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.
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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.
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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.
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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.
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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.
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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).
Supplementary information
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Redacted study protocol (v.3.0, 2023.01.01).
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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 (2025). https://doi.org/10.1038/s41591-025-03883-5
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DOI: https://doi.org/10.1038/s41591-025-03883-5
