Abstract
Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18–75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m−2 on day 1 plus 5-fluorouracil 800 mg m−2 day−1 on days 1–4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54–0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55–0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352.
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Data availability
The data that support the findings of this study are not publicly available due to restrictions on patient privacy, but are available on reasonable request to CStone Pharmaceuticals. Request for access to the patient-level data from this study can be submitted via email to Q.S. (shiqingmei@cstonepharma.com) with detailed proposals for use of information, and responses to such requests can be expected within 1 month. The data request will be reviewed and, if agreed, a signed agreement with the sponsor is required before accessing the data. The authors were involved in data analysis and interpretation, verification of data accuracy and completeness and the decision to submit the manuscript for publication. The corresponding authors affirm that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.
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Acknowledgements
This trial was funded by CStone Pharmaceuticals (Suzhou) Co. Ltd., China. We thank all the patients who participated in this study and their families, as well as the investigators and research staff and their institutions, and study coordinators. Medical writing and editorial assistance were provided by M. Chen, E. Zhang and X. Duan of CStone Pharmaceuticals.
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J.L., Z.C., C.Q., J.N., B.W., J.H., Y.X., Q.S. and J.Y. provided substantial contributions to the conception and design of the study. J.L., Z.C., Y.B., B.L., Q.L., J. Zhou, J. Zhang, T.D., F.Z., S.G., S.Y., F.Y., L.C., W.B., X.Y., S.C., L.L., Y.P., H.L., Y.J., Z.Z., J.W., Q.Y., N.L. and R.H. enrolled and treated patients. J.H. performed statistical analyses. J.L., Z.C., C.Q., J.N., B.W., J.H., Y.X., Q.S. and J.Y. drafted the manuscript and provided critical revision of the manuscript for key intellectual content. All authors reviewed the data, contributed to the development of the manuscript and approved the final version for publication.
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C.Q., J.N., B.W., J.H., Y.X., Q.S. and J.Y. are employees of CStone Pharmaceuticals (Suzhou) Co. Ltd. All other authors declare no competing interests.
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Nature Medicine thanks Ken Kato, Bianca Mostert, Wencheng Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team
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Extended data
Extended Data Fig. 1 Kaplan-Meier plots of overall survival (A-C) and the progression-free survival by BICR (D-F) in patients with different PD-L1 expression levels (exploratory analysis).
a. Kaplan-Meier plots of OS in patient with PD-L1 expression level <1%. Sugemalimab+chemo group, n = 41, median OS 14.4 months; placebo+chemo group, n = 21, median OS 10.5 months. HR 0.63, (95% CI 0.32 to 1.24). b. Kaplan-Meier plots of OS in patient with 1% ≤ PD-L1 expression level <10%. Sugemalimab+chemo group, n = 163, median OS 13.7 months; placebo+chemo group, n = 83, median OS 12.4 months; HR 0.92, (95% CI 0.64 to 1.32). c. Kaplan-Meier plots of OS in the patient with PD-L1 expression level ≥10%. Sugemalimab+chemo group, n = 154, median OS 15.7 months; placebo+chemo group, n = 78, median OS 11.2 months; HR 0.57, (95% CI 0.39 to 0.83). d. Kaplan-Meier plots of PFS in patient with PD-L1 expression level <1%. Sugemalimab+chemo group, n = 41, median PFS 5.4 months; placebo+chemo group, n = 21, median PFS 5.6 months. HR 0.70, (95% CI 0.39 to 1.26). e. Kaplan-Meier plots of PFS in patient with 1% ≤ PD-L1 expression level <10%. Sugemalimab+chemo group, n = 163, median PFS 5.7 months; placebo+chemo group, n = 83, median PFS 5.7 months; HR 0.82, (95% CI 0.61 to 1.10). f. Kaplan-Meier plots of PFS in patient with PD-L1 expression level ≥10%. Sugemalimab+chemo group, n = 154, median PFS 7.0 months; placebo+chemo group, n = 78, median PFS 5.4 months; HR 0.50, (95% CI 0.36 to 0.69). Hazard ratio and corresponding 95% CIs are estimated using an unstratified Cox proportional hazards model. Tick marks represent the censored data at the date of last tumor assessment. PFS was assessed by BICR based on RECIST v1.1. BICR: blinded independent central review; Chemo: chemotherapy.
Extended Data Fig. 2 Kaplan-Meier plots of the DoR assessed by BICR.
For sugemalimab+chemo group, n = 209, median DoR 6.0 months (95% CI, 5.5 to 7.0); for placebo+chemo group, n = 80, median DoR 4.5 months (95% CI, 4.1 to 5.3). The survival curves in this plot and the median DoR in the annotation box are estimated by Kaplan-Meier method, while confidence interval for the median is calculated using the method by Brookmeyer and Crowley with log-log transformation. BICR: blinded independent central review; Chemo: Chemotherapy; DoR: duration of response.
Supplementary information
Supplementary Information
GEMSTONOE-304 investigators, redacted protocol and redacted statistical analysis plan.
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Li, J., Chen, Z., Bai, Y. et al. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med 30, 740–748 (2024). https://doi.org/10.1038/s41591-024-02797-y
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DOI: https://doi.org/10.1038/s41591-024-02797-y
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