Abstract
Trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating EGFR mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled EGFR-wild-type and EGFR-mutant NSCLC (n = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25–56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3–11.3). Post-hoc subgroup analyses found better outcomes in the EGFR-mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23–47) and median PFS of 9.3 months (95% CI, 7.6–11.4) in 64 patients with EGFR-mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of EGFR mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: NCT04152499, NCT05631262.
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Data availability
De-identified patient-level data generated during the current study are available under restricted access due to proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to [email protected], [email protected] or [email protected]. The anticipated timeframe for response is around 2 weeks. All requests will be reviewed by 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, statistical analysis plan and the remaining data are available within the article or Supplementary Information. Source data are provided with this paper.
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Acknowledgements
This study is 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. The study was also supported, in part, by the National Natural Science Foundation of China (grants 82241232 and 82272789 awarded to L.Z., grants 82173101 and 82373262 awarded to W.F., grant 82002408 awarded to S.Z.) and Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0060 to S.Z.). We thank patients and their families for participating in the clinical trial. We also thank investigators and clinical research coordinators from all study sites.
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S.Z., J.R., J.L., J.G., L.Z. and W.F. contributed to study design, data acquisition, interpretation and manuscript writing. S.Z., Y.C., Q.W., X.L., J.L., J.R., X.M., Yongzhong Luo, L.Z. and W.F. contributed to patient enrollment, administration, data acquisition and interpretation. Z.C., W.W., T.Y., Yongsheng Li, Y.Y., H.X., G.Y., Y.M., Y.F., Z.A.W., X.W., C.S., Q.Y., S.L., L.S., W.Z., X.W. and J.L. contributed to patient enrollment and administration. J.Y. and Yaling Li contributed to data acquisition and interpretation. J.Y., Yaling Li and J.G. contributed to data acquisition and technical support. All authors contributed to manuscript editing and approved the submission of the manuscript.
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J.Y. and Yaling Li are employees of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. J.G. is a stakeholder of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. L.Z. has received research support from AstraZeneca, Eli Lilly and Roche. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Changes from baseline in the sum of target lesions over time.
Spider plot displaying percentage changes from baseline in the sum of target lesions over time in patients from the KL264-01 cohort 3A (A, n = 43), EGFR wildtype subset (B, n = 21) and EGFR-mutant subset (C, n = 22). Five patients in the FAS of cohort 3 (2 belonged to EGFR-wildtype subset, 3 to the EGFR-mutant subset) were unevaluable and are not shown here.
Extended Data Fig. 2 Subgroup analysis in KL264-01.
Subgroup analyses of objective response rate (ORR, A) and progression-free survival (PFS, B) in patients enrolled into KL264-01 cohort 3A (n = 43). Dots denote point estimate of ORR or median PFS. Error bars indicate the 95% confidence intervals.
Extended Data Fig. 3 Subgroup analysis in SKB264-II-08.
Subgroup analyses of objective response rate (ORR, A) and progression-free survival (PFS, B) in patients enrolled into SKB264-II-08 cohort 1-2 (n = 64). Dots denote point estimate of ORR or median PFS. Error bars indicate the 95% confidence intervals.
Extended Data Fig. 4 Biomarker analyses by Trop2 expression levels.
Objective response rate (ORR, left) and progression-free survival (PFS, right) by Trop2 expression levels in patients from two studies (A, n = 92), from KL264-01 cohort 3A (B, n = 34); fromSKB264-II-08 cohort 1 and cohort 2 (C, N = 58). The bar indicates point estimate of ORR; error bar indicates 95% confidence interval (CI). PFS is displayed as median and 95%CI.
Supplementary information
Supplementary Information
Supplementary Figs. 1–4 and study protocols of KL264-01 and SKB264-II-08.
Source data
Source Data for Fig. 4 and Supplementary Figs. 2–4
Supplementary data for Methods: Sequences of oligonucleotides used in the in vitro study. Raw data for Fig. 4, showing the presence of EGFR activating mutations increasing the internalization and activity of sac-TMT. Unprocessed western blots in Supplementary Fig. 4. Raw data for Supplementary Fig. 4, showing dose–response curves of parental and resistant cells for PC9 (C) and H1975 (D)
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Zhao, S., Cheng, Y., Wang, Q. et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nat Med 31, 1976–1986 (2025). https://doi.org/10.1038/s41591-025-03638-2
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DOI: https://doi.org/10.1038/s41591-025-03638-2
