypothesis testing precluded definitive statistical inferences. Third, the relatively short follow-up period in cohort 1B rendered the PFS outcomes and DOR data preliminary. Future efforts will focus on reporting long-term toxicity and efficacy data. Furthermore, the relationship between TROP2 and PD-L1 expression and treatment response remains unclear because of the limited sample size. Further biomarker-driven studies that focus on tumor microenvironment and dynamic changes in blood biomarkers are necessary to better identify patients who are more likely to benefit from sac-TMT plus anti-PD-1 or anti-PD-L1 immunotherapy. Limitations aside, the OptiTROP-Lung01 study established the safety, tolerability and preliminary efficacy of sac-TMT with tagitanlimab in patients with advanced NSCLC lacking actionable genomic alterations. These results support ongoing studies that aim to validate our findings and delineate the therapeutic potential of combining TROP2-directed ADC with immunotherapy in various disease scenarios. Methods Study design, participants and ethics The OptiTROP-Lung01 trial (NCT05351788) is an ongoing, open-label, multicohort, multicenter, phase 2 study of sac-TMT plus tagitanlimab (KL-A167) with or without carboplatin or cisplatin, in patients with advanced NSCLC. Cohort 1 enrolled patients with locally advanced or metastatic NSCLC harboring wild-type EGFR and negative anaplastic lymphoma kinase (ALK) fusion gene, with no known actionable alterations in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic tyrosine receptor kinase (NTRK) or v-raf murine sarcoma viral oncogene homolog B (BRAF), with no known driver gene alterations targetable by other approved therapies. Eligible patients should not have received prior ICI therapy and have no prior or at most one prior line of systemic therapy. Cohort 1 is further divided into cohorts 1A and 1B. Patients in cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks (Q3W)) + tagitanlimab (1,200 mg, Q3W) in each 3-week cycle, and patients in cohort 1B were treated with sac-TMT (5 mg kg−1, every 2 weeks (Q2W)) + tagitanlimab (900 mg, Q2W) in each 4-week cycle. These two cohorts were initiated sequentially to assess tolerability and optimize dosing regimens to inform subsequent phase 3 study design. Here, we presented the initial safety and efficacy data from both cohort 1A and cohort 1B. The dosing strategies for cohorts 1A and 1B were determined based on phase 1 studies that suggested optimal efficacy and safety profiles (details are provided in Supplementary Information). Specifically, in the phase 1–2, dose escalation–expansion, global first-in-human study of sac-TMT (ClinicalTrials.gov identifier: NCT04152499), the maximum tolerated dose was 5.5 mg kg−1 Q2W and the recommended doses for expansion were 4 mg kg−1 Q2W and 5 mg kg−1 Q2W. Similarly, in the phase 1 study of tagitanlimab (ChinaTRugtrials.org identifier: CTR20181198), 900 mg Q2W and 1,200 mg Q3W were both selected as the recommended doses for tagitanlimab based on their similar efficacy and exposure levels. Given these findings, we chose to explore the combination of sac-TMT and tagitanlimab at two different dosing frequencies: Q2W and Q3W. The Q2W dosing strategy was selected based on the recommended dose of each agent, whereas the Q3W dosing strategy was explored to align with the more common dose interval for anti-PD-1 or anti-PD-L1 therapy in clinical practice. Cohort 1A also was designed to establish initial safety with a lower dose intensity of sac-TMT (5 mg kg−1 Q3W), whereas cohort 1B explored a higher dose intensity of sac-TMT (5 mg kg−1 Q2W) to evaluate potential efficacy gains. All enrolled patients received continuous treatment until intolerable toxicity, no further clinical benefit as assessed by the investigator (based on a comprehensive assessment of imaging and clinical condition), or the patient’s request for discontinuation of treatment, whichever occurs first; the maximum duration of treatment with tagitanlimab is 24 months. Further details of key inclusion and exclusion criteria are provided below and in Supplementary Information. Key inclusion criteria were: (1) Male or female patients ≥18 and ≤75 years of age at the time of signing the informed consent form (2) Histologically and cytologically confirmed NSCLC, locally advanced (stage IIIB and IIIC) or metastatic (stage IV) NSCLC not amenable to radical surgery and/or radical radiotherapy (regardless of concurrent chemotherapy) (according to the 8th edition of TNM Staging of Lung Cancer published by the International Union Against Cancer and American Joint Committee on Cancer)34 (3) For patients with nonsquamous NSCLC, prior tissue-based EGFR and ALK reports must be available, otherwise tumor tissue samples (archival or fresh, primary or metastatic) must be collected for assessment of EGFR and ALK status (either in a local laboratory or in a central laboratory). For patients with squamous NSCLC, if the prior EGFR and ALK statuses are unknown, the corresponding tests would not be required for study enrollment, and the EGFR and ALK status of these patients would be considered negative. (4) Patients with locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion gene, no known ROS1, NTRK, BRAF gene alterations, or no known driver gene alterations that can also be targeted by other approved therapies, no prior ICI therapy, and no prior or at most one prior line of systemic therapy. Prior adjuvant, neoadjuvant or radical chemoradiotherapy may be considered first-line therapy if there is disease progression during the treatment or within 6 months after completion of treatment. (5) Be able to provide fresh or archival tumor tissue for biomarker testing and analysis (PD-L1 and TROP2 expression level) (6) Patients with at least one measurable lesion per RECIST v.1.1 criteria (7) Patients with an ECOG performance status of 0 to 1 with an expected survival of ≥12 weeks (8) Adequate organ and bone marrow function (no blood transfusion, recombinant human thrombopoietin or colony-stimulating factor therapy within 2 weeks before first dose) (9) Patients must recover from all toxicities (≤grade 1 or the inclusion criterion specified in the protocol based on Common Terminology Criteria for Adverse Events v.5.0 assessment) due to prior treatment, except for alopecia and vitiligo (10) Female patients of childbearing potential and male patients with partners of childbearing potential who use effective medical contraception during the study treatment period and for 6 months after the end of dosing (see Supplementary Information for specific contraceptive measures) (11) Each patient must voluntarily agree to participate in the study, sign the informed consent form and comply with the protocol-specified visits and relevant procedures. Key exclusion criteria were: (1) Presence of small cell lung carcinoma components in histological pathology (2) History of other malignancies, except locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, or other solid tumors curatively treated with no evidence of disease for ≥3 years (3) Presence of metastases to the brainstem, meninges and spinal cord, or spinal cord compression (4) Patients with active brain metastases (5) Patients who have received any chemotherapy, immunotherapy, biotherapy and so on within 4 weeks before the first dose of study treatment, or received small molecule tyrosine kinase inhibitors, antitumor hormone therapy, systemic immune stimulators (including but not limited to interferon, interleukin-2), radiotherapy or herbal products preparations for approved antitumor indications within 2 weeks before the first dose of study treatment (6) Patients who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of the study treatment, or received more than 30 Gy of radiation for lung lesions within 6 months before the first dose of the study treatment (7) Patients who required the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks before the first dose of the study treatment and during the study (concomitant use of strong inhibitors or inducers of CYP3A4 are not allowed in this study, and the representative drugs for known strong CYP3A4 inhibitors or inducers are listed in Supplementary Information) (8) Patients who have received systemic corticosteroids (>10 mg d−1 prednisone or equivalent, or low-dose corticosteroids, such as ≤10 mg d−1 prednisone or equivalent, are allowed if the dose is stable for 4 weeks), or other immunosuppressive therapy within 2 weeks before the first dose. Steroids are allowed as prophylaxis for hypersensitivity reactions. (9) Received any live vaccine 4 weeks before the first dose of study treatment (10) With active infections requiring systemic treatment within 2 weeks before the first dose of study treatment (11) With Grade 2 or above peripheral neuropathy (12) History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment (13) Arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy that have resolved as judged by the investigator) and pulmonary embolism within 6 months before the first dose of study treatment (14) Active or previous clear history of inflammatory bowel disease (for example, Crohn’s disease, ulcerative colitis, or chronic diarrhea) (15) Prior TROP2-targeted therapy (16) Serious or uncontrolled cardiac disease or clinical symptoms requiring treatment, including any of the following: (i) New York Heart Association Grade 3 or 4 congestive heart failure within 6 months before the first dose of study treatment (ii) Unstable angina pectoris uncontrolled by medication within 6 months before the first dose of study treatment (iii) History of myocardial infarction (iv) Serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia) within 6 months before the first dose of study treatment (v) Corrected QT interval >480 ms at baseline (17) History of (noninfectious) ILD or noninfectious pneumonitis requiring steroid therapy and current ILD or noninfectious pneumonitis, or suspected ILD or noninfectious pneumonitis at screening that cannot be excluded by imaging (18) Uncontrolled systemic disease as judged by the investigator (19) Active autoimmune disease requiring systemic treatment within the past 2 years (hormone replacement therapy is not considered a systemic therapy), such as type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenal or pituitary insufficiency requiring only physiologic doses of glucocorticoid replacement therapy (20) Certain viral infections including active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥500 IU ml−1 or upper limit of normal, which is higher) or hepatitis C (hepatitis C antibody positive, and HCV-RNA above the upper limit of normal); known history of positive human immunodeficiency virus test or known acquired immunodeficiency syndrome, or known active syphilis infection (21) Known active tuberculosis (22) Known hypersensitivity to the study drug or any of its components, or severe allergic reactions to other monoclonal antibodies (23) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation (24) Pregnant or lactating women (25) Any patient whose condition deteriorates rapidly during the screening process before the first dose, such as severe changes in performance status and so on (26) Other circumstances that, in the opinion of the investigator, are not appropriate for participation in this study. The study was conducted at 17 sites in China following the moral, ethical and scientific principles outlined in the Declaration of Helsinki and the Good Clinical Practice. Approvals for the study protocol, any amendments and informed consent were obtained from independent ethics committees of each participating site and central approval was obtained from the Sun Yat-sen University Cancer Center institutional review board before study initiation. All patients provided written informed consent. Any amendment to the protocol must be reviewed and approved by the ethics committee before implementation. Clinical trial objectives The primary objectives were to assess the safety, tolerability and antitumor activity of sac-TMT in combination with tagitanlimab in patients with advanced or metastatic NSCLC. The secondary objectives were to assess the efficacy, pharmacokinetics and immunogenicity of sac-TMT in combination with tagitanlimab. Other objectives were to assess the correlation between the expression level of TROP2 in tumor tissue and antitumor activity and the correlation between the expression level of PD-L1 in tumor tissue and antitumor activity. Clinical endpoint and assessments The primary endpoints included the safety endpoint measured by the incidence and severity of adverse events and the efficacy endpoint, namely ORR as assessed by the investigator according to RECIST v.1.1. The secondary endpoints included efficacy, namely PFS, DOR and DCR assessed by the investigator according to RECIST v.1.1. Other endpoints include the correlation between antitumor activity and the expression level of TROP2 and PD-L1 in tumor tissue. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. The severity of each adverse event was also recorded. An irAE refers to an adverse event related to tagitanlimab injection and is considered to be caused by an immune-mediated mechanism, and may require corticosteroid hormone, other immunosuppressants or hormone replacement therapy. Tumor response assessments based on RECIST v.1.1 were performed every 6 weeks by investigators. Immunohistochemistry and biomarker analysis Patients should provide approximately ten tumor tissue slides at or after diagnosis of locally advanced or metastatic tumor for TROP2 and PD-L1 protein assessment (five slides for TROP2 and five for PD-L1 detection, respectively). TROP2 and PD-L1 expression levels in formalin-fixed tumor samples were assessed using immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd). In detail, TROP2 expression was stained and assessed with anti-TROP2 monoclonal antibody (1:3,000; Abcam, cat. no. EPR20043). For PD-L1 expression, we used the ready-to-use companion diagnostic assay PD-L1 IHC 22C3 pharmDx (Agilent), which is approved by the US Food and Drug Administration and National Medical Products Administration, and is prevalidated for clinical use. All the areas in each tissue section were evaluated for TROP2 or PD-L1 expression. H-score refers to the product of tumor cell staining intensity and the percentage of stained cells at a given intensity in the membrane compartment, which was calculated as ‘(1 × % cells with weak intensity staining) + (2 × % cells with moderate intensity staining) + (3 × % cells with strong intensity staining)’. TROP2 expression level was divided into two subgroups: low expression with an H-score of ≤200, and high expression with an H-score of >200. PD-L1 expression was documented as TPS, with scores of 0–1% being defined as negative expression, 1–49% as low expression and ≥50% as high expression. Statistical analyses The statistical analyses of cohorts 1A and 1B were mainly descriptive and focused on safety and efficacy estimates, without formal hypothesis testing. Thus, no statistical power calculations were performed to determine the sample sizes for cohorts 1A and 1B. Based on regulatory guidance, a minimum of 30 patients per cohort was required. To adequately characterize the safety profile and preliminary efficacy, each cohort was planned to enroll between 30 and 60 patients. If not otherwise specified, the data were summarized using descriptive statistical methods according to the following general principles. The descriptive statistics for continuous variables were presented using number, mean, s.d., maximum, minimum and median, and the descriptive statistics for categorical variables were presented using incidence and frequency or number and percentage of patients. Safety was assessed on the safety set, defined as all patients who have received at least one dose of the investigational product and have safety evaluation data. The biomarker analysis set included all patients who received at least one dose of the study drugs and had pretreatment specimens for TROP2 and/or PD-L1 assessment. Median follow-up time was calculated based on the reverse Kaplan–Meier method. The primary endpoint of investigator-assessed ORR was based on the FAS, and the 95% CI of ORR was estimated using the Clopper–Pearson method. Analysis of the secondary endpoint of DCR was based on the FAS, and the 95% CI of DCR was estimated using the Clopper–Pearson method. The secondary endpoint of investigator-assessed PFS was based on the FAS population, and the median values of the two groups were estimated using the Kaplan–Meier method, and their 95% CI values were calculated using the Brookmeyer–Crowley method. At the time of primary analysis, for patients without disease progression or death, PFS was censored at the date of the last valid imaging examination. For patients without postbaseline tumor assessments, PFS was censored at the time of administration. For patients whose date of first disease progression or death was more than two assessment cycles away from the date of the previous imaging, the date of PFS was censored to the date of the last valid imaging before progression. DOR as assessed by the investigator was defined as the time from the date of the first obtained complete response (CR) or PR to disease progression or death due to any cause, whichever occurs first. Analysis of DOR was based on patients with CR and PR in the FAS, the median values of each group was estimated using the Kaplan–Meier method, and the corresponding 95% CI was calculated using the Brookmeyer–Crowley method. For patients without progression or death, DOR was censored at the date of the last valid imaging examination. No imputation for missing values was conducted for ORR and DCR. Comparisons of biomarker levels between groups were performed using Dunn’s test for multiple comparisons. The chi-squared test was used for categorical variables. Pearson test was used to determine the correlation between the TROP2 expression level (H-score) and PD-L1 TPS level in cohorts 1A and 1B. Statistical significance was defined as a two-sided P value < 0.05. Data were collected using an electronic data capture system (Clinflash EDC, v.2024.3.0). Statistical analyses and graph drawing were conducted using the SAS v.9.4 and R v.4.1.3. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to fangwf@sysucc.org.cn, zhangli@sysucc.org.cn or mict@kelun.com. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by the corresponding authors, the SYSUCC institutional review board, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. to evaluate the merit of the research proposed, the availability of the data, the intended use of the data and the presence of conflict of interests. A signed data access agreement with the sponsors is required before data sharing. The study protocol and the remaining data are available in the Article or Supplementary Information. References Bray, F. et al. 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Oncol. 35, 2790–2797 (2017). Article CAS PubMed Google Scholar Shi, Y. et al. Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. Lancet Reg. Health West. Pac. 31, 100617 (2023). PubMed Google Scholar Lababede, O. & Meziane, M.A. The eighth edition of TNM staging of lung cancer: reference chart and diagrams. Oncologist 23, 844–848 (2018). Article PubMed PubMed Central Google Scholar Download references Acknowledgements The study was sponsored by Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. The sponsor provided the investigated drug and worked with investigators on the trial design, data collection, data analyses and results interpretation. This study was also supported, in part by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2024ZD0519700 awarded to L.Z.; grant nos 2024ZD0520200 and 2024ZD0520205 awarded to S. Hong), National Natural Science Foundation of China (grant nos 82272789 and 82241232 awarded to L.Z., grant nos 82373262 and 82173101 awarded to W.F., grant no. 82172713 awarded to S. Hong), Natural Science Foundation of Guangdong Province (grant no. 2023B1515020008 awarded to S. Hong) and Guangzhou Science and Technology Program (grant no. 2024A04J6485 awarded to S. Hong). We thank all the patients who volunteered to participate in the OptiTROP-Lung01 study and their families for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and their devoted team members for participating in the OptiTROP-Lung01 study. Author information Author notes These authors contributed equally: Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu. Authors and Affiliations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China Shaodong Hong, Li Zhang & Wenfeng Fang The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China Qiming Wang Henan Cancer Hospital, Zhengzhou, China Qiming Wang Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China Qiming Wang Jilin Cancer Hospital, Changchun, China Ying Cheng Hunan Cancer Hospital, Changsha, China Yongzhong Luo & Lin Wu The First Hospital of China Medical University, Shenyang, China Xiujuan Qu Shanxi Cancer Hospital, Taiyuan, China Haibo Zhu West China Hospital of Sichuan University, Chengdu, China Zhenyu Ding The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Xingya Li Harbin Medical University Cancer Hospital, Harbin, China Yan Wang Hubei Cancer Hospital, Wuhan, China Sheng Hu Chongqing University Cancer Hospital, Chongqing, China Enwen Wang The Second Affiliated Hospital of Nanchang University, Nanchang, China Anwen Liu Shandong Cancer Hospital, Jinan, China Yuping Sun Zhejiang Cancer Hospital, Hangzhou, China Yun Fan The First Affiliated Hospital of Xiamen University, Xiamen, China Feng Ye Jiangsu Province Hospital, Nanjing, China Kaihua Lu Beijing Cancer Hospital, Beijing, China Jian Fang Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China Yuping Shen, Xiaoping Jin & Junyou Ge National Engineering Research Center of Targeted Biologics, Chengdu, China Junyou Ge Contributions S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. conceived and designed the study. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. provided study materials and recruited participants. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. collected and assembled the data. S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. analyzed and interpreted the data. All authors were involved in writing, reviewing and editing of the paper, and in final approval of the paper. All authors are accountable for all aspects of the work. Corresponding authors Correspondence to Li Zhang or Wenfeng Fang. Ethics declarations Competing interests Y. Shen, X.J. and J.G. are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma, and consulting for MSD, Beigene and Xiansheng Pharma. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks Melissa Johnson, Maiying Kong and Shengxiang Ren for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Efficacy in the full analysis set population. a, b, Spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in cohort 1 A (a) and cohort 1B (b). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). c, d, Kaplan-Meier survival curves of progression-free survival for cohort 1 A (c) and cohort 1B (d), respectively. Solid step lines represent Kaplan-Meier estimates of PFS probability, where vertical drops indicate events; shaded bands depict pointwise 95% confidence intervals around that estimate using the Brookmeyer–Crowley method; marks (+) denote censored data points. PFS, progression-free survival; CI, confidence interval; N.E., not estimable. Extended Data Fig. 2 The correlation between PD-L1 expression, TROP2 expression and treatment response. a, b, Expression of PD-L1 (tumor proportion score, TPS) (a) and TROP2 (b) in cohort 1A and cohort 1B. c, scatter plot of PD-L1 versus TROP2 expression in patients with both biomarkers available. Correlation was assessed using a two-sided Pearson test (no adjustment for multiple comparisons); the gray shaded area represents 95% confidence bands for the linear regression fit. d, e, Association between PD-L1 expression and confirmed best overall response in cohort 1 A (d) and cohort 1B (e). f, g, Association between TROP2 expression and response in cohort 1 A (f) and cohort 1B (g). Box plots in panels a, b, d–g depict the median (center line), first quartile (Q1; box bottom), and third quartile (Q3; box top). Whiskers encompass 1.5 times the interquartile range (IQR), with points beyond whiskers representing outliers. Group comparisons were performed using a two-sided Dunn’s test for multiple comparisons (d–g). TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 3 Tumor response distribution by PD-L1 expression and TROP2 expression categories. a, b, the difference of tumor response among three PD-L1 TPS categories was compared in cohort 1 A (a) and cohort 1B (b). c, d, according to the cutoff of the H-score of 200, patients were divided into two groups: low TROP2 expression and high TROP2 expression, and the difference of tumor response between two TROP2 expression groups was compared in cohort 1 A (c) and cohort 1B (d). Statistical significance was determined using Chi-squared test. TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 4 Forrest plots for confirmed overall response rate in different patient subgroups. a, cohort 1 A; b, cohort 1B. Subgroup with sample size ≥ 10 were shown. The central mark on each horizontal error bar represents the point estimate of the cORR for the respective subgroup. The horizontal error bar represents the 95% confidence interval for each cORR value. cORR, confirmed objective response rate; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 5 Depth and duration of response by PD-L1 expression. a, b, c, waterfall plot depicting the maximum change from baseline in target lesion size in patients with PD-L1 TPS of < 1% (a), between 1 and 49% (b) and ≥ 50% (c); d, e, f, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with PD-L1 TPS of < 1% (d), between 1 and 49% (e), and ≥ 50% (f). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 6 Depth and duration of response by TROP2 expression. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with TROP2 H-score of ≤ 200 (a) and TROP2 H-score of > 200 (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with TROP2 H-score of ≤ 200 (c) and TROP2 H-score of > 200 (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Fig. 7 Depth and duration of response by histology subgroup. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with non-squamous carcinoma (a) and squamous carcinoma (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with non-squamous carcinoma (c) and squamous carcinoma (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Table 1 Subgroup efficacy in cohort 1A and cohort 1B grouped by PD-L1 expression among TROP2 low or high-expression population Full size table Extended Data Table 2 Subgroup efficacy analysis by PD-L1/TROP2 expression and histology Full size table Extended Data Table 3 Immune-related adverse events (irAEs) (occurring in ≥ 2% of patients) and grade 3-5 irAEs (occurring in at least one patient) Full size table Supplementary information Supplementary Information Redacted study protocol (v.3.0, 2023.01.01). Reporting Summary Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Hong, S., Wang, Q., Cheng, Y. et al. First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial. Nat Med 31, 3654–3661 (2025). https://doi.org/10.1038/s41591-025-03883-5 Download citation Received 16 August 2024 Accepted 03 July 2025 Published 19 August 2025 Version of record 19 August 2025 Issue date November 2025 DOI https://doi.org/10.1038/s41591-025-03883-5 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer immunotherapy Non-small-cell lung cancer This article is cited by Perioperative Immunotherapy for Non-Small Cell Lung Cancer (NSCLC) Sarafina Urenna OtisGiuseppe Luigi BannaAkash Maniam Current Oncology Reports (2025) You have full access to this article via Sun Yat-sen University. Download PDF Sections Figures References Abstract Main Results Discussion Methods Data availability References Acknowledgements Author information Ethics declarations Peer review Additional information Extended data Supplementary information Rights and permissions About this article This article is cited by Advertisement Nature Medicine (Nat Med) ISSN 1546-170X (online) ISSN 1078-8956 (print) nature.com sitemap About Nature Portfolio About us Press releases Press office Contact us Discover content Journals A-Z Articles by subject protocols.io Nature Index Publishing policies Nature portfolio policies Open access Author & Researcher services Reprints & permissions Research data Language editing Scientific editing Nature Masterclasses Research Solutions Libraries & institutions Librarian service & tools Librarian portal Open research Recommend to library Advertising & partnerships Advertising Partnerships & Services Media kits Branded content Professional development Nature Awards Nature Careers Nature Conferences Regional websites Nature Africa Nature China Nature India Nature Japan Nature Middle East Privacy Policy Use of cookies Your privacy choices/Manage cookies Legal notice Accessibility statement Terms & Conditions Your US state privacy rights Springer Nature © 2025 Springer Nature Limited CloseNature Briefing Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Email address e.g. jo.smith@university.ac.uk Sign up I agree my information will be processed in accordance with the Nature and Springer Nature Limited Privacy Policy.". An AI-generated interactive educational simulation created by Anonymous on MyPopku."> 200 (ref. 24). TROP2 expression levels were low (H-score ≤200) in 52.5% and 19.0%, and high (H-score >200) in 47.5% and 69.8% of the patients in cohorts 1A and 1B, respectively (Table 1). There was a trend toward an inverse correlation between PD-L1 and TROP2 expression (r = −0.14, P = 0.18) (Extended Data Fig. 2c). No significant association was found between PD-L1 TPS (%) and clinical response (Extended Data Fig. 2d,e), although patients with a PD-L1 TPS of ≥50% tended to have a higher response rate in cohort 1B (78.3%) (Extended Data Fig. 3a,b). Similarly, no significant association was detected between TROP2 expression and objective response (Extended Data Figs. 2f,g and 3c,d). Further exploratory analysis of the combined impact of the TROP2 and PD-L1 categories indicated that PD-L1 expression levels appeared to be positively correlated with treatment response in the TROP2 high-expression subgroup but not in the TROP2 low-expression subgroup (Extended Data Table 1). Efficacy by subgroups Post hoc subgroup analysis by clinicopathological characteristics showed that the efficacy of sac-TMT with tagitanlimab was consistent across subgroups in both cohorts (Extended Data Fig. 4). Detailed subgroup analyses of cohorts 1A and 1B revealed that combination therapy was effective in patients with different levels of PD-L1 and TROP2 expression and those with squamous cell or nonsquamous cell histology (Extended Data Table 2). Clinically meaningful responses to sac-TMT and tagitanlimab were observed across various PD-L1 levels in both cohorts. Specifically, patients with a PD-L1 TPS of <1% had an ORR of 41.7% in cohort 1A and 57.1% in cohort 1B. Those with a PD-L1 TPS between 1% and 49% experienced an ORR of 38.5% in cohort 1A and 63.2% in cohort 1B. For patients with a PD-L1 TPS ≥50%, ORR was 40.0% in cohort 1A and 78.3% in cohort 1B (Extended Data Fig. 5 and Extended Data Table 2). ORR in TROP2-low patients was 42.9% in cohort 1A and 83.3% in cohort 1B. ORR in TROP2-high patients was 36.8% in cohort 1A and 68.2% in cohort 1B (Extended Data Fig. 6 and Extended Data Table 2). Patients with nonsquamous carcinoma and squamous carcinoma exhibited similar responses to the combination of sac-TMT and tagitanlimab. In cohort 1A, the ORR was 44.4% for nonsquamous carcinoma and 36.4% for squamous carcinoma. In cohort 1B, the ORR was 64.7% for nonsquamous carcinoma and 69.0% for squamous carcinoma (Extended Data Fig. 7 and Extended Data Table 2). Safety of sac-TMT combined with tagitanlimab A total of 40 patients in cohort 1A and 63 patients in cohort 1B were included in the safety set for safety assessment. The median dose intensity for sac-TMT in cohort 1A and cohort 1B was 1.6 mg per kg per week and 2.1 mg per kg per week, respectively. The median dose intensity for tagitanlimab in cohort 1A and cohort 1B was 387.7 mg per week and 418.8 mg per week, respectively. In cohort 1A, 38 of 40 (95.0%) patients reported at least one treatment-related adverse event (TRAE), compared to 61 of 63 (96.8%) patients in cohort 1B. Grade 3 or higher TRAEs were observed in 42.5% of patients (17 of 40) in cohort 1A and 58.7% (37 of 63) in cohort 1B (Table 3). TRAEs led to treatment interruption in 27.5% (11 of 40) of the patients in cohort 1A and 54.0% (34 of 63) of the patients in cohort 1B. sac-TMT dose reduction because of TRAEs was required in 17.5% (7 of 40) of the patients in cohort 1A and 42.9% (27 of 63) in cohort 1B. Treatment discontinuation of any drug because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 6.3% (4 of 63) of the patients in cohort 1B. Discontinuation of sac-TMT occurred in two patients in cohort 1B (one because of drug hypersensitivity and one because of an infusion-related reaction), whereas no patient experienced TRAEs leading to sac-TMT discontinuation in cohort 1A. Treatment discontinuation of tagitanlimab because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 3.2% (2 of 63) of the patients in cohort 1B. Treatment-related serious adverse events occurred in 10.0% (4 of 40) and 20.6% (13 of 63) of the patients in cohort 1A and cohort 1B, respectively. No treatment-related deaths were reported. Table 3 Overall safety summary Full size table The most common TRAEs of any grade (occurring in ≥20% of patients) included anemia (80.0% and 79.4%), decreased neutrophil count (62.5% and 66.7%), decreased white blood cell count (50.0% and 54.0%), alopecia (45.0% and 49.2%), rash (40.0% and 38.1%), nausea (27.5% and 36.5%), decreased appetite (25.0% and 28.6%), increased alanine transaminase (ALT) (22.5% and 27.0%) and stomatitis (22.5% and 55.6%) in cohorts 1A and 1B, respectively (Table 4). The most common grade ≥3 TRAEs in cohorts 1A and 1B were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%), anemia (5.0% and 19.0%), rash (5.0% and 7.9%), stomatitis (0% and 9.5%) and drug eruption (7.5% and 0%) (Table 4). Interstitial lung disease (ILD) occurred in one patient in cohort 1B (grade 2), with no grade ≥3 pneumonitis or ILD reported. Table 4 Most common TRAEs (occurring in ≥20% of patients) and grade 3–5 TRAEs (occurring in ≥5% of patients) Full size table Immune-related adverse events (irAEs) were reported in 25.0% of patients (10 of 40) in cohort 1A and 39.7% (25 of 63) in cohort 1B. Grade 3 or higher irAEs occurred in 7.5% of cohort 1A (3 of 40) and 12.7% of cohort 1B (8 of 63) (Extended Data Table 3). The most common irAEs in cohorts 1A and 1B included rash (12.5% and 14.3%), increased alanine aminotransferase (ALT) (0% and 11.1%), hypothyroidism (2.5% and 7.9%), increased aspartate aminotransferase (AST) (0% and 6.3%) and hyperthyroidism (0% and 6.3%). Discussion In this phase 2 study, the combination of sac-TMT and tagitanlimab exhibited encouraging efficacy and a manageable safety profile in patients with advanced or metastatic NSCLC in the first-line setting. The observed ORR of 40.0% in cohort 1A and 66.7% in cohort 1B, together with the substantial depth and duration of response, underscore the potential of this combination strategy. Notably, the treatment response was consistent across diverse NSCLC subgroups, irrespective of PD-L1 expression status, TROP2 expression levels or histological subtype (squamous versus nonsquamous). These findings provide a rationale for further investigation of sac-TMT plus immunotherapy in a broad spectrum of patients with NSCLC, as evidenced by the increasing number of phase 3 studies evaluating this combination therapy. The ORR observed with biweekly (every 2 weeks (Q2W)) administration of sac-TMT and tagitanlimab is promising and suggests a potential improvement over the historical ORR of 48.0% to 57.9% achieved with conventional platinum-based chemotherapy plus an anti-PD-1 or anti-PD-L1 antibody for patients with NSCLC2,5. Moreover, the toxicity profile associated with the Q2W regimen was manageable. Therefore, sac-TMT administered Q2W has been adopted in most ongoing phase 3 trials for further investigation. ADCs have been shown to potentiate the effectiveness of anti-PD-1 or anti-PD-L1 therapies through a multifaceted mechanism of action. These include Fc-mediated effector functions, induction of immunogenic cell death, maturation of dendritic cells, increased T cell infiltration, boosted immunological memory and upregulation of immunomodulatory proteins, including PD-L1 and major histocompatibility complex21,22,23,25,26. Empirical evidence indicates a pronounced immunomodulatory effect of ADCs in immunocompetent animal models compared with their immunodeficient counterparts, highlighting the important role of ADCs in modulating the tumor microenvironment27,28. Collectively, these mechanisms underpin the potentially enhanced therapeutic outcomes observed with the combination of sac-TMT and tagitanlimab. In particular, in the subset of patients with a PD-L1 TPS value of 50% or greater, the ORR was 78.3% in cohort 1B. This rate is approximately twice that observed with pembrolizumab alone29 and surpasses by nearly 20% the ORR achieved with pembrolizumab plus platinum-based chemotherapy4,5. In light of these findings, randomized controlled trials are encouraged to explore whether sac-TMT plus pembrolizumab could further improve patient outcomes in people with high PD-L1 expression (NCT06170788) or positive PD-L1 expression (NCT06448312) compared with pembrolizumab alone. Another TROP2-targeting ADC, datopotamab deruxtecan, is also being evaluated in combination with pembrolizumab, with or without chemotherapy, in the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) studies. The results of these randomized trials are awaited given the early efficacy signal noted in the current study. Our study indicated that sac-TMT plus tagitanlimab is active in squamous NSCLC, a subtype with a high unmet medical need30. Specifically, patients with squamous carcinoma demonstrated an ORR of 36.4% in cohort 1A and 69.0% in cohort 1B. These results are comparable with those observed in patients with nonsquamous lung cancer, who demonstrated ORR of 44.4% in cohort 1A and 64.7% in cohort 1B. Further research is being conducted to evaluate the potential benefits of sac-TMT in patients with squamous NSCLC. A phase 3 clinical trial (NCT06422143) has been initiated to investigate this potential. This study was designed to compare the outcomes of pembrolizumab with or without maintenance therapy with sac-TMT, following induction treatment with pembrolizumab plus carboplatin and taxane, in patients with metastatic squamous NSCLC. Although not designed for comprehensive translational research, the current study focused on exploring the impact of two key biomarkers, TROP2 and PD-L1, on the efficacy of sac-TMT plus tagitanlimab therapy. Consistent with the known mechanisms of ICIs, we observed potentially enhanced treatment responses in patients with PD-L1 TPS ≥50% in cohort 1B. TROP2 expression levels showed no clear correlation with efficacy, a finding aligned with previous TROP2-directed ADC monotherapy studies31,32. This suggests that TROP2 membrane expression alone may not reliably predict the response to TROP2-directed ADC combined with immunotherapy. Accordingly, several ongoing phase 3 studies of first-line NSCLC have been initiated to further investigate the efficacy of sac-TMT plus pembrolizumab based on different PD-L1 expression levels (for example, with PD-L1 TPS ≥1% (NCT06448312), ≥50% (NCT06170788) and <1% (NCT06711900)), without TROP2-based patient selection. Intriguingly, our exploratory analysis indicated a trend toward a positive correlation between PD-L1 expression and treatment response, specifically in the TROP2 high-expression subgroup, but not in the TROP2 low-expression subgroup (Extended Data Table 1). These preliminary findings suggest a complex interplay between TROP2 and PD-L1 biomarkers, although validation requires in-depth translational studies in the future. In terms of safety, the combination of sac-TMT and tagitanlimab is generally manageable and consistent with the known profiles of individual agents, with no new safety signals19,33. Hematological toxicities, the most common TRAEs, were in the expected range and could be addressed with standard care. Although patients in cohort 1B experienced a higher incidence of grade 3 or higher hematological adverse events compared with those in cohort 1A, these events were manageable in both groups. Stomatitis also occurred more frequently in cohort 1B; however, the majority of cases were in grades 1 and 2. Of note, ILD, a concerning adverse event linked to irinotecan and other ADCs (for example, DS-8201) is rare with sac-TMT and tagitanlimab. We reported a single case of grade 2 ILD in cohort 1B. The most common irAEs reported were rash, elevations in ALT and AST levels, hypothyroidism and hyperthyroidism, consistent with the known safety profile of tagitanlimab33. Some 17.5% of patients in cohort 1A and 42.9% of patients in cohort 1B experienced dose reduction of sac-TMT. However, discontinuation of any investigational drug because of TRAEs was rare (2.5% in cohort 1A and 6.3% in cohort 1B). No treatment-related deaths were reported. Our study has several limitations. First, this was an open-label study without a comparator arm. Therefore, the benefits of sac-TMT plus tagitanlimab over traditional platinum-based chemotherapy plus immunotherapy remain to be elucidated. Second, the modest cohort size and lack of formal hypothesis testing precluded definitive statistical inferences. Third, the relatively short follow-up period in cohort 1B rendered the PFS outcomes and DOR data preliminary. Future efforts will focus on reporting long-term toxicity and efficacy data. Furthermore, the relationship between TROP2 and PD-L1 expression and treatment response remains unclear because of the limited sample size. Further biomarker-driven studies that focus on tumor microenvironment and dynamic changes in blood biomarkers are necessary to better identify patients who are more likely to benefit from sac-TMT plus anti-PD-1 or anti-PD-L1 immunotherapy. Limitations aside, the OptiTROP-Lung01 study established the safety, tolerability and preliminary efficacy of sac-TMT with tagitanlimab in patients with advanced NSCLC lacking actionable genomic alterations. These results support ongoing studies that aim to validate our findings and delineate the therapeutic potential of combining TROP2-directed ADC with immunotherapy in various disease scenarios. Methods Study design, participants and ethics The OptiTROP-Lung01 trial (NCT05351788) is an ongoing, open-label, multicohort, multicenter, phase 2 study of sac-TMT plus tagitanlimab (KL-A167) with or without carboplatin or cisplatin, in patients with advanced NSCLC. Cohort 1 enrolled patients with locally advanced or metastatic NSCLC harboring wild-type EGFR and negative anaplastic lymphoma kinase (ALK) fusion gene, with no known actionable alterations in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic tyrosine receptor kinase (NTRK) or v-raf murine sarcoma viral oncogene homolog B (BRAF), with no known driver gene alterations targetable by other approved therapies. Eligible patients should not have received prior ICI therapy and have no prior or at most one prior line of systemic therapy. Cohort 1 is further divided into cohorts 1A and 1B. Patients in cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks (Q3W)) + tagitanlimab (1,200 mg, Q3W) in each 3-week cycle, and patients in cohort 1B were treated with sac-TMT (5 mg kg−1, every 2 weeks (Q2W)) + tagitanlimab (900 mg, Q2W) in each 4-week cycle. These two cohorts were initiated sequentially to assess tolerability and optimize dosing regimens to inform subsequent phase 3 study design. Here, we presented the initial safety and efficacy data from both cohort 1A and cohort 1B. The dosing strategies for cohorts 1A and 1B were determined based on phase 1 studies that suggested optimal efficacy and safety profiles (details are provided in Supplementary Information). Specifically, in the phase 1–2, dose escalation–expansion, global first-in-human study of sac-TMT (ClinicalTrials.gov identifier: NCT04152499), the maximum tolerated dose was 5.5 mg kg−1 Q2W and the recommended doses for expansion were 4 mg kg−1 Q2W and 5 mg kg−1 Q2W. Similarly, in the phase 1 study of tagitanlimab (ChinaTRugtrials.org identifier: CTR20181198), 900 mg Q2W and 1,200 mg Q3W were both selected as the recommended doses for tagitanlimab based on their similar efficacy and exposure levels. Given these findings, we chose to explore the combination of sac-TMT and tagitanlimab at two different dosing frequencies: Q2W and Q3W. The Q2W dosing strategy was selected based on the recommended dose of each agent, whereas the Q3W dosing strategy was explored to align with the more common dose interval for anti-PD-1 or anti-PD-L1 therapy in clinical practice. Cohort 1A also was designed to establish initial safety with a lower dose intensity of sac-TMT (5 mg kg−1 Q3W), whereas cohort 1B explored a higher dose intensity of sac-TMT (5 mg kg−1 Q2W) to evaluate potential efficacy gains. All enrolled patients received continuous treatment until intolerable toxicity, no further clinical benefit as assessed by the investigator (based on a comprehensive assessment of imaging and clinical condition), or the patient’s request for discontinuation of treatment, whichever occurs first; the maximum duration of treatment with tagitanlimab is 24 months. Further details of key inclusion and exclusion criteria are provided below and in Supplementary Information. Key inclusion criteria were: (1) Male or female patients ≥18 and ≤75 years of age at the time of signing the informed consent form (2) Histologically and cytologically confirmed NSCLC, locally advanced (stage IIIB and IIIC) or metastatic (stage IV) NSCLC not amenable to radical surgery and/or radical radiotherapy (regardless of concurrent chemotherapy) (according to the 8th edition of TNM Staging of Lung Cancer published by the International Union Against Cancer and American Joint Committee on Cancer)34 (3) For patients with nonsquamous NSCLC, prior tissue-based EGFR and ALK reports must be available, otherwise tumor tissue samples (archival or fresh, primary or metastatic) must be collected for assessment of EGFR and ALK status (either in a local laboratory or in a central laboratory). For patients with squamous NSCLC, if the prior EGFR and ALK statuses are unknown, the corresponding tests would not be required for study enrollment, and the EGFR and ALK status of these patients would be considered negative. (4) Patients with locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion gene, no known ROS1, NTRK, BRAF gene alterations, or no known driver gene alterations that can also be targeted by other approved therapies, no prior ICI therapy, and no prior or at most one prior line of systemic therapy. Prior adjuvant, neoadjuvant or radical chemoradiotherapy may be considered first-line therapy if there is disease progression during the treatment or within 6 months after completion of treatment. (5) Be able to provide fresh or archival tumor tissue for biomarker testing and analysis (PD-L1 and TROP2 expression level) (6) Patients with at least one measurable lesion per RECIST v.1.1 criteria (7) Patients with an ECOG performance status of 0 to 1 with an expected survival of ≥12 weeks (8) Adequate organ and bone marrow function (no blood transfusion, recombinant human thrombopoietin or colony-stimulating factor therapy within 2 weeks before first dose) (9) Patients must recover from all toxicities (≤grade 1 or the inclusion criterion specified in the protocol based on Common Terminology Criteria for Adverse Events v.5.0 assessment) due to prior treatment, except for alopecia and vitiligo (10) Female patients of childbearing potential and male patients with partners of childbearing potential who use effective medical contraception during the study treatment period and for 6 months after the end of dosing (see Supplementary Information for specific contraceptive measures) (11) Each patient must voluntarily agree to participate in the study, sign the informed consent form and comply with the protocol-specified visits and relevant procedures. Key exclusion criteria were: (1) Presence of small cell lung carcinoma components in histological pathology (2) History of other malignancies, except locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, or other solid tumors curatively treated with no evidence of disease for ≥3 years (3) Presence of metastases to the brainstem, meninges and spinal cord, or spinal cord compression (4) Patients with active brain metastases (5) Patients who have received any chemotherapy, immunotherapy, biotherapy and so on within 4 weeks before the first dose of study treatment, or received small molecule tyrosine kinase inhibitors, antitumor hormone therapy, systemic immune stimulators (including but not limited to interferon, interleukin-2), radiotherapy or herbal products preparations for approved antitumor indications within 2 weeks before the first dose of study treatment (6) Patients who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of the study treatment, or received more than 30 Gy of radiation for lung lesions within 6 months before the first dose of the study treatment (7) Patients who required the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks before the first dose of the study treatment and during the study (concomitant use of strong inhibitors or inducers of CYP3A4 are not allowed in this study, and the representative drugs for known strong CYP3A4 inhibitors or inducers are listed in Supplementary Information) (8) Patients who have received systemic corticosteroids (>10 mg d−1 prednisone or equivalent, or low-dose corticosteroids, such as ≤10 mg d−1 prednisone or equivalent, are allowed if the dose is stable for 4 weeks), or other immunosuppressive therapy within 2 weeks before the first dose. Steroids are allowed as prophylaxis for hypersensitivity reactions. (9) Received any live vaccine 4 weeks before the first dose of study treatment (10) With active infections requiring systemic treatment within 2 weeks before the first dose of study treatment (11) With Grade 2 or above peripheral neuropathy (12) History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment (13) Arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy that have resolved as judged by the investigator) and pulmonary embolism within 6 months before the first dose of study treatment (14) Active or previous clear history of inflammatory bowel disease (for example, Crohn’s disease, ulcerative colitis, or chronic diarrhea) (15) Prior TROP2-targeted therapy (16) Serious or uncontrolled cardiac disease or clinical symptoms requiring treatment, including any of the following: (i) New York Heart Association Grade 3 or 4 congestive heart failure within 6 months before the first dose of study treatment (ii) Unstable angina pectoris uncontrolled by medication within 6 months before the first dose of study treatment (iii) History of myocardial infarction (iv) Serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia) within 6 months before the first dose of study treatment (v) Corrected QT interval >480 ms at baseline (17) History of (noninfectious) ILD or noninfectious pneumonitis requiring steroid therapy and current ILD or noninfectious pneumonitis, or suspected ILD or noninfectious pneumonitis at screening that cannot be excluded by imaging (18) Uncontrolled systemic disease as judged by the investigator (19) Active autoimmune disease requiring systemic treatment within the past 2 years (hormone replacement therapy is not considered a systemic therapy), such as type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenal or pituitary insufficiency requiring only physiologic doses of glucocorticoid replacement therapy (20) Certain viral infections including active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥500 IU ml−1 or upper limit of normal, which is higher) or hepatitis C (hepatitis C antibody positive, and HCV-RNA above the upper limit of normal); known history of positive human immunodeficiency virus test or known acquired immunodeficiency syndrome, or known active syphilis infection (21) Known active tuberculosis (22) Known hypersensitivity to the study drug or any of its components, or severe allergic reactions to other monoclonal antibodies (23) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation (24) Pregnant or lactating women (25) Any patient whose condition deteriorates rapidly during the screening process before the first dose, such as severe changes in performance status and so on (26) Other circumstances that, in the opinion of the investigator, are not appropriate for participation in this study. The study was conducted at 17 sites in China following the moral, ethical and scientific principles outlined in the Declaration of Helsinki and the Good Clinical Practice. Approvals for the study protocol, any amendments and informed consent were obtained from independent ethics committees of each participating site and central approval was obtained from the Sun Yat-sen University Cancer Center institutional review board before study initiation. All patients provided written informed consent. Any amendment to the protocol must be reviewed and approved by the ethics committee before implementation. Clinical trial objectives The primary objectives were to assess the safety, tolerability and antitumor activity of sac-TMT in combination with tagitanlimab in patients with advanced or metastatic NSCLC. The secondary objectives were to assess the efficacy, pharmacokinetics and immunogenicity of sac-TMT in combination with tagitanlimab. Other objectives were to assess the correlation between the expression level of TROP2 in tumor tissue and antitumor activity and the correlation between the expression level of PD-L1 in tumor tissue and antitumor activity. Clinical endpoint and assessments The primary endpoints included the safety endpoint measured by the incidence and severity of adverse events and the efficacy endpoint, namely ORR as assessed by the investigator according to RECIST v.1.1. The secondary endpoints included efficacy, namely PFS, DOR and DCR assessed by the investigator according to RECIST v.1.1. Other endpoints include the correlation between antitumor activity and the expression level of TROP2 and PD-L1 in tumor tissue. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. The severity of each adverse event was also recorded. An irAE refers to an adverse event related to tagitanlimab injection and is considered to be caused by an immune-mediated mechanism, and may require corticosteroid hormone, other immunosuppressants or hormone replacement therapy. Tumor response assessments based on RECIST v.1.1 were performed every 6 weeks by investigators. Immunohistochemistry and biomarker analysis Patients should provide approximately ten tumor tissue slides at or after diagnosis of locally advanced or metastatic tumor for TROP2 and PD-L1 protein assessment (five slides for TROP2 and five for PD-L1 detection, respectively). TROP2 and PD-L1 expression levels in formalin-fixed tumor samples were assessed using immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd). In detail, TROP2 expression was stained and assessed with anti-TROP2 monoclonal antibody (1:3,000; Abcam, cat. no. EPR20043). For PD-L1 expression, we used the ready-to-use companion diagnostic assay PD-L1 IHC 22C3 pharmDx (Agilent), which is approved by the US Food and Drug Administration and National Medical Products Administration, and is prevalidated for clinical use. All the areas in each tissue section were evaluated for TROP2 or PD-L1 expression. H-score refers to the product of tumor cell staining intensity and the percentage of stained cells at a given intensity in the membrane compartment, which was calculated as ‘(1 × % cells with weak intensity staining) + (2 × % cells with moderate intensity staining) + (3 × % cells with strong intensity staining)’. TROP2 expression level was divided into two subgroups: low expression with an H-score of ≤200, and high expression with an H-score of >200. PD-L1 expression was documented as TPS, with scores of 0–1% being defined as negative expression, 1–49% as low expression and ≥50% as high expression. Statistical analyses The statistical analyses of cohorts 1A and 1B were mainly descriptive and focused on safety and efficacy estimates, without formal hypothesis testing. Thus, no statistical power calculations were performed to determine the sample sizes for cohorts 1A and 1B. Based on regulatory guidance, a minimum of 30 patients per cohort was required. To adequately characterize the safety profile and preliminary efficacy, each cohort was planned to enroll between 30 and 60 patients. If not otherwise specified, the data were summarized using descriptive statistical methods according to the following general principles. The descriptive statistics for continuous variables were presented using number, mean, s.d., maximum, minimum and median, and the descriptive statistics for categorical variables were presented using incidence and frequency or number and percentage of patients. Safety was assessed on the safety set, defined as all patients who have received at least one dose of the investigational product and have safety evaluation data. The biomarker analysis set included all patients who received at least one dose of the study drugs and had pretreatment specimens for TROP2 and/or PD-L1 assessment. Median follow-up time was calculated based on the reverse Kaplan–Meier method. The primary endpoint of investigator-assessed ORR was based on the FAS, and the 95% CI of ORR was estimated using the Clopper–Pearson method. Analysis of the secondary endpoint of DCR was based on the FAS, and the 95% CI of DCR was estimated using the Clopper–Pearson method. The secondary endpoint of investigator-assessed PFS was based on the FAS population, and the median values of the two groups were estimated using the Kaplan–Meier method, and their 95% CI values were calculated using the Brookmeyer–Crowley method. At the time of primary analysis, for patients without disease progression or death, PFS was censored at the date of the last valid imaging examination. For patients without postbaseline tumor assessments, PFS was censored at the time of administration. For patients whose date of first disease progression or death was more than two assessment cycles away from the date of the previous imaging, the date of PFS was censored to the date of the last valid imaging before progression. DOR as assessed by the investigator was defined as the time from the date of the first obtained complete response (CR) or PR to disease progression or death due to any cause, whichever occurs first. Analysis of DOR was based on patients with CR and PR in the FAS, the median values of each group was estimated using the Kaplan–Meier method, and the corresponding 95% CI was calculated using the Brookmeyer–Crowley method. For patients without progression or death, DOR was censored at the date of the last valid imaging examination. No imputation for missing values was conducted for ORR and DCR. Comparisons of biomarker levels between groups were performed using Dunn’s test for multiple comparisons. The chi-squared test was used for categorical variables. Pearson test was used to determine the correlation between the TROP2 expression level (H-score) and PD-L1 TPS level in cohorts 1A and 1B. Statistical significance was defined as a two-sided P value < 0.05. Data were collected using an electronic data capture system (Clinflash EDC, v.2024.3.0). Statistical analyses and graph drawing were conducted using the SAS v.9.4 and R v.4.1.3. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to fangwf@sysucc.org.cn, zhangli@sysucc.org.cn or mict@kelun.com. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by the corresponding authors, the SYSUCC institutional review board, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. to evaluate the merit of the research proposed, the availability of the data, the intended use of the data and the presence of conflict of interests. A signed data access agreement with the sponsors is required before data sharing. The study protocol and the remaining data are available in the Article or Supplementary Information. References Bray, F. et al. 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Hong), National Natural Science Foundation of China (grant nos 82272789 and 82241232 awarded to L.Z., grant nos 82373262 and 82173101 awarded to W.F., grant no. 82172713 awarded to S. Hong), Natural Science Foundation of Guangdong Province (grant no. 2023B1515020008 awarded to S. Hong) and Guangzhou Science and Technology Program (grant no. 2024A04J6485 awarded to S. Hong). We thank all the patients who volunteered to participate in the OptiTROP-Lung01 study and their families for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and their devoted team members for participating in the OptiTROP-Lung01 study. Author information Author notes These authors contributed equally: Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu. Authors and Affiliations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China Shaodong Hong, Li Zhang & Wenfeng Fang The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China Qiming Wang Henan Cancer Hospital, Zhengzhou, China Qiming Wang Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China Qiming Wang Jilin Cancer Hospital, Changchun, China Ying Cheng Hunan Cancer Hospital, Changsha, China Yongzhong Luo & Lin Wu The First Hospital of China Medical University, Shenyang, China Xiujuan Qu Shanxi Cancer Hospital, Taiyuan, China Haibo Zhu West China Hospital of Sichuan University, Chengdu, China Zhenyu Ding The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Xingya Li Harbin Medical University Cancer Hospital, Harbin, China Yan Wang Hubei Cancer Hospital, Wuhan, China Sheng Hu Chongqing University Cancer Hospital, Chongqing, China Enwen Wang The Second Affiliated Hospital of Nanchang University, Nanchang, China Anwen Liu Shandong Cancer Hospital, Jinan, China Yuping Sun Zhejiang Cancer Hospital, Hangzhou, China Yun Fan The First Affiliated Hospital of Xiamen University, Xiamen, China Feng Ye Jiangsu Province Hospital, Nanjing, China Kaihua Lu Beijing Cancer Hospital, Beijing, China Jian Fang Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China Yuping Shen, Xiaoping Jin & Junyou Ge National Engineering Research Center of Targeted Biologics, Chengdu, China Junyou Ge Contributions S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. conceived and designed the study. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. provided study materials and recruited participants. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. collected and assembled the data. S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. analyzed and interpreted the data. All authors were involved in writing, reviewing and editing of the paper, and in final approval of the paper. All authors are accountable for all aspects of the work. Corresponding authors Correspondence to Li Zhang or Wenfeng Fang. Ethics declarations Competing interests Y. Shen, X.J. and J.G. are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma, and consulting for MSD, Beigene and Xiansheng Pharma. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks Melissa Johnson, Maiying Kong and Shengxiang Ren for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Efficacy in the full analysis set population. a, b, Spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in cohort 1 A (a) and cohort 1B (b). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). c, d, Kaplan-Meier survival curves of progression-free survival for cohort 1 A (c) and cohort 1B (d), respectively. Solid step lines represent Kaplan-Meier estimates of PFS probability, where vertical drops indicate events; shaded bands depict pointwise 95% confidence intervals around that estimate using the Brookmeyer–Crowley method; marks (+) denote censored data points. PFS, progression-free survival; CI, confidence interval; N.E., not estimable. Extended Data Fig. 2 The correlation between PD-L1 expression, TROP2 expression and treatment response. a, b, Expression of PD-L1 (tumor proportion score, TPS) (a) and TROP2 (b) in cohort 1A and cohort 1B. c, scatter plot of PD-L1 versus TROP2 expression in patients with both biomarkers available. Correlation was assessed using a two-sided Pearson test (no adjustment for multiple comparisons); the gray shaded area represents 95% confidence bands for the linear regression fit. d, e, Association between PD-L1 expression and confirmed best overall response in cohort 1 A (d) and cohort 1B (e). f, g, Association between TROP2 expression and response in cohort 1 A (f) and cohort 1B (g). Box plots in panels a, b, d–g depict the median (center line), first quartile (Q1; box bottom), and third quartile (Q3; box top). Whiskers encompass 1.5 times the interquartile range (IQR), with points beyond whiskers representing outliers. Group comparisons were performed using a two-sided Dunn’s test for multiple comparisons (d–g). TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 3 Tumor response distribution by PD-L1 expression and TROP2 expression categories. a, b, the difference of tumor response among three PD-L1 TPS categories was compared in cohort 1 A (a) and cohort 1B (b). c, d, according to the cutoff of the H-score of 200, patients were divided into two groups: low TROP2 expression and high TROP2 expression, and the difference of tumor response between two TROP2 expression groups was compared in cohort 1 A (c) and cohort 1B (d). Statistical significance was determined using Chi-squared test. TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 4 Forrest plots for confirmed overall response rate in different patient subgroups. a, cohort 1 A; b, cohort 1B. Subgroup with sample size ≥ 10 were shown. The central mark on each horizontal error bar represents the point estimate of the cORR for the respective subgroup. The horizontal error bar represents the 95% confidence interval for each cORR value. cORR, confirmed objective response rate; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 5 Depth and duration of response by PD-L1 expression. a, b, c, waterfall plot depicting the maximum change from baseline in target lesion size in patients with PD-L1 TPS of < 1% (a), between 1 and 49% (b) and ≥ 50% (c); d, e, f, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with PD-L1 TPS of < 1% (d), between 1 and 49% (e), and ≥ 50% (f). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 6 Depth and duration of response by TROP2 expression. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with TROP2 H-score of ≤ 200 (a) and TROP2 H-score of > 200 (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with TROP2 H-score of ≤ 200 (c) and TROP2 H-score of > 200 (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Fig. 7 Depth and duration of response by histology subgroup. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with non-squamous carcinoma (a) and squamous carcinoma (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with non-squamous carcinoma (c) and squamous carcinoma (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Table 1 Subgroup efficacy in cohort 1A and cohort 1B grouped by PD-L1 expression among TROP2 low or high-expression population Full size table Extended Data Table 2 Subgroup efficacy analysis by PD-L1/TROP2 expression and histology Full size table Extended Data Table 3 Immune-related adverse events (irAEs) (occurring in ≥ 2% of patients) and grade 3-5 irAEs (occurring in at least one patient) Full size table Supplementary information Supplementary Information Redacted study protocol (v.3.0, 2023.01.01). Reporting Summary Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Hong, S., Wang, Q., Cheng, Y. et al. First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial. Nat Med 31, 3654–3661 (2025). https://doi.org/10.1038/s41591-025-03883-5 Download citation Received 16 August 2024 Accepted 03 July 2025 Published 19 August 2025 Version of record 19 August 2025 Issue date November 2025 DOI https://doi.org/10.1038/s41591-025-03883-5 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer immunotherapy Non-small-cell lung cancer This article is cited by Perioperative Immunotherapy for Non-Small Cell Lung Cancer (NSCLC) Sarafina Urenna OtisGiuseppe Luigi BannaAkash Maniam Current Oncology Reports (2025) You have full access to this article via Sun Yat-sen University. 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Skip to main content Advertisement Nature Medicine View all journals Search Log in Explore content About the journal Publish with us Sign up for alerts RSS feed nature nature medicine articles article First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Download PDF Article Published: 19 August 2025 First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu, Haibo Zhu, Zhenyu Ding, Xingya Li, Lin Wu, Yan Wang, Sheng Hu, Enwen Wang, Anwen Liu, Yuping Sun, Yun Fan, Feng Ye, Kaihua Lu, Jian Fang, Yuping Shen, Xiaoping Jin, Junyou Ge, Li Zhang & Wenfeng Fang Nature Medicine volume 31, pages3654–3661 (2025)Cite this article 2859 Accesses 1 Citations 90 Altmetric Metricsdetails Abstract Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody–drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks) plus tagitanlimab (1,200 mg, every 3 weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5 mg kg−1, every 2 weeks) plus tagitanlimab (900 mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63 years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ≥3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3 months for cohort 1A and 13.0 months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4 months (95% confidence interval 6.7–17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration: NCT05351788. Similar content being viewed by others Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer: a randomized phase 3 trial Article 11 April 2025 Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial Article Open access 27 September 2024 Induction chemotherapy followed by camrelizumab plus apatinib and chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, single-arm trial Article Open access 18 February 2025 Main Lung cancer remains the leading cause of cancer-related mortality globally, with an estimated 1.8 million deaths annually1. The standard first-line treatment for advanced non-small-cell lung cancer (NSCLC) without targetable driver mutations now includes a combination of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy regimens or the use of ICI monotherapy or an ICI plus another ICI2,3,4,5,6. However, a substantial proportion of patients either do not benefit from immunotherapy or eventually develop resistance7,8. For patients with advanced NSCLC without targetable genomic alterations, the 5-year survival rate remains low at around 20%, highlighting the urgent need for new therapeutic targets and combination strategies9,10,11,12. Antibody–drug conjugates (ADCs) constitute an important breakthrough in cancer therapy, offering target specificity with antibodies and cytotoxicity with the conjugated payload (typically a chemotherapeutic agent). This dual approach preferentially targets cancer cells, thereby minimizing damage to normal tissues13. Trophoblast cell surface antigen 2 (TROP2), which is expressed in most solid tumors, is a promising target for ADC development. TROP2 is overexpressed in approximately 70% of NSCLC cases and is associated with more aggressive disease and a poor prognosis14,15,16. In recent years, a growing number of TROP2-targeted ADCs have been investigated in various cancer types17. Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is a TROP2-directed ADC that specifically binds to TROP2-positive tumor cells and is then internalized to release the payload KL610023 intracellularly18. As a potent topoisomerase I inhibitor, KL610023 induces DNA damage in these cells, resulting in cell-cycle arrest and subsequent apoptosis. In addition, the membrane permeability of KL610023 also promotes cytotoxic bystander activity18. sac-TMT has a high drug-to-antibody ratio of 7.4:1 with linker conjugation technology that minimizes payload release in the circulation and maximizes intracellular payload release18. Preliminary results have shown encouraging antitumor activity and a manageable safety profile for sac-TMT monotherapy in patients with advanced epidermal growth factor receptor (EGFR) wild-type NSCLC who have undergone prior systemic therapy19,20. Among the 19 patients who had at least one post-treatment evaluation, the objective response rate (ORR) was 26.3%, with a median duration of response (DOR) of 9.6 months20. This raises the question of whether sac-TMT can be advanced from later-line to first-line treatment, and from monotherapy to combination therapy, to further improve clinical outcomes in NSCLC. In addition to their intrinsic cytotoxic properties, ADCs exert immunomodulatory effects that may augment the effectiveness of ICIs, a hypothesis pending confirmation through clinical trials21,22,23. To explore the potential synergistic effects of combining TROP2-targeting ADCs with ICIs, we initiated the OptiTROP-Lung01 trial. This multicenter, multicohort, open-label, phase 2 study aimed to assess the safety, tolerability and efficacy of sac-TMT plus tagitanlimab (KL-A167), an anti-programmed cell death ligand 1 (PD-L1) antibody, with or without a platinum agent, in patients with advanced or metastatic NSCLC (ClinicalTrials.gov identifier: NCT05351788). In this report, we present the initial results for patients with NSCLC who did not possess targetable genetic changes and were treated with a first-line regimen of sac-TMT at 5 mg kg−1 every 3 weeks and tagitanlimab at 1,200 mg every 3 weeks (cohort 1A) or sac-TMT at 5 mg kg−1 every 2 weeks and tagitanlimab at 900 mg every 2 weeks (cohort 1B). Results Patient disposition and baseline demographics From 20 May 2022 to 11 August 2023, a total of 103 patients were enrolled: 40 in cohort 1A and 63 in cohort 1B (Fig. 1). The baseline patient characteristics are presented in Table 1. All included patients were treatment-naive for advanced or metastatic diseases. The median age was 63 years (range 49–72 years) in cohort 1A and 63 years (range 38–75 years) in cohort 1B. Men comprised 85.0% of cohort 1A and 76.2% of cohort 1B, with smoking histories reported in 72.5% and 60.3% of the patients, respectively. An Eastern Cooperative Oncology Group (ECOG) performance status of 1 was documented in 97.5% of cohort 1A and 85.7% of cohort 1B. Stage IV diagnosis was present in 92.5% of the patients in cohort 1A and 81.0% of the patients in cohort 1B. Brain metastases were observed in 12.5% and 3.2% of the patients, and liver metastases were observed in 10.0% and 14.3% of the patients in cohort 1A and cohort 1B, respectively. Approximately half of the patients in both cohorts had squamous cell carcinoma (55.0% in cohort 1A and 46.0% in cohort 1B). Fig. 1: Study flowchart and patient disposition. figure 1 sac-TMT, sacituzumab tirumotecan; Q3W, every 3 weeks; KL-A167, tagitanlimab; Q2W, every 2 weeks. Full size image Table 1 Patient demographics and baseline characteristics Full size table As of the data cutoff date (27 May 2024), 9 and 29 patients remained on the study drug treatment in cohorts 1A and 1B, respectively. In cohort 1A, with a median follow-up of 19.3 months (95% confidence interval (CI) 18.6–21.9), 31 patients (77.5%) discontinued treatment. The main reason for discontinuation was disease progression (n = 19, 47.5%). In cohort 1B, with a median follow-up of 13.0 months (95% CI 11.3–13.3), 34 patients (54.0%) discontinued treatment, primarily because of disease progression (22 patients, 34.9%) (Fig. 1). Efficacy A total of 40 patients in cohort 1A and 63 in cohort 1B were included in the full analysis set (FAS) for efficacy assessment. As of the data cutoff date, the median treatment durations for sac-TMT were 8.1 months in cohort 1A and 9.9 months in cohort 1B, while the median durations for tagitanlimab were 6.7 months in cohort 1A and 9.7 months in cohort 1B. The efficacy results are presented in Table 2. The median best percentage change in target lesions from baseline was −30.6% (range −91.8 to 13.0) for cohort 1A and −44.8% (range −89.6 to 0) for cohort 1B (Fig. 2a). Treatment duration and response are illustrated in a swimming plot (Fig. 2b), and dynamic changes in target lesions from baseline are depicted in spider plots (Extended Data Fig. 1a,b). Table 2 Efficacy summary Full size table Fig. 2: Waterfall plot of tumor response from baseline and swimming plot. figure 2 a, Waterfall plot showing maximum percentage change from baseline in target lesion size. The gray horizontal dashed line represents the minimum requirement of tumor regression of target lesions for a PR (−30%) and progression disease (20%) according to RECIST v.1.1. b, Swimming plot showing treatment duration and response. Arrows denote patients who remained on the study drug treatment at the data cutoff date. Full size image In cohort 1A, the confirmed ORR was 40.0% (16 of 40, 95% CI 24.9–56.7) with a disease control rate (DCR) of 85.0% (34 of 40, 95% CI 70.2–94.3). Among the 16 responders, the median DOR was 16.6 months (95% CI 8.3 to not estimable (N.E.)). Median progression-free survival (PFS) was 15.4 months (95% CI 6.7–17.9), with a 6-month PFS rate of 69.2% (95% CI 51.2–81.6), and a 12-month PFS rate of 51.1% (95% CI 33.5–66.2) (Table 2 and Extended Data Fig. 1c). In cohort 1B, the confirmed ORR was 66.7% (42 of 63, 95% CI 53.7–78.0), and the DCR was 92.1% (58 of 63, 95% CI 82.4–97.4). Among the 42 responders, the median DOR was not reached (95% CI 11.2–N.E.). The median PFS was also not reached (95% CI 9.6–N.E.), with a 6-month PFS rate of 84.2% (95% CI 71.8–91.4), and a 12-month PFS rate of 58.4% (95% CI 44.2–70.1) (Table 2 and Extended Data Fig. 1d). Biomarkers All the patients had pretreatment specimens available for PD-L1 expression assessment. The median PD-L1 tumor proportion score (TPS) was 8% in cohort 1A and 5% in cohort 1B (Extended Data Fig. 2a). In cohort 1A, 30.0% of the patients had a PD-L1 TPS <1%, 32.5% had a PD-L1 TPS between 1% and 49%, and 37.5% had a PD-L1 TPS ≥50%. In cohort 1B, these proportions were 33.3%, 30.2% and 36.5%, respectively (Table 1). For TROP2 membrane expression, specimens were available from all patients in cohort 1A and from 56 patients in cohort 1B. The median baseline TROP2 histochemical scores (H-scores) in cohorts 1A and 1B were 195 and 250, respectively (Extended Data Fig. 2b). TROP2 expression was divided into two subgroups: low expression with an H-score of ≤200 and high expression with an H-score of >200 (ref. 24). TROP2 expression levels were low (H-score ≤200) in 52.5% and 19.0%, and high (H-score >200) in 47.5% and 69.8% of the patients in cohorts 1A and 1B, respectively (Table 1). There was a trend toward an inverse correlation between PD-L1 and TROP2 expression (r = −0.14, P = 0.18) (Extended Data Fig. 2c). No significant association was found between PD-L1 TPS (%) and clinical response (Extended Data Fig. 2d,e), although patients with a PD-L1 TPS of ≥50% tended to have a higher response rate in cohort 1B (78.3%) (Extended Data Fig. 3a,b). Similarly, no significant association was detected between TROP2 expression and objective response (Extended Data Figs. 2f,g and 3c,d). Further exploratory analysis of the combined impact of the TROP2 and PD-L1 categories indicated that PD-L1 expression levels appeared to be positively correlated with treatment response in the TROP2 high-expression subgroup but not in the TROP2 low-expression subgroup (Extended Data Table 1). Efficacy by subgroups Post hoc subgroup analysis by clinicopathological characteristics showed that the efficacy of sac-TMT with tagitanlimab was consistent across subgroups in both cohorts (Extended Data Fig. 4). Detailed subgroup analyses of cohorts 1A and 1B revealed that combination therapy was effective in patients with different levels of PD-L1 and TROP2 expression and those with squamous cell or nonsquamous cell histology (Extended Data Table 2). Clinically meaningful responses to sac-TMT and tagitanlimab were observed across various PD-L1 levels in both cohorts. Specifically, patients with a PD-L1 TPS of <1% had an ORR of 41.7% in cohort 1A and 57.1% in cohort 1B. Those with a PD-L1 TPS between 1% and 49% experienced an ORR of 38.5% in cohort 1A and 63.2% in cohort 1B. For patients with a PD-L1 TPS ≥50%, ORR was 40.0% in cohort 1A and 78.3% in cohort 1B (Extended Data Fig. 5 and Extended Data Table 2). ORR in TROP2-low patients was 42.9% in cohort 1A and 83.3% in cohort 1B. ORR in TROP2-high patients was 36.8% in cohort 1A and 68.2% in cohort 1B (Extended Data Fig. 6 and Extended Data Table 2). Patients with nonsquamous carcinoma and squamous carcinoma exhibited similar responses to the combination of sac-TMT and tagitanlimab. In cohort 1A, the ORR was 44.4% for nonsquamous carcinoma and 36.4% for squamous carcinoma. In cohort 1B, the ORR was 64.7% for nonsquamous carcinoma and 69.0% for squamous carcinoma (Extended Data Fig. 7 and Extended Data Table 2). Safety of sac-TMT combined with tagitanlimab A total of 40 patients in cohort 1A and 63 patients in cohort 1B were included in the safety set for safety assessment. The median dose intensity for sac-TMT in cohort 1A and cohort 1B was 1.6 mg per kg per week and 2.1 mg per kg per week, respectively. The median dose intensity for tagitanlimab in cohort 1A and cohort 1B was 387.7 mg per week and 418.8 mg per week, respectively. In cohort 1A, 38 of 40 (95.0%) patients reported at least one treatment-related adverse event (TRAE), compared to 61 of 63 (96.8%) patients in cohort 1B. Grade 3 or higher TRAEs were observed in 42.5% of patients (17 of 40) in cohort 1A and 58.7% (37 of 63) in cohort 1B (Table 3). TRAEs led to treatment interruption in 27.5% (11 of 40) of the patients in cohort 1A and 54.0% (34 of 63) of the patients in cohort 1B. sac-TMT dose reduction because of TRAEs was required in 17.5% (7 of 40) of the patients in cohort 1A and 42.9% (27 of 63) in cohort 1B. Treatment discontinuation of any drug because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 6.3% (4 of 63) of the patients in cohort 1B. Discontinuation of sac-TMT occurred in two patients in cohort 1B (one because of drug hypersensitivity and one because of an infusion-related reaction), whereas no patient experienced TRAEs leading to sac-TMT discontinuation in cohort 1A. Treatment discontinuation of tagitanlimab because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 3.2% (2 of 63) of the patients in cohort 1B. Treatment-related serious adverse events occurred in 10.0% (4 of 40) and 20.6% (13 of 63) of the patients in cohort 1A and cohort 1B, respectively. No treatment-related deaths were reported. Table 3 Overall safety summary Full size table The most common TRAEs of any grade (occurring in ≥20% of patients) included anemia (80.0% and 79.4%), decreased neutrophil count (62.5% and 66.7%), decreased white blood cell count (50.0% and 54.0%), alopecia (45.0% and 49.2%), rash (40.0% and 38.1%), nausea (27.5% and 36.5%), decreased appetite (25.0% and 28.6%), increased alanine transaminase (ALT) (22.5% and 27.0%) and stomatitis (22.5% and 55.6%) in cohorts 1A and 1B, respectively (Table 4). The most common grade ≥3 TRAEs in cohorts 1A and 1B were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%), anemia (5.0% and 19.0%), rash (5.0% and 7.9%), stomatitis (0% and 9.5%) and drug eruption (7.5% and 0%) (Table 4). Interstitial lung disease (ILD) occurred in one patient in cohort 1B (grade 2), with no grade ≥3 pneumonitis or ILD reported. Table 4 Most common TRAEs (occurring in ≥20% of patients) and grade 3–5 TRAEs (occurring in ≥5% of patients) Full size table Immune-related adverse events (irAEs) were reported in 25.0% of patients (10 of 40) in cohort 1A and 39.7% (25 of 63) in cohort 1B. Grade 3 or higher irAEs occurred in 7.5% of cohort 1A (3 of 40) and 12.7% of cohort 1B (8 of 63) (Extended Data Table 3). The most common irAEs in cohorts 1A and 1B included rash (12.5% and 14.3%), increased alanine aminotransferase (ALT) (0% and 11.1%), hypothyroidism (2.5% and 7.9%), increased aspartate aminotransferase (AST) (0% and 6.3%) and hyperthyroidism (0% and 6.3%). Discussion In this phase 2 study, the combination of sac-TMT and tagitanlimab exhibited encouraging efficacy and a manageable safety profile in patients with advanced or metastatic NSCLC in the first-line setting. The observed ORR of 40.0% in cohort 1A and 66.7% in cohort 1B, together with the substantial depth and duration of response, underscore the potential of this combination strategy. Notably, the treatment response was consistent across diverse NSCLC subgroups, irrespective of PD-L1 expression status, TROP2 expression levels or histological subtype (squamous versus nonsquamous). These findings provide a rationale for further investigation of sac-TMT plus immunotherapy in a broad spectrum of patients with NSCLC, as evidenced by the increasing number of phase 3 studies evaluating this combination therapy. The ORR observed with biweekly (every 2 weeks (Q2W)) administration of sac-TMT and tagitanlimab is promising and suggests a potential improvement over the historical ORR of 48.0% to 57.9% achieved with conventional platinum-based chemotherapy plus an anti-PD-1 or anti-PD-L1 antibody for patients with NSCLC2,5. Moreover, the toxicity profile associated with the Q2W regimen was manageable. Therefore, sac-TMT administered Q2W has been adopted in most ongoing phase 3 trials for further investigation. ADCs have been shown to potentiate the effectiveness of anti-PD-1 or anti-PD-L1 therapies through a multifaceted mechanism of action. These include Fc-mediated effector functions, induction of immunogenic cell death, maturation of dendritic cells, increased T cell infiltration, boosted immunological memory and upregulation of immunomodulatory proteins, including PD-L1 and major histocompatibility complex21,22,23,25,26. Empirical evidence indicates a pronounced immunomodulatory effect of ADCs in immunocompetent animal models compared with their immunodeficient counterparts, highlighting the important role of ADCs in modulating the tumor microenvironment27,28. Collectively, these mechanisms underpin the potentially enhanced therapeutic outcomes observed with the combination of sac-TMT and tagitanlimab. In particular, in the subset of patients with a PD-L1 TPS value of 50% or greater, the ORR was 78.3% in cohort 1B. This rate is approximately twice that observed with pembrolizumab alone29 and surpasses by nearly 20% the ORR achieved with pembrolizumab plus platinum-based chemotherapy4,5. In light of these findings, randomized controlled trials are encouraged to explore whether sac-TMT plus pembrolizumab could further improve patient outcomes in people with high PD-L1 expression (NCT06170788) or positive PD-L1 expression (NCT06448312) compared with pembrolizumab alone. Another TROP2-targeting ADC, datopotamab deruxtecan, is also being evaluated in combination with pembrolizumab, with or without chemotherapy, in the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) studies. The results of these randomized trials are awaited given the early efficacy signal noted in the current study. Our study indicated that sac-TMT plus tagitanlimab is active in squamous NSCLC, a subtype with a high unmet medical need30. Specifically, patients with squamous carcinoma demonstrated an ORR of 36.4% in cohort 1A and 69.0% in cohort 1B. These results are comparable with those observed in patients with nonsquamous lung cancer, who demonstrated ORR of 44.4% in cohort 1A and 64.7% in cohort 1B. Further research is being conducted to evaluate the potential benefits of sac-TMT in patients with squamous NSCLC. A phase 3 clinical trial (NCT06422143) has been initiated to investigate this potential. This study was designed to compare the outcomes of pembrolizumab with or without maintenance therapy with sac-TMT, following induction treatment with pembrolizumab plus carboplatin and taxane, in patients with metastatic squamous NSCLC. Although not designed for comprehensive translational research, the current study focused on exploring the impact of two key biomarkers, TROP2 and PD-L1, on the efficacy of sac-TMT plus tagitanlimab therapy. Consistent with the known mechanisms of ICIs, we observed potentially enhanced treatment responses in patients with PD-L1 TPS ≥50% in cohort 1B. TROP2 expression levels showed no clear correlation with efficacy, a finding aligned with previous TROP2-directed ADC monotherapy studies31,32. This suggests that TROP2 membrane expression alone may not reliably predict the response to TROP2-directed ADC combined with immunotherapy. Accordingly, several ongoing phase 3 studies of first-line NSCLC have been initiated to further investigate the efficacy of sac-TMT plus pembrolizumab based on different PD-L1 expression levels (for example, with PD-L1 TPS ≥1% (NCT06448312), ≥50% (NCT06170788) and <1% (NCT06711900)), without TROP2-based patient selection. Intriguingly, our exploratory analysis indicated a trend toward a positive correlation between PD-L1 expression and treatment response, specifically in the TROP2 high-expression subgroup, but not in the TROP2 low-expression subgroup (Extended Data Table 1). These preliminary findings suggest a complex interplay between TROP2 and PD-L1 biomarkers, although validation requires in-depth translational studies in the future. In terms of safety, the combination of sac-TMT and tagitanlimab is generally manageable and consistent with the known profiles of individual agents, with no new safety signals19,33. Hematological toxicities, the most common TRAEs, were in the expected range and could be addressed with standard care. Although patients in cohort 1B experienced a higher incidence of grade 3 or higher hematological adverse events compared with those in cohort 1A, these events were manageable in both groups. Stomatitis also occurred more frequently in cohort 1B; however, the majority of cases were in grades 1 and 2. Of note, ILD, a concerning adverse event linked to irinotecan and other ADCs (for example, DS-8201) is rare with sac-TMT and tagitanlimab. We reported a single case of grade 2 ILD in cohort 1B. The most common irAEs reported were rash, elevations in ALT and AST levels, hypothyroidism and hyperthyroidism, consistent with the known safety profile of tagitanlimab33. Some 17.5% of patients in cohort 1A and 42.9% of patients in cohort 1B experienced dose reduction of sac-TMT. However, discontinuation of any investigational drug because of TRAEs was rare (2.5% in cohort 1A and 6.3% in cohort 1B). No treatment-related deaths were reported. Our study has several limitations. First, this was an open-label study without a comparator arm. Therefore, the benefits of sac-TMT plus tagitanlimab over traditional platinum-based chemotherapy plus immunotherapy remain to be elucidated. Second, the modest cohort size and lack of formal hypothesis testing precluded definitive statistical inferences. Third, the relatively short follow-up period in cohort 1B rendered the PFS outcomes and DOR data preliminary. Future efforts will focus on reporting long-term toxicity and efficacy data. Furthermore, the relationship between TROP2 and PD-L1 expression and treatment response remains unclear because of the limited sample size. Further biomarker-driven studies that focus on tumor microenvironment and dynamic changes in blood biomarkers are necessary to better identify patients who are more likely to benefit from sac-TMT plus anti-PD-1 or anti-PD-L1 immunotherapy. Limitations aside, the OptiTROP-Lung01 study established the safety, tolerability and preliminary efficacy of sac-TMT with tagitanlimab in patients with advanced NSCLC lacking actionable genomic alterations. These results support ongoing studies that aim to validate our findings and delineate the therapeutic potential of combining TROP2-directed ADC with immunotherapy in various disease scenarios. Methods Study design, participants and ethics The OptiTROP-Lung01 trial (NCT05351788) is an ongoing, open-label, multicohort, multicenter, phase 2 study of sac-TMT plus tagitanlimab (KL-A167) with or without carboplatin or cisplatin, in patients with advanced NSCLC. Cohort 1 enrolled patients with locally advanced or metastatic NSCLC harboring wild-type EGFR and negative anaplastic lymphoma kinase (ALK) fusion gene, with no known actionable alterations in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic tyrosine receptor kinase (NTRK) or v-raf murine sarcoma viral oncogene homolog B (BRAF), with no known driver gene alterations targetable by other approved therapies. Eligible patients should not have received prior ICI therapy and have no prior or at most one prior line of systemic therapy. Cohort 1 is further divided into cohorts 1A and 1B. Patients in cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks (Q3W)) + tagitanlimab (1,200 mg, Q3W) in each 3-week cycle, and patients in cohort 1B were treated with sac-TMT (5 mg kg−1, every 2 weeks (Q2W)) + tagitanlimab (900 mg, Q2W) in each 4-week cycle. These two cohorts were initiated sequentially to assess tolerability and optimize dosing regimens to inform subsequent phase 3 study design. Here, we presented the initial safety and efficacy data from both cohort 1A and cohort 1B. The dosing strategies for cohorts 1A and 1B were determined based on phase 1 studies that suggested optimal efficacy and safety profiles (details are provided in Supplementary Information). Specifically, in the phase 1–2, dose escalation–expansion, global first-in-human study of sac-TMT (ClinicalTrials.gov identifier: NCT04152499), the maximum tolerated dose was 5.5 mg kg−1 Q2W and the recommended doses for expansion were 4 mg kg−1 Q2W and 5 mg kg−1 Q2W. Similarly, in the phase 1 study of tagitanlimab (ChinaTRugtrials.org identifier: CTR20181198), 900 mg Q2W and 1,200 mg Q3W were both selected as the recommended doses for tagitanlimab based on their similar efficacy and exposure levels. Given these findings, we chose to explore the combination of sac-TMT and tagitanlimab at two different dosing frequencies: Q2W and Q3W. The Q2W dosing strategy was selected based on the recommended dose of each agent, whereas the Q3W dosing strategy was explored to align with the more common dose interval for anti-PD-1 or anti-PD-L1 therapy in clinical practice. Cohort 1A also was designed to establish initial safety with a lower dose intensity of sac-TMT (5 mg kg−1 Q3W), whereas cohort 1B explored a higher dose intensity of sac-TMT (5 mg kg−1 Q2W) to evaluate potential efficacy gains. All enrolled patients received continuous treatment until intolerable toxicity, no further clinical benefit as assessed by the investigator (based on a comprehensive assessment of imaging and clinical condition), or the patient’s request for discontinuation of treatment, whichever occurs first; the maximum duration of treatment with tagitanlimab is 24 months. Further details of key inclusion and exclusion criteria are provided below and in Supplementary Information. Key inclusion criteria were: (1) Male or female patients ≥18 and ≤75 years of age at the time of signing the informed consent form (2) Histologically and cytologically confirmed NSCLC, locally advanced (stage IIIB and IIIC) or metastatic (stage IV) NSCLC not amenable to radical surgery and/or radical radiotherapy (regardless of concurrent chemotherapy) (according to the 8th edition of TNM Staging of Lung Cancer published by the International Union Against Cancer and American Joint Committee on Cancer)34 (3) For patients with nonsquamous NSCLC, prior tissue-based EGFR and ALK reports must be available, otherwise tumor tissue samples (archival or fresh, primary or metastatic) must be collected for assessment of EGFR and ALK status (either in a local laboratory or in a central laboratory). For patients with squamous NSCLC, if the prior EGFR and ALK statuses are unknown, the corresponding tests would not be required for study enrollment, and the EGFR and ALK status of these patients would be considered negative. (4) Patients with locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion gene, no known ROS1, NTRK, BRAF gene alterations, or no known driver gene alterations that can also be targeted by other approved therapies, no prior ICI therapy, and no prior or at most one prior line of systemic therapy. Prior adjuvant, neoadjuvant or radical chemoradiotherapy may be considered first-line therapy if there is disease progression during the treatment or within 6 months after completion of treatment. (5) Be able to provide fresh or archival tumor tissue for biomarker testing and analysis (PD-L1 and TROP2 expression level) (6) Patients with at least one measurable lesion per RECIST v.1.1 criteria (7) Patients with an ECOG performance status of 0 to 1 with an expected survival of ≥12 weeks (8) Adequate organ and bone marrow function (no blood transfusion, recombinant human thrombopoietin or colony-stimulating factor therapy within 2 weeks before first dose) (9) Patients must recover from all toxicities (≤grade 1 or the inclusion criterion specified in the protocol based on Common Terminology Criteria for Adverse Events v.5.0 assessment) due to prior treatment, except for alopecia and vitiligo (10) Female patients of childbearing potential and male patients with partners of childbearing potential who use effective medical contraception during the study treatment period and for 6 months after the end of dosing (see Supplementary Information for specific contraceptive measures) (11) Each patient must voluntarily agree to participate in the study, sign the informed consent form and comply with the protocol-specified visits and relevant procedures. Key exclusion criteria were: (1) Presence of small cell lung carcinoma components in histological pathology (2) History of other malignancies, except locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, or other solid tumors curatively treated with no evidence of disease for ≥3 years (3) Presence of metastases to the brainstem, meninges and spinal cord, or spinal cord compression (4) Patients with active brain metastases (5) Patients who have received any chemotherapy, immunotherapy, biotherapy and so on within 4 weeks before the first dose of study treatment, or received small molecule tyrosine kinase inhibitors, antitumor hormone therapy, systemic immune stimulators (including but not limited to interferon, interleukin-2), radiotherapy or herbal products preparations for approved antitumor indications within 2 weeks before the first dose of study treatment (6) Patients who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of the study treatment, or received more than 30 Gy of radiation for lung lesions within 6 months before the first dose of the study treatment (7) Patients who required the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks before the first dose of the study treatment and during the study (concomitant use of strong inhibitors or inducers of CYP3A4 are not allowed in this study, and the representative drugs for known strong CYP3A4 inhibitors or inducers are listed in Supplementary Information) (8) Patients who have received systemic corticosteroids (>10 mg d−1 prednisone or equivalent, or low-dose corticosteroids, such as ≤10 mg d−1 prednisone or equivalent, are allowed if the dose is stable for 4 weeks), or other immunosuppressive therapy within 2 weeks before the first dose. Steroids are allowed as prophylaxis for hypersensitivity reactions. (9) Received any live vaccine 4 weeks before the first dose of study treatment (10) With active infections requiring systemic treatment within 2 weeks before the first dose of study treatment (11) With Grade 2 or above peripheral neuropathy (12) History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment (13) Arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy that have resolved as judged by the investigator) and pulmonary embolism within 6 months before the first dose of study treatment (14) Active or previous clear history of inflammatory bowel disease (for example, Crohn’s disease, ulcerative colitis, or chronic diarrhea) (15) Prior TROP2-targeted therapy (16) Serious or uncontrolled cardiac disease or clinical symptoms requiring treatment, including any of the following: (i) New York Heart Association Grade 3 or 4 congestive heart failure within 6 months before the first dose of study treatment (ii) Unstable angina pectoris uncontrolled by medication within 6 months before the first dose of study treatment (iii) History of myocardial infarction (iv) Serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia) within 6 months before the first dose of study treatment (v) Corrected QT interval >480 ms at baseline (17) History of (noninfectious) ILD or noninfectious pneumonitis requiring steroid therapy and current ILD or noninfectious pneumonitis, or suspected ILD or noninfectious pneumonitis at screening that cannot be excluded by imaging (18) Uncontrolled systemic disease as judged by the investigator (19) Active autoimmune disease requiring systemic treatment within the past 2 years (hormone replacement therapy is not considered a systemic therapy), such as type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenal or pituitary insufficiency requiring only physiologic doses of glucocorticoid replacement therapy (20) Certain viral infections including active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥500 IU ml−1 or upper limit of normal, which is higher) or hepatitis C (hepatitis C antibody positive, and HCV-RNA above the upper limit of normal); known history of positive human immunodeficiency virus test or known acquired immunodeficiency syndrome, or known active syphilis infection (21) Known active tuberculosis (22) Known hypersensitivity to the study drug or any of its components, or severe allergic reactions to other monoclonal antibodies (23) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation (24) Pregnant or lactating women (25) Any patient whose condition deteriorates rapidly during the screening process before the first dose, such as severe changes in performance status and so on (26) Other circumstances that, in the opinion of the investigator, are not appropriate for participation in this study. The study was conducted at 17 sites in China following the moral, ethical and scientific principles outlined in the Declaration of Helsinki and the Good Clinical Practice. Approvals for the study protocol, any amendments and informed consent were obtained from independent ethics committees of each participating site and central approval was obtained from the Sun Yat-sen University Cancer Center institutional review board before study initiation. All patients provided written informed consent. Any amendment to the protocol must be reviewed and approved by the ethics committee before implementation. Clinical trial objectives The primary objectives were to assess the safety, tolerability and antitumor activity of sac-TMT in combination with tagitanlimab in patients with advanced or metastatic NSCLC. The secondary objectives were to assess the efficacy, pharmacokinetics and immunogenicity of sac-TMT in combination with tagitanlimab. Other objectives were to assess the correlation between the expression level of TROP2 in tumor tissue and antitumor activity and the correlation between the expression level of PD-L1 in tumor tissue and antitumor activity. Clinical endpoint and assessments The primary endpoints included the safety endpoint measured by the incidence and severity of adverse events and the efficacy endpoint, namely ORR as assessed by the investigator according to RECIST v.1.1. The secondary endpoints included efficacy, namely PFS, DOR and DCR assessed by the investigator according to RECIST v.1.1. Other endpoints include the correlation between antitumor activity and the expression level of TROP2 and PD-L1 in tumor tissue. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. The severity of each adverse event was also recorded. An irAE refers to an adverse event related to tagitanlimab injection and is considered to be caused by an immune-mediated mechanism, and may require corticosteroid hormone, other immunosuppressants or hormone replacement therapy. Tumor response assessments based on RECIST v.1.1 were performed every 6 weeks by investigators. Immunohistochemistry and biomarker analysis Patients should provide approximately ten tumor tissue slides at or after diagnosis of locally advanced or metastatic tumor for TROP2 and PD-L1 protein assessment (five slides for TROP2 and five for PD-L1 detection, respectively). TROP2 and PD-L1 expression levels in formalin-fixed tumor samples were assessed using immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd). In detail, TROP2 expression was stained and assessed with anti-TROP2 monoclonal antibody (1:3,000; Abcam, cat. no. EPR20043). For PD-L1 expression, we used the ready-to-use companion diagnostic assay PD-L1 IHC 22C3 pharmDx (Agilent), which is approved by the US Food and Drug Administration and National Medical Products Administration, and is prevalidated for clinical use. All the areas in each tissue section were evaluated for TROP2 or PD-L1 expression. H-score refers to the product of tumor cell staining intensity and the percentage of stained cells at a given intensity in the membrane compartment, which was calculated as ‘(1 × % cells with weak intensity staining) + (2 × % cells with moderate intensity staining) + (3 × % cells with strong intensity staining)’. TROP2 expression level was divided into two subgroups: low expression with an H-score of ≤200, and high expression with an H-score of >200. PD-L1 expression was documented as TPS, with scores of 0–1% being defined as negative expression, 1–49% as low expression and ≥50% as high expression. Statistical analyses The statistical analyses of cohorts 1A and 1B were mainly descriptive and focused on safety and efficacy estimates, without formal hypothesis testing. Thus, no statistical power calculations were performed to determine the sample sizes for cohorts 1A and 1B. Based on regulatory guidance, a minimum of 30 patients per cohort was required. To adequately characterize the safety profile and preliminary efficacy, each cohort was planned to enroll between 30 and 60 patients. If not otherwise specified, the data were summarized using descriptive statistical methods according to the following general principles. The descriptive statistics for continuous variables were presented using number, mean, s.d., maximum, minimum and median, and the descriptive statistics for categorical variables were presented using incidence and frequency or number and percentage of patients. Safety was assessed on the safety set, defined as all patients who have received at least one dose of the investigational product and have safety evaluation data. The biomarker analysis set included all patients who received at least one dose of the study drugs and had pretreatment specimens for TROP2 and/or PD-L1 assessment. Median follow-up time was calculated based on the reverse Kaplan–Meier method. The primary endpoint of investigator-assessed ORR was based on the FAS, and the 95% CI of ORR was estimated using the Clopper–Pearson method. Analysis of the secondary endpoint of DCR was based on the FAS, and the 95% CI of DCR was estimated using the Clopper–Pearson method. The secondary endpoint of investigator-assessed PFS was based on the FAS population, and the median values of the two groups were estimated using the Kaplan–Meier method, and their 95% CI values were calculated using the Brookmeyer–Crowley method. At the time of primary analysis, for patients without disease progression or death, PFS was censored at the date of the last valid imaging examination. For patients without postbaseline tumor assessments, PFS was censored at the time of administration. For patients whose date of first disease progression or death was more than two assessment cycles away from the date of the previous imaging, the date of PFS was censored to the date of the last valid imaging before progression. DOR as assessed by the investigator was defined as the time from the date of the first obtained complete response (CR) or PR to disease progression or death due to any cause, whichever occurs first. Analysis of DOR was based on patients with CR and PR in the FAS, the median values of each group was estimated using the Kaplan–Meier method, and the corresponding 95% CI was calculated using the Brookmeyer–Crowley method. For patients without progression or death, DOR was censored at the date of the last valid imaging examination. No imputation for missing values was conducted for ORR and DCR. Comparisons of biomarker levels between groups were performed using Dunn’s test for multiple comparisons. The chi-squared test was used for categorical variables. Pearson test was used to determine the correlation between the TROP2 expression level (H-score) and PD-L1 TPS level in cohorts 1A and 1B. Statistical significance was defined as a two-sided P value < 0.05. Data were collected using an electronic data capture system (Clinflash EDC, v.2024.3.0). Statistical analyses and graph drawing were conducted using the SAS v.9.4 and R v.4.1.3. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to fangwf@sysucc.org.cn, zhangli@sysucc.org.cn or mict@kelun.com. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by the corresponding authors, the SYSUCC institutional review board, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. to evaluate the merit of the research proposed, the availability of the data, the intended use of the data and the presence of conflict of interests. A signed data access agreement with the sponsors is required before data sharing. The study protocol and the remaining data are available in the Article or Supplementary Information. References Bray, F. et al. 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Oncol. 35, 2790–2797 (2017). Article CAS PubMed Google Scholar Shi, Y. et al. Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. Lancet Reg. Health West. Pac. 31, 100617 (2023). PubMed Google Scholar Lababede, O. & Meziane, M.A. The eighth edition of TNM staging of lung cancer: reference chart and diagrams. Oncologist 23, 844–848 (2018). Article PubMed PubMed Central Google Scholar Download references Acknowledgements The study was sponsored by Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. The sponsor provided the investigated drug and worked with investigators on the trial design, data collection, data analyses and results interpretation. This study was also supported, in part by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2024ZD0519700 awarded to L.Z.; grant nos 2024ZD0520200 and 2024ZD0520205 awarded to S. Hong), National Natural Science Foundation of China (grant nos 82272789 and 82241232 awarded to L.Z., grant nos 82373262 and 82173101 awarded to W.F., grant no. 82172713 awarded to S. Hong), Natural Science Foundation of Guangdong Province (grant no. 2023B1515020008 awarded to S. Hong) and Guangzhou Science and Technology Program (grant no. 2024A04J6485 awarded to S. Hong). We thank all the patients who volunteered to participate in the OptiTROP-Lung01 study and their families for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and their devoted team members for participating in the OptiTROP-Lung01 study. Author information Author notes These authors contributed equally: Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu. Authors and Affiliations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China Shaodong Hong, Li Zhang & Wenfeng Fang The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China Qiming Wang Henan Cancer Hospital, Zhengzhou, China Qiming Wang Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China Qiming Wang Jilin Cancer Hospital, Changchun, China Ying Cheng Hunan Cancer Hospital, Changsha, China Yongzhong Luo & Lin Wu The First Hospital of China Medical University, Shenyang, China Xiujuan Qu Shanxi Cancer Hospital, Taiyuan, China Haibo Zhu West China Hospital of Sichuan University, Chengdu, China Zhenyu Ding The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Xingya Li Harbin Medical University Cancer Hospital, Harbin, China Yan Wang Hubei Cancer Hospital, Wuhan, China Sheng Hu Chongqing University Cancer Hospital, Chongqing, China Enwen Wang The Second Affiliated Hospital of Nanchang University, Nanchang, China Anwen Liu Shandong Cancer Hospital, Jinan, China Yuping Sun Zhejiang Cancer Hospital, Hangzhou, China Yun Fan The First Affiliated Hospital of Xiamen University, Xiamen, China Feng Ye Jiangsu Province Hospital, Nanjing, China Kaihua Lu Beijing Cancer Hospital, Beijing, China Jian Fang Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China Yuping Shen, Xiaoping Jin & Junyou Ge National Engineering Research Center of Targeted Biologics, Chengdu, China Junyou Ge Contributions S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. conceived and designed the study. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. provided study materials and recruited participants. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. collected and assembled the data. S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. analyzed and interpreted the data. All authors were involved in writing, reviewing and editing of the paper, and in final approval of the paper. All authors are accountable for all aspects of the work. Corresponding authors Correspondence to Li Zhang or Wenfeng Fang. Ethics declarations Competing interests Y. Shen, X.J. and J.G. are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma, and consulting for MSD, Beigene and Xiansheng Pharma. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks Melissa Johnson, Maiying Kong and Shengxiang Ren for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Efficacy in the full analysis set population. a, b, Spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in cohort 1 A (a) and cohort 1B (b). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). c, d, Kaplan-Meier survival curves of progression-free survival for cohort 1 A (c) and cohort 1B (d), respectively. Solid step lines represent Kaplan-Meier estimates of PFS probability, where vertical drops indicate events; shaded bands depict pointwise 95% confidence intervals around that estimate using the Brookmeyer–Crowley method; marks (+) denote censored data points. PFS, progression-free survival; CI, confidence interval; N.E., not estimable. Extended Data Fig. 2 The correlation between PD-L1 expression, TROP2 expression and treatment response. a, b, Expression of PD-L1 (tumor proportion score, TPS) (a) and TROP2 (b) in cohort 1A and cohort 1B. c, scatter plot of PD-L1 versus TROP2 expression in patients with both biomarkers available. Correlation was assessed using a two-sided Pearson test (no adjustment for multiple comparisons); the gray shaded area represents 95% confidence bands for the linear regression fit. d, e, Association between PD-L1 expression and confirmed best overall response in cohort 1 A (d) and cohort 1B (e). f, g, Association between TROP2 expression and response in cohort 1 A (f) and cohort 1B (g). Box plots in panels a, b, d–g depict the median (center line), first quartile (Q1; box bottom), and third quartile (Q3; box top). Whiskers encompass 1.5 times the interquartile range (IQR), with points beyond whiskers representing outliers. Group comparisons were performed using a two-sided Dunn’s test for multiple comparisons (d–g). TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 3 Tumor response distribution by PD-L1 expression and TROP2 expression categories. a, b, the difference of tumor response among three PD-L1 TPS categories was compared in cohort 1 A (a) and cohort 1B (b). c, d, according to the cutoff of the H-score of 200, patients were divided into two groups: low TROP2 expression and high TROP2 expression, and the difference of tumor response between two TROP2 expression groups was compared in cohort 1 A (c) and cohort 1B (d). Statistical significance was determined using Chi-squared test. TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 4 Forrest plots for confirmed overall response rate in different patient subgroups. a, cohort 1 A; b, cohort 1B. Subgroup with sample size ≥ 10 were shown. The central mark on each horizontal error bar represents the point estimate of the cORR for the respective subgroup. The horizontal error bar represents the 95% confidence interval for each cORR value. cORR, confirmed objective response rate; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 5 Depth and duration of response by PD-L1 expression. a, b, c, waterfall plot depicting the maximum change from baseline in target lesion size in patients with PD-L1 TPS of < 1% (a), between 1 and 49% (b) and ≥ 50% (c); d, e, f, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with PD-L1 TPS of < 1% (d), between 1 and 49% (e), and ≥ 50% (f). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 6 Depth and duration of response by TROP2 expression. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with TROP2 H-score of ≤ 200 (a) and TROP2 H-score of > 200 (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with TROP2 H-score of ≤ 200 (c) and TROP2 H-score of > 200 (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Fig. 7 Depth and duration of response by histology subgroup. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with non-squamous carcinoma (a) and squamous carcinoma (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with non-squamous carcinoma (c) and squamous carcinoma (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Table 1 Subgroup efficacy in cohort 1A and cohort 1B grouped by PD-L1 expression among TROP2 low or high-expression population Full size table Extended Data Table 2 Subgroup efficacy analysis by PD-L1/TROP2 expression and histology Full size table Extended Data Table 3 Immune-related adverse events (irAEs) (occurring in ≥ 2% of patients) and grade 3-5 irAEs (occurring in at least one patient) Full size table Supplementary information Supplementary Information Redacted study protocol (v.3.0, 2023.01.01). Reporting Summary Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Hong, S., Wang, Q., Cheng, Y. et al. First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial. Nat Med 31, 3654–3661 (2025). https://doi.org/10.1038/s41591-025-03883-5 Download citation Received 16 August 2024 Accepted 03 July 2025 Published 19 August 2025 Version of record 19 August 2025 Issue date November 2025 DOI https://doi.org/10.1038/s41591-025-03883-5 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer immunotherapy Non-small-cell lung cancer This article is cited by Perioperative Immunotherapy for Non-Small Cell Lung Cancer (NSCLC) Sarafina Urenna OtisGiuseppe Luigi BannaAkash Maniam Current Oncology Reports (2025) You have full access to this article via Sun Yat-sen University. 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Play and explore "Skip to main content Advertisement Nature Medicine View all journals Search Log in Explore content About the journal Publish with us Sign up for alerts RSS feed nature nature medicine articles article First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Download PDF Article Published: 19 August 2025 First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu, Haibo Zhu, Zhenyu Ding, Xingya Li, Lin Wu, Yan Wang, Sheng Hu, Enwen Wang, Anwen Liu, Yuping Sun, Yun Fan, Feng Ye, Kaihua Lu, Jian Fang, Yuping Shen, Xiaoping Jin, Junyou Ge, Li Zhang & Wenfeng Fang Nature Medicine volume 31, pages3654–3661 (2025)Cite this article 2859 Accesses 1 Citations 90 Altmetric Metricsdetails Abstract Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody–drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks) plus tagitanlimab (1,200 mg, every 3 weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5 mg kg−1, every 2 weeks) plus tagitanlimab (900 mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63 years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ≥3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3 months for cohort 1A and 13.0 months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4 months (95% confidence interval 6.7–17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration: NCT05351788. Similar content being viewed by others Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer: a randomized phase 3 trial Article 11 April 2025 Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial Article Open access 27 September 2024 Induction chemotherapy followed by camrelizumab plus apatinib and chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, single-arm trial Article Open access 18 February 2025 Main Lung cancer remains the leading cause of cancer-related mortality globally, with an estimated 1.8 million deaths annually1. The standard first-line treatment for advanced non-small-cell lung cancer (NSCLC) without targetable driver mutations now includes a combination of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy regimens or the use of ICI monotherapy or an ICI plus another ICI2,3,4,5,6. However, a substantial proportion of patients either do not benefit from immunotherapy or eventually develop resistance7,8. For patients with advanced NSCLC without targetable genomic alterations, the 5-year survival rate remains low at around 20%, highlighting the urgent need for new therapeutic targets and combination strategies9,10,11,12. Antibody–drug conjugates (ADCs) constitute an important breakthrough in cancer therapy, offering target specificity with antibodies and cytotoxicity with the conjugated payload (typically a chemotherapeutic agent). This dual approach preferentially targets cancer cells, thereby minimizing damage to normal tissues13. Trophoblast cell surface antigen 2 (TROP2), which is expressed in most solid tumors, is a promising target for ADC development. TROP2 is overexpressed in approximately 70% of NSCLC cases and is associated with more aggressive disease and a poor prognosis14,15,16. In recent years, a growing number of TROP2-targeted ADCs have been investigated in various cancer types17. Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is a TROP2-directed ADC that specifically binds to TROP2-positive tumor cells and is then internalized to release the payload KL610023 intracellularly18. As a potent topoisomerase I inhibitor, KL610023 induces DNA damage in these cells, resulting in cell-cycle arrest and subsequent apoptosis. In addition, the membrane permeability of KL610023 also promotes cytotoxic bystander activity18. sac-TMT has a high drug-to-antibody ratio of 7.4:1 with linker conjugation technology that minimizes payload release in the circulation and maximizes intracellular payload release18. Preliminary results have shown encouraging antitumor activity and a manageable safety profile for sac-TMT monotherapy in patients with advanced epidermal growth factor receptor (EGFR) wild-type NSCLC who have undergone prior systemic therapy19,20. Among the 19 patients who had at least one post-treatment evaluation, the objective response rate (ORR) was 26.3%, with a median duration of response (DOR) of 9.6 months20. This raises the question of whether sac-TMT can be advanced from later-line to first-line treatment, and from monotherapy to combination therapy, to further improve clinical outcomes in NSCLC. In addition to their intrinsic cytotoxic properties, ADCs exert immunomodulatory effects that may augment the effectiveness of ICIs, a hypothesis pending confirmation through clinical trials21,22,23. To explore the potential synergistic effects of combining TROP2-targeting ADCs with ICIs, we initiated the OptiTROP-Lung01 trial. This multicenter, multicohort, open-label, phase 2 study aimed to assess the safety, tolerability and efficacy of sac-TMT plus tagitanlimab (KL-A167), an anti-programmed cell death ligand 1 (PD-L1) antibody, with or without a platinum agent, in patients with advanced or metastatic NSCLC (ClinicalTrials.gov identifier: NCT05351788). In this report, we present the initial results for patients with NSCLC who did not possess targetable genetic changes and were treated with a first-line regimen of sac-TMT at 5 mg kg−1 every 3 weeks and tagitanlimab at 1,200 mg every 3 weeks (cohort 1A) or sac-TMT at 5 mg kg−1 every 2 weeks and tagitanlimab at 900 mg every 2 weeks (cohort 1B). Results Patient disposition and baseline demographics From 20 May 2022 to 11 August 2023, a total of 103 patients were enrolled: 40 in cohort 1A and 63 in cohort 1B (Fig. 1). The baseline patient characteristics are presented in Table 1. All included patients were treatment-naive for advanced or metastatic diseases. The median age was 63 years (range 49–72 years) in cohort 1A and 63 years (range 38–75 years) in cohort 1B. Men comprised 85.0% of cohort 1A and 76.2% of cohort 1B, with smoking histories reported in 72.5% and 60.3% of the patients, respectively. An Eastern Cooperative Oncology Group (ECOG) performance status of 1 was documented in 97.5% of cohort 1A and 85.7% of cohort 1B. Stage IV diagnosis was present in 92.5% of the patients in cohort 1A and 81.0% of the patients in cohort 1B. Brain metastases were observed in 12.5% and 3.2% of the patients, and liver metastases were observed in 10.0% and 14.3% of the patients in cohort 1A and cohort 1B, respectively. Approximately half of the patients in both cohorts had squamous cell carcinoma (55.0% in cohort 1A and 46.0% in cohort 1B). Fig. 1: Study flowchart and patient disposition. figure 1 sac-TMT, sacituzumab tirumotecan; Q3W, every 3 weeks; KL-A167, tagitanlimab; Q2W, every 2 weeks. Full size image Table 1 Patient demographics and baseline characteristics Full size table As of the data cutoff date (27 May 2024), 9 and 29 patients remained on the study drug treatment in cohorts 1A and 1B, respectively. In cohort 1A, with a median follow-up of 19.3 months (95% confidence interval (CI) 18.6–21.9), 31 patients (77.5%) discontinued treatment. The main reason for discontinuation was disease progression (n = 19, 47.5%). In cohort 1B, with a median follow-up of 13.0 months (95% CI 11.3–13.3), 34 patients (54.0%) discontinued treatment, primarily because of disease progression (22 patients, 34.9%) (Fig. 1). Efficacy A total of 40 patients in cohort 1A and 63 in cohort 1B were included in the full analysis set (FAS) for efficacy assessment. As of the data cutoff date, the median treatment durations for sac-TMT were 8.1 months in cohort 1A and 9.9 months in cohort 1B, while the median durations for tagitanlimab were 6.7 months in cohort 1A and 9.7 months in cohort 1B. The efficacy results are presented in Table 2. The median best percentage change in target lesions from baseline was −30.6% (range −91.8 to 13.0) for cohort 1A and −44.8% (range −89.6 to 0) for cohort 1B (Fig. 2a). Treatment duration and response are illustrated in a swimming plot (Fig. 2b), and dynamic changes in target lesions from baseline are depicted in spider plots (Extended Data Fig. 1a,b). Table 2 Efficacy summary Full size table Fig. 2: Waterfall plot of tumor response from baseline and swimming plot. figure 2 a, Waterfall plot showing maximum percentage change from baseline in target lesion size. The gray horizontal dashed line represents the minimum requirement of tumor regression of target lesions for a PR (−30%) and progression disease (20%) according to RECIST v.1.1. b, Swimming plot showing treatment duration and response. Arrows denote patients who remained on the study drug treatment at the data cutoff date. Full size image In cohort 1A, the confirmed ORR was 40.0% (16 of 40, 95% CI 24.9–56.7) with a disease control rate (DCR) of 85.0% (34 of 40, 95% CI 70.2–94.3). Among the 16 responders, the median DOR was 16.6 months (95% CI 8.3 to not estimable (N.E.)). Median progression-free survival (PFS) was 15.4 months (95% CI 6.7–17.9), with a 6-month PFS rate of 69.2% (95% CI 51.2–81.6), and a 12-month PFS rate of 51.1% (95% CI 33.5–66.2) (Table 2 and Extended Data Fig. 1c). In cohort 1B, the confirmed ORR was 66.7% (42 of 63, 95% CI 53.7–78.0), and the DCR was 92.1% (58 of 63, 95% CI 82.4–97.4). Among the 42 responders, the median DOR was not reached (95% CI 11.2–N.E.). The median PFS was also not reached (95% CI 9.6–N.E.), with a 6-month PFS rate of 84.2% (95% CI 71.8–91.4), and a 12-month PFS rate of 58.4% (95% CI 44.2–70.1) (Table 2 and Extended Data Fig. 1d). Biomarkers All the patients had pretreatment specimens available for PD-L1 expression assessment. The median PD-L1 tumor proportion score (TPS) was 8% in cohort 1A and 5% in cohort 1B (Extended Data Fig. 2a). In cohort 1A, 30.0% of the patients had a PD-L1 TPS <1%, 32.5% had a PD-L1 TPS between 1% and 49%, and 37.5% had a PD-L1 TPS ≥50%. In cohort 1B, these proportions were 33.3%, 30.2% and 36.5%, respectively (Table 1). For TROP2 membrane expression, specimens were available from all patients in cohort 1A and from 56 patients in cohort 1B. The median baseline TROP2 histochemical scores (H-scores) in cohorts 1A and 1B were 195 and 250, respectively (Extended Data Fig. 2b). TROP2 expression was divided into two subgroups: low expression with an H-score of ≤200 and high expression with an H-score of >200 (ref. 24). TROP2 expression levels were low (H-score ≤200) in 52.5% and 19.0%, and high (H-score >200) in 47.5% and 69.8% of the patients in cohorts 1A and 1B, respectively (Table 1). There was a trend toward an inverse correlation between PD-L1 and TROP2 expression (r = −0.14, P = 0.18) (Extended Data Fig. 2c). No significant association was found between PD-L1 TPS (%) and clinical response (Extended Data Fig. 2d,e), although patients with a PD-L1 TPS of ≥50% tended to have a higher response rate in cohort 1B (78.3%) (Extended Data Fig. 3a,b). Similarly, no significant association was detected between TROP2 expression and objective response (Extended Data Figs. 2f,g and 3c,d). Further exploratory analysis of the combined impact of the TROP2 and PD-L1 categories indicated that PD-L1 expression levels appeared to be positively correlated with treatment response in the TROP2 high-expression subgroup but not in the TROP2 low-expression subgroup (Extended Data Table 1). Efficacy by subgroups Post hoc subgroup analysis by clinicopathological characteristics showed that the efficacy of sac-TMT with tagitanlimab was consistent across subgroups in both cohorts (Extended Data Fig. 4). Detailed subgroup analyses of cohorts 1A and 1B revealed that combination therapy was effective in patients with different levels of PD-L1 and TROP2 expression and those with squamous cell or nonsquamous cell histology (Extended Data Table 2). Clinically meaningful responses to sac-TMT and tagitanlimab were observed across various PD-L1 levels in both cohorts. Specifically, patients with a PD-L1 TPS of <1% had an ORR of 41.7% in cohort 1A and 57.1% in cohort 1B. Those with a PD-L1 TPS between 1% and 49% experienced an ORR of 38.5% in cohort 1A and 63.2% in cohort 1B. For patients with a PD-L1 TPS ≥50%, ORR was 40.0% in cohort 1A and 78.3% in cohort 1B (Extended Data Fig. 5 and Extended Data Table 2). ORR in TROP2-low patients was 42.9% in cohort 1A and 83.3% in cohort 1B. ORR in TROP2-high patients was 36.8% in cohort 1A and 68.2% in cohort 1B (Extended Data Fig. 6 and Extended Data Table 2). Patients with nonsquamous carcinoma and squamous carcinoma exhibited similar responses to the combination of sac-TMT and tagitanlimab. In cohort 1A, the ORR was 44.4% for nonsquamous carcinoma and 36.4% for squamous carcinoma. In cohort 1B, the ORR was 64.7% for nonsquamous carcinoma and 69.0% for squamous carcinoma (Extended Data Fig. 7 and Extended Data Table 2). Safety of sac-TMT combined with tagitanlimab A total of 40 patients in cohort 1A and 63 patients in cohort 1B were included in the safety set for safety assessment. The median dose intensity for sac-TMT in cohort 1A and cohort 1B was 1.6 mg per kg per week and 2.1 mg per kg per week, respectively. The median dose intensity for tagitanlimab in cohort 1A and cohort 1B was 387.7 mg per week and 418.8 mg per week, respectively. In cohort 1A, 38 of 40 (95.0%) patients reported at least one treatment-related adverse event (TRAE), compared to 61 of 63 (96.8%) patients in cohort 1B. Grade 3 or higher TRAEs were observed in 42.5% of patients (17 of 40) in cohort 1A and 58.7% (37 of 63) in cohort 1B (Table 3). TRAEs led to treatment interruption in 27.5% (11 of 40) of the patients in cohort 1A and 54.0% (34 of 63) of the patients in cohort 1B. sac-TMT dose reduction because of TRAEs was required in 17.5% (7 of 40) of the patients in cohort 1A and 42.9% (27 of 63) in cohort 1B. Treatment discontinuation of any drug because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 6.3% (4 of 63) of the patients in cohort 1B. Discontinuation of sac-TMT occurred in two patients in cohort 1B (one because of drug hypersensitivity and one because of an infusion-related reaction), whereas no patient experienced TRAEs leading to sac-TMT discontinuation in cohort 1A. Treatment discontinuation of tagitanlimab because of TRAEs occurred in 2.5% (1 of 40) of the patients in cohort 1A and 3.2% (2 of 63) of the patients in cohort 1B. Treatment-related serious adverse events occurred in 10.0% (4 of 40) and 20.6% (13 of 63) of the patients in cohort 1A and cohort 1B, respectively. No treatment-related deaths were reported. Table 3 Overall safety summary Full size table The most common TRAEs of any grade (occurring in ≥20% of patients) included anemia (80.0% and 79.4%), decreased neutrophil count (62.5% and 66.7%), decreased white blood cell count (50.0% and 54.0%), alopecia (45.0% and 49.2%), rash (40.0% and 38.1%), nausea (27.5% and 36.5%), decreased appetite (25.0% and 28.6%), increased alanine transaminase (ALT) (22.5% and 27.0%) and stomatitis (22.5% and 55.6%) in cohorts 1A and 1B, respectively (Table 4). The most common grade ≥3 TRAEs in cohorts 1A and 1B were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%), anemia (5.0% and 19.0%), rash (5.0% and 7.9%), stomatitis (0% and 9.5%) and drug eruption (7.5% and 0%) (Table 4). Interstitial lung disease (ILD) occurred in one patient in cohort 1B (grade 2), with no grade ≥3 pneumonitis or ILD reported. Table 4 Most common TRAEs (occurring in ≥20% of patients) and grade 3–5 TRAEs (occurring in ≥5% of patients) Full size table Immune-related adverse events (irAEs) were reported in 25.0% of patients (10 of 40) in cohort 1A and 39.7% (25 of 63) in cohort 1B. Grade 3 or higher irAEs occurred in 7.5% of cohort 1A (3 of 40) and 12.7% of cohort 1B (8 of 63) (Extended Data Table 3). The most common irAEs in cohorts 1A and 1B included rash (12.5% and 14.3%), increased alanine aminotransferase (ALT) (0% and 11.1%), hypothyroidism (2.5% and 7.9%), increased aspartate aminotransferase (AST) (0% and 6.3%) and hyperthyroidism (0% and 6.3%). Discussion In this phase 2 study, the combination of sac-TMT and tagitanlimab exhibited encouraging efficacy and a manageable safety profile in patients with advanced or metastatic NSCLC in the first-line setting. The observed ORR of 40.0% in cohort 1A and 66.7% in cohort 1B, together with the substantial depth and duration of response, underscore the potential of this combination strategy. Notably, the treatment response was consistent across diverse NSCLC subgroups, irrespective of PD-L1 expression status, TROP2 expression levels or histological subtype (squamous versus nonsquamous). These findings provide a rationale for further investigation of sac-TMT plus immunotherapy in a broad spectrum of patients with NSCLC, as evidenced by the increasing number of phase 3 studies evaluating this combination therapy. The ORR observed with biweekly (every 2 weeks (Q2W)) administration of sac-TMT and tagitanlimab is promising and suggests a potential improvement over the historical ORR of 48.0% to 57.9% achieved with conventional platinum-based chemotherapy plus an anti-PD-1 or anti-PD-L1 antibody for patients with NSCLC2,5. Moreover, the toxicity profile associated with the Q2W regimen was manageable. Therefore, sac-TMT administered Q2W has been adopted in most ongoing phase 3 trials for further investigation. ADCs have been shown to potentiate the effectiveness of anti-PD-1 or anti-PD-L1 therapies through a multifaceted mechanism of action. These include Fc-mediated effector functions, induction of immunogenic cell death, maturation of dendritic cells, increased T cell infiltration, boosted immunological memory and upregulation of immunomodulatory proteins, including PD-L1 and major histocompatibility complex21,22,23,25,26. Empirical evidence indicates a pronounced immunomodulatory effect of ADCs in immunocompetent animal models compared with their immunodeficient counterparts, highlighting the important role of ADCs in modulating the tumor microenvironment27,28. Collectively, these mechanisms underpin the potentially enhanced therapeutic outcomes observed with the combination of sac-TMT and tagitanlimab. In particular, in the subset of patients with a PD-L1 TPS value of 50% or greater, the ORR was 78.3% in cohort 1B. This rate is approximately twice that observed with pembrolizumab alone29 and surpasses by nearly 20% the ORR achieved with pembrolizumab plus platinum-based chemotherapy4,5. In light of these findings, randomized controlled trials are encouraged to explore whether sac-TMT plus pembrolizumab could further improve patient outcomes in people with high PD-L1 expression (NCT06170788) or positive PD-L1 expression (NCT06448312) compared with pembrolizumab alone. Another TROP2-targeting ADC, datopotamab deruxtecan, is also being evaluated in combination with pembrolizumab, with or without chemotherapy, in the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) studies. The results of these randomized trials are awaited given the early efficacy signal noted in the current study. Our study indicated that sac-TMT plus tagitanlimab is active in squamous NSCLC, a subtype with a high unmet medical need30. Specifically, patients with squamous carcinoma demonstrated an ORR of 36.4% in cohort 1A and 69.0% in cohort 1B. These results are comparable with those observed in patients with nonsquamous lung cancer, who demonstrated ORR of 44.4% in cohort 1A and 64.7% in cohort 1B. Further research is being conducted to evaluate the potential benefits of sac-TMT in patients with squamous NSCLC. A phase 3 clinical trial (NCT06422143) has been initiated to investigate this potential. This study was designed to compare the outcomes of pembrolizumab with or without maintenance therapy with sac-TMT, following induction treatment with pembrolizumab plus carboplatin and taxane, in patients with metastatic squamous NSCLC. Although not designed for comprehensive translational research, the current study focused on exploring the impact of two key biomarkers, TROP2 and PD-L1, on the efficacy of sac-TMT plus tagitanlimab therapy. Consistent with the known mechanisms of ICIs, we observed potentially enhanced treatment responses in patients with PD-L1 TPS ≥50% in cohort 1B. TROP2 expression levels showed no clear correlation with efficacy, a finding aligned with previous TROP2-directed ADC monotherapy studies31,32. This suggests that TROP2 membrane expression alone may not reliably predict the response to TROP2-directed ADC combined with immunotherapy. Accordingly, several ongoing phase 3 studies of first-line NSCLC have been initiated to further investigate the efficacy of sac-TMT plus pembrolizumab based on different PD-L1 expression levels (for example, with PD-L1 TPS ≥1% (NCT06448312), ≥50% (NCT06170788) and <1% (NCT06711900)), without TROP2-based patient selection. Intriguingly, our exploratory analysis indicated a trend toward a positive correlation between PD-L1 expression and treatment response, specifically in the TROP2 high-expression subgroup, but not in the TROP2 low-expression subgroup (Extended Data Table 1). These preliminary findings suggest a complex interplay between TROP2 and PD-L1 biomarkers, although validation requires in-depth translational studies in the future. In terms of safety, the combination of sac-TMT and tagitanlimab is generally manageable and consistent with the known profiles of individual agents, with no new safety signals19,33. Hematological toxicities, the most common TRAEs, were in the expected range and could be addressed with standard care. Although patients in cohort 1B experienced a higher incidence of grade 3 or higher hematological adverse events compared with those in cohort 1A, these events were manageable in both groups. Stomatitis also occurred more frequently in cohort 1B; however, the majority of cases were in grades 1 and 2. Of note, ILD, a concerning adverse event linked to irinotecan and other ADCs (for example, DS-8201) is rare with sac-TMT and tagitanlimab. We reported a single case of grade 2 ILD in cohort 1B. The most common irAEs reported were rash, elevations in ALT and AST levels, hypothyroidism and hyperthyroidism, consistent with the known safety profile of tagitanlimab33. Some 17.5% of patients in cohort 1A and 42.9% of patients in cohort 1B experienced dose reduction of sac-TMT. However, discontinuation of any investigational drug because of TRAEs was rare (2.5% in cohort 1A and 6.3% in cohort 1B). No treatment-related deaths were reported. Our study has several limitations. First, this was an open-label study without a comparator arm. Therefore, the benefits of sac-TMT plus tagitanlimab over traditional platinum-based chemotherapy plus immunotherapy remain to be elucidated. Second, the modest cohort size and lack of formal hypothesis testing precluded definitive statistical inferences. Third, the relatively short follow-up period in cohort 1B rendered the PFS outcomes and DOR data preliminary. Future efforts will focus on reporting long-term toxicity and efficacy data. Furthermore, the relationship between TROP2 and PD-L1 expression and treatment response remains unclear because of the limited sample size. Further biomarker-driven studies that focus on tumor microenvironment and dynamic changes in blood biomarkers are necessary to better identify patients who are more likely to benefit from sac-TMT plus anti-PD-1 or anti-PD-L1 immunotherapy. Limitations aside, the OptiTROP-Lung01 study established the safety, tolerability and preliminary efficacy of sac-TMT with tagitanlimab in patients with advanced NSCLC lacking actionable genomic alterations. These results support ongoing studies that aim to validate our findings and delineate the therapeutic potential of combining TROP2-directed ADC with immunotherapy in various disease scenarios. Methods Study design, participants and ethics The OptiTROP-Lung01 trial (NCT05351788) is an ongoing, open-label, multicohort, multicenter, phase 2 study of sac-TMT plus tagitanlimab (KL-A167) with or without carboplatin or cisplatin, in patients with advanced NSCLC. Cohort 1 enrolled patients with locally advanced or metastatic NSCLC harboring wild-type EGFR and negative anaplastic lymphoma kinase (ALK) fusion gene, with no known actionable alterations in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic tyrosine receptor kinase (NTRK) or v-raf murine sarcoma viral oncogene homolog B (BRAF), with no known driver gene alterations targetable by other approved therapies. Eligible patients should not have received prior ICI therapy and have no prior or at most one prior line of systemic therapy. Cohort 1 is further divided into cohorts 1A and 1B. Patients in cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks (Q3W)) + tagitanlimab (1,200 mg, Q3W) in each 3-week cycle, and patients in cohort 1B were treated with sac-TMT (5 mg kg−1, every 2 weeks (Q2W)) + tagitanlimab (900 mg, Q2W) in each 4-week cycle. These two cohorts were initiated sequentially to assess tolerability and optimize dosing regimens to inform subsequent phase 3 study design. Here, we presented the initial safety and efficacy data from both cohort 1A and cohort 1B. The dosing strategies for cohorts 1A and 1B were determined based on phase 1 studies that suggested optimal efficacy and safety profiles (details are provided in Supplementary Information). Specifically, in the phase 1–2, dose escalation–expansion, global first-in-human study of sac-TMT (ClinicalTrials.gov identifier: NCT04152499), the maximum tolerated dose was 5.5 mg kg−1 Q2W and the recommended doses for expansion were 4 mg kg−1 Q2W and 5 mg kg−1 Q2W. Similarly, in the phase 1 study of tagitanlimab (ChinaTRugtrials.org identifier: CTR20181198), 900 mg Q2W and 1,200 mg Q3W were both selected as the recommended doses for tagitanlimab based on their similar efficacy and exposure levels. Given these findings, we chose to explore the combination of sac-TMT and tagitanlimab at two different dosing frequencies: Q2W and Q3W. The Q2W dosing strategy was selected based on the recommended dose of each agent, whereas the Q3W dosing strategy was explored to align with the more common dose interval for anti-PD-1 or anti-PD-L1 therapy in clinical practice. Cohort 1A also was designed to establish initial safety with a lower dose intensity of sac-TMT (5 mg kg−1 Q3W), whereas cohort 1B explored a higher dose intensity of sac-TMT (5 mg kg−1 Q2W) to evaluate potential efficacy gains. All enrolled patients received continuous treatment until intolerable toxicity, no further clinical benefit as assessed by the investigator (based on a comprehensive assessment of imaging and clinical condition), or the patient’s request for discontinuation of treatment, whichever occurs first; the maximum duration of treatment with tagitanlimab is 24 months. Further details of key inclusion and exclusion criteria are provided below and in Supplementary Information. Key inclusion criteria were: (1) Male or female patients ≥18 and ≤75 years of age at the time of signing the informed consent form (2) Histologically and cytologically confirmed NSCLC, locally advanced (stage IIIB and IIIC) or metastatic (stage IV) NSCLC not amenable to radical surgery and/or radical radiotherapy (regardless of concurrent chemotherapy) (according to the 8th edition of TNM Staging of Lung Cancer published by the International Union Against Cancer and American Joint Committee on Cancer)34 (3) For patients with nonsquamous NSCLC, prior tissue-based EGFR and ALK reports must be available, otherwise tumor tissue samples (archival or fresh, primary or metastatic) must be collected for assessment of EGFR and ALK status (either in a local laboratory or in a central laboratory). For patients with squamous NSCLC, if the prior EGFR and ALK statuses are unknown, the corresponding tests would not be required for study enrollment, and the EGFR and ALK status of these patients would be considered negative. (4) Patients with locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion gene, no known ROS1, NTRK, BRAF gene alterations, or no known driver gene alterations that can also be targeted by other approved therapies, no prior ICI therapy, and no prior or at most one prior line of systemic therapy. Prior adjuvant, neoadjuvant or radical chemoradiotherapy may be considered first-line therapy if there is disease progression during the treatment or within 6 months after completion of treatment. (5) Be able to provide fresh or archival tumor tissue for biomarker testing and analysis (PD-L1 and TROP2 expression level) (6) Patients with at least one measurable lesion per RECIST v.1.1 criteria (7) Patients with an ECOG performance status of 0 to 1 with an expected survival of ≥12 weeks (8) Adequate organ and bone marrow function (no blood transfusion, recombinant human thrombopoietin or colony-stimulating factor therapy within 2 weeks before first dose) (9) Patients must recover from all toxicities (≤grade 1 or the inclusion criterion specified in the protocol based on Common Terminology Criteria for Adverse Events v.5.0 assessment) due to prior treatment, except for alopecia and vitiligo (10) Female patients of childbearing potential and male patients with partners of childbearing potential who use effective medical contraception during the study treatment period and for 6 months after the end of dosing (see Supplementary Information for specific contraceptive measures) (11) Each patient must voluntarily agree to participate in the study, sign the informed consent form and comply with the protocol-specified visits and relevant procedures. Key exclusion criteria were: (1) Presence of small cell lung carcinoma components in histological pathology (2) History of other malignancies, except locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, or other solid tumors curatively treated with no evidence of disease for ≥3 years (3) Presence of metastases to the brainstem, meninges and spinal cord, or spinal cord compression (4) Patients with active brain metastases (5) Patients who have received any chemotherapy, immunotherapy, biotherapy and so on within 4 weeks before the first dose of study treatment, or received small molecule tyrosine kinase inhibitors, antitumor hormone therapy, systemic immune stimulators (including but not limited to interferon, interleukin-2), radiotherapy or herbal products preparations for approved antitumor indications within 2 weeks before the first dose of study treatment (6) Patients who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of the study treatment, or received more than 30 Gy of radiation for lung lesions within 6 months before the first dose of the study treatment (7) Patients who required the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks before the first dose of the study treatment and during the study (concomitant use of strong inhibitors or inducers of CYP3A4 are not allowed in this study, and the representative drugs for known strong CYP3A4 inhibitors or inducers are listed in Supplementary Information) (8) Patients who have received systemic corticosteroids (>10 mg d−1 prednisone or equivalent, or low-dose corticosteroids, such as ≤10 mg d−1 prednisone or equivalent, are allowed if the dose is stable for 4 weeks), or other immunosuppressive therapy within 2 weeks before the first dose. Steroids are allowed as prophylaxis for hypersensitivity reactions. (9) Received any live vaccine 4 weeks before the first dose of study treatment (10) With active infections requiring systemic treatment within 2 weeks before the first dose of study treatment (11) With Grade 2 or above peripheral neuropathy (12) History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment (13) Arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy that have resolved as judged by the investigator) and pulmonary embolism within 6 months before the first dose of study treatment (14) Active or previous clear history of inflammatory bowel disease (for example, Crohn’s disease, ulcerative colitis, or chronic diarrhea) (15) Prior TROP2-targeted therapy (16) Serious or uncontrolled cardiac disease or clinical symptoms requiring treatment, including any of the following: (i) New York Heart Association Grade 3 or 4 congestive heart failure within 6 months before the first dose of study treatment (ii) Unstable angina pectoris uncontrolled by medication within 6 months before the first dose of study treatment (iii) History of myocardial infarction (iv) Serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia) within 6 months before the first dose of study treatment (v) Corrected QT interval >480 ms at baseline (17) History of (noninfectious) ILD or noninfectious pneumonitis requiring steroid therapy and current ILD or noninfectious pneumonitis, or suspected ILD or noninfectious pneumonitis at screening that cannot be excluded by imaging (18) Uncontrolled systemic disease as judged by the investigator (19) Active autoimmune disease requiring systemic treatment within the past 2 years (hormone replacement therapy is not considered a systemic therapy), such as type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenal or pituitary insufficiency requiring only physiologic doses of glucocorticoid replacement therapy (20) Certain viral infections including active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥500 IU ml−1 or upper limit of normal, which is higher) or hepatitis C (hepatitis C antibody positive, and HCV-RNA above the upper limit of normal); known history of positive human immunodeficiency virus test or known acquired immunodeficiency syndrome, or known active syphilis infection (21) Known active tuberculosis (22) Known hypersensitivity to the study drug or any of its components, or severe allergic reactions to other monoclonal antibodies (23) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation (24) Pregnant or lactating women (25) Any patient whose condition deteriorates rapidly during the screening process before the first dose, such as severe changes in performance status and so on (26) Other circumstances that, in the opinion of the investigator, are not appropriate for participation in this study. The study was conducted at 17 sites in China following the moral, ethical and scientific principles outlined in the Declaration of Helsinki and the Good Clinical Practice. Approvals for the study protocol, any amendments and informed consent were obtained from independent ethics committees of each participating site and central approval was obtained from the Sun Yat-sen University Cancer Center institutional review board before study initiation. All patients provided written informed consent. Any amendment to the protocol must be reviewed and approved by the ethics committee before implementation. Clinical trial objectives The primary objectives were to assess the safety, tolerability and antitumor activity of sac-TMT in combination with tagitanlimab in patients with advanced or metastatic NSCLC. The secondary objectives were to assess the efficacy, pharmacokinetics and immunogenicity of sac-TMT in combination with tagitanlimab. Other objectives were to assess the correlation between the expression level of TROP2 in tumor tissue and antitumor activity and the correlation between the expression level of PD-L1 in tumor tissue and antitumor activity. Clinical endpoint and assessments The primary endpoints included the safety endpoint measured by the incidence and severity of adverse events and the efficacy endpoint, namely ORR as assessed by the investigator according to RECIST v.1.1. The secondary endpoints included efficacy, namely PFS, DOR and DCR assessed by the investigator according to RECIST v.1.1. Other endpoints include the correlation between antitumor activity and the expression level of TROP2 and PD-L1 in tumor tissue. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. The severity of each adverse event was also recorded. An irAE refers to an adverse event related to tagitanlimab injection and is considered to be caused by an immune-mediated mechanism, and may require corticosteroid hormone, other immunosuppressants or hormone replacement therapy. Tumor response assessments based on RECIST v.1.1 were performed every 6 weeks by investigators. Immunohistochemistry and biomarker analysis Patients should provide approximately ten tumor tissue slides at or after diagnosis of locally advanced or metastatic tumor for TROP2 and PD-L1 protein assessment (five slides for TROP2 and five for PD-L1 detection, respectively). TROP2 and PD-L1 expression levels in formalin-fixed tumor samples were assessed using immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd). In detail, TROP2 expression was stained and assessed with anti-TROP2 monoclonal antibody (1:3,000; Abcam, cat. no. EPR20043). For PD-L1 expression, we used the ready-to-use companion diagnostic assay PD-L1 IHC 22C3 pharmDx (Agilent), which is approved by the US Food and Drug Administration and National Medical Products Administration, and is prevalidated for clinical use. All the areas in each tissue section were evaluated for TROP2 or PD-L1 expression. H-score refers to the product of tumor cell staining intensity and the percentage of stained cells at a given intensity in the membrane compartment, which was calculated as ‘(1 × % cells with weak intensity staining) + (2 × % cells with moderate intensity staining) + (3 × % cells with strong intensity staining)’. TROP2 expression level was divided into two subgroups: low expression with an H-score of ≤200, and high expression with an H-score of >200. PD-L1 expression was documented as TPS, with scores of 0–1% being defined as negative expression, 1–49% as low expression and ≥50% as high expression. Statistical analyses The statistical analyses of cohorts 1A and 1B were mainly descriptive and focused on safety and efficacy estimates, without formal hypothesis testing. Thus, no statistical power calculations were performed to determine the sample sizes for cohorts 1A and 1B. Based on regulatory guidance, a minimum of 30 patients per cohort was required. To adequately characterize the safety profile and preliminary efficacy, each cohort was planned to enroll between 30 and 60 patients. If not otherwise specified, the data were summarized using descriptive statistical methods according to the following general principles. The descriptive statistics for continuous variables were presented using number, mean, s.d., maximum, minimum and median, and the descriptive statistics for categorical variables were presented using incidence and frequency or number and percentage of patients. Safety was assessed on the safety set, defined as all patients who have received at least one dose of the investigational product and have safety evaluation data. The biomarker analysis set included all patients who received at least one dose of the study drugs and had pretreatment specimens for TROP2 and/or PD-L1 assessment. Median follow-up time was calculated based on the reverse Kaplan–Meier method. The primary endpoint of investigator-assessed ORR was based on the FAS, and the 95% CI of ORR was estimated using the Clopper–Pearson method. Analysis of the secondary endpoint of DCR was based on the FAS, and the 95% CI of DCR was estimated using the Clopper–Pearson method. The secondary endpoint of investigator-assessed PFS was based on the FAS population, and the median values of the two groups were estimated using the Kaplan–Meier method, and their 95% CI values were calculated using the Brookmeyer–Crowley method. At the time of primary analysis, for patients without disease progression or death, PFS was censored at the date of the last valid imaging examination. For patients without postbaseline tumor assessments, PFS was censored at the time of administration. For patients whose date of first disease progression or death was more than two assessment cycles away from the date of the previous imaging, the date of PFS was censored to the date of the last valid imaging before progression. DOR as assessed by the investigator was defined as the time from the date of the first obtained complete response (CR) or PR to disease progression or death due to any cause, whichever occurs first. Analysis of DOR was based on patients with CR and PR in the FAS, the median values of each group was estimated using the Kaplan–Meier method, and the corresponding 95% CI was calculated using the Brookmeyer–Crowley method. For patients without progression or death, DOR was censored at the date of the last valid imaging examination. No imputation for missing values was conducted for ORR and DCR. Comparisons of biomarker levels between groups were performed using Dunn’s test for multiple comparisons. The chi-squared test was used for categorical variables. Pearson test was used to determine the correlation between the TROP2 expression level (H-score) and PD-L1 TPS level in cohorts 1A and 1B. Statistical significance was defined as a two-sided P value < 0.05. Data were collected using an electronic data capture system (Clinflash EDC, v.2024.3.0). Statistical analyses and graph drawing were conducted using the SAS v.9.4 and R v.4.1.3. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to fangwf@sysucc.org.cn, zhangli@sysucc.org.cn or mict@kelun.com. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by the corresponding authors, the SYSUCC institutional review board, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. to evaluate the merit of the research proposed, the availability of the data, the intended use of the data and the presence of conflict of interests. A signed data access agreement with the sponsors is required before data sharing. The study protocol and the remaining data are available in the Article or Supplementary Information. References Bray, F. et al. 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Oncol. 35, 2790–2797 (2017). Article CAS PubMed Google Scholar Shi, Y. et al. Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. Lancet Reg. Health West. Pac. 31, 100617 (2023). PubMed Google Scholar Lababede, O. & Meziane, M.A. The eighth edition of TNM staging of lung cancer: reference chart and diagrams. Oncologist 23, 844–848 (2018). Article PubMed PubMed Central Google Scholar Download references Acknowledgements The study was sponsored by Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. The sponsor provided the investigated drug and worked with investigators on the trial design, data collection, data analyses and results interpretation. This study was also supported, in part by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2024ZD0519700 awarded to L.Z.; grant nos 2024ZD0520200 and 2024ZD0520205 awarded to S. Hong), National Natural Science Foundation of China (grant nos 82272789 and 82241232 awarded to L.Z., grant nos 82373262 and 82173101 awarded to W.F., grant no. 82172713 awarded to S. Hong), Natural Science Foundation of Guangdong Province (grant no. 2023B1515020008 awarded to S. Hong) and Guangzhou Science and Technology Program (grant no. 2024A04J6485 awarded to S. Hong). We thank all the patients who volunteered to participate in the OptiTROP-Lung01 study and their families for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and their devoted team members for participating in the OptiTROP-Lung01 study. Author information Author notes These authors contributed equally: Shaodong Hong, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu. Authors and Affiliations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China Shaodong Hong, Li Zhang & Wenfeng Fang The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China Qiming Wang Henan Cancer Hospital, Zhengzhou, China Qiming Wang Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China Qiming Wang Jilin Cancer Hospital, Changchun, China Ying Cheng Hunan Cancer Hospital, Changsha, China Yongzhong Luo & Lin Wu The First Hospital of China Medical University, Shenyang, China Xiujuan Qu Shanxi Cancer Hospital, Taiyuan, China Haibo Zhu West China Hospital of Sichuan University, Chengdu, China Zhenyu Ding The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Xingya Li Harbin Medical University Cancer Hospital, Harbin, China Yan Wang Hubei Cancer Hospital, Wuhan, China Sheng Hu Chongqing University Cancer Hospital, Chongqing, China Enwen Wang The Second Affiliated Hospital of Nanchang University, Nanchang, China Anwen Liu Shandong Cancer Hospital, Jinan, China Yuping Sun Zhejiang Cancer Hospital, Hangzhou, China Yun Fan The First Affiliated Hospital of Xiamen University, Xiamen, China Feng Ye Jiangsu Province Hospital, Nanjing, China Kaihua Lu Beijing Cancer Hospital, Beijing, China Jian Fang Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China Yuping Shen, Xiaoping Jin & Junyou Ge National Engineering Research Center of Targeted Biologics, Chengdu, China Junyou Ge Contributions S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. conceived and designed the study. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. provided study materials and recruited participants. L.Z., W.F., S. Hong, Q.W., Y.C., Y.L., X.Q., H.Z., Z.D., X.L., L.W., Y.W., S. Hu, E.W., A.L., Y. Sun, Y.F., F.Y., K.L. and J.F. collected and assembled the data. S. Hong, J.G., Y. Shen, X.J., L.Z. and W.F. analyzed and interpreted the data. All authors were involved in writing, reviewing and editing of the paper, and in final approval of the paper. All authors are accountable for all aspects of the work. Corresponding authors Correspondence to Li Zhang or Wenfeng Fang. Ethics declarations Competing interests Y. Shen, X.J. and J.G. are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma, and consulting for MSD, Beigene and Xiansheng Pharma. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks Melissa Johnson, Maiying Kong and Shengxiang Ren for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Efficacy in the full analysis set population. a, b, Spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in cohort 1 A (a) and cohort 1B (b). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). c, d, Kaplan-Meier survival curves of progression-free survival for cohort 1 A (c) and cohort 1B (d), respectively. Solid step lines represent Kaplan-Meier estimates of PFS probability, where vertical drops indicate events; shaded bands depict pointwise 95% confidence intervals around that estimate using the Brookmeyer–Crowley method; marks (+) denote censored data points. PFS, progression-free survival; CI, confidence interval; N.E., not estimable. Extended Data Fig. 2 The correlation between PD-L1 expression, TROP2 expression and treatment response. a, b, Expression of PD-L1 (tumor proportion score, TPS) (a) and TROP2 (b) in cohort 1A and cohort 1B. c, scatter plot of PD-L1 versus TROP2 expression in patients with both biomarkers available. Correlation was assessed using a two-sided Pearson test (no adjustment for multiple comparisons); the gray shaded area represents 95% confidence bands for the linear regression fit. d, e, Association between PD-L1 expression and confirmed best overall response in cohort 1 A (d) and cohort 1B (e). f, g, Association between TROP2 expression and response in cohort 1 A (f) and cohort 1B (g). Box plots in panels a, b, d–g depict the median (center line), first quartile (Q1; box bottom), and third quartile (Q3; box top). Whiskers encompass 1.5 times the interquartile range (IQR), with points beyond whiskers representing outliers. Group comparisons were performed using a two-sided Dunn’s test for multiple comparisons (d–g). TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 3 Tumor response distribution by PD-L1 expression and TROP2 expression categories. a, b, the difference of tumor response among three PD-L1 TPS categories was compared in cohort 1 A (a) and cohort 1B (b). c, d, according to the cutoff of the H-score of 200, patients were divided into two groups: low TROP2 expression and high TROP2 expression, and the difference of tumor response between two TROP2 expression groups was compared in cohort 1 A (c) and cohort 1B (d). Statistical significance was determined using Chi-squared test. TPS, tumor proportion score; cBOR, confirmed best overall response; PR, partial response; SD, stable disease; NE, not evaluable; PD, progressive disease. Note: two patients in cohort 1 A and 3 patients in cohort 1B had unconfirmed PRs but met the minimum criteria for SD duration, so their best overall response was defined as SD according to RECIST 1.1. Extended Data Fig. 4 Forrest plots for confirmed overall response rate in different patient subgroups. a, cohort 1 A; b, cohort 1B. Subgroup with sample size ≥ 10 were shown. The central mark on each horizontal error bar represents the point estimate of the cORR for the respective subgroup. The horizontal error bar represents the 95% confidence interval for each cORR value. cORR, confirmed objective response rate; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 5 Depth and duration of response by PD-L1 expression. a, b, c, waterfall plot depicting the maximum change from baseline in target lesion size in patients with PD-L1 TPS of < 1% (a), between 1 and 49% (b) and ≥ 50% (c); d, e, f, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with PD-L1 TPS of < 1% (d), between 1 and 49% (e), and ≥ 50% (f). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). PD-L1, programmed death ligand 1; TPS, tumor proportion score. Extended Data Fig. 6 Depth and duration of response by TROP2 expression. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with TROP2 H-score of ≤ 200 (a) and TROP2 H-score of > 200 (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with TROP2 H-score of ≤ 200 (c) and TROP2 H-score of > 200 (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Fig. 7 Depth and duration of response by histology subgroup. a, b, waterfall plot depicting the maximum change from baseline in target lesion size in patients with non-squamous carcinoma (a) and squamous carcinoma (b); c, d, spider plots showing the percentage change from baseline in the sum of the longest diameters (SLD) of target lesions over time in patients with non-squamous carcinoma (c) and squamous carcinoma (d). Each line represents an individual patient; timepoints (x-axis) show scheduled assessments; the y-axis indicates SLD change (%). The end of each line is marked with a square to indicate treatment discontinuation (last assessment before stopping treatment for any reason) or a triangle to indicate treatment ongoing (patient still receiving therapy at the data cutoff). Extended Data Table 1 Subgroup efficacy in cohort 1A and cohort 1B grouped by PD-L1 expression among TROP2 low or high-expression population Full size table Extended Data Table 2 Subgroup efficacy analysis by PD-L1/TROP2 expression and histology Full size table Extended Data Table 3 Immune-related adverse events (irAEs) (occurring in ≥ 2% of patients) and grade 3-5 irAEs (occurring in at least one patient) Full size table Supplementary information Supplementary Information Redacted study protocol (v.3.0, 2023.01.01). Reporting Summary Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Hong, S., Wang, Q., Cheng, Y. et al. First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial. Nat Med 31, 3654–3661 (2025). https://doi.org/10.1038/s41591-025-03883-5 Download citation Received 16 August 2024 Accepted 03 July 2025 Published 19 August 2025 Version of record 19 August 2025 Issue date November 2025 DOI https://doi.org/10.1038/s41591-025-03883-5 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer immunotherapy Non-small-cell lung cancer This article is cited by Perioperative Immunotherapy for Non-Small Cell Lung Cancer (NSCLC) Sarafina Urenna OtisGiuseppe Luigi BannaAkash Maniam Current Oncology Reports (2025) You have full access to this article via Sun Yat-sen University. 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