First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

Abstract

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m²) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m²) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48-0.75; P < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53-0.87; P = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov ( NCT03958890 ).

Fig. 1. Trial profile.

Among patients who were randomized to receive placebo plus chemotherapy, 15 received serplulimab plus chemotherapy because of an error in drug distribution.

Fig. 2. Kaplan–Meier estimates of PFS.

a, All randomized patients. For serplulimab + CF, n = 368, median PFS 5.8 months (95% CI, 5.7–6.9 months). For placebo + CF, n = 183, median PFS 5.3 months (95% CI, 4.3–5.6 months). HR, 0.60; 95% CI, 0.48–0.75; P < 0.0001. b, Patients with PD-L1 expression level of 1 ≤ CPS < 10. For serplulimab + CF, n = 206, median PFS 5.7 months (95% CI, 5.5–6.3 months). For placebo + CF, n = 104, median PFS 5.3 months (95% CI, 4.2–5.6 months). HR, 0.70; 95% CI, 0.52–0.94; P = 0.017. c, Patients with PD-L1 CPS ≥ 10. For serplulimab + CF, n = 162, median PFS 7.1 months (95% CI, 5.8–9.1 months). For placebo + CF, n = 79, median PFS 5.3 months (95% CI, 4.1–6.0 months). HR, 0.48; 95% CI, 0.34–0.68; P < 0.0001. Tick marks, data censored at the time of last valid tumor assessment. PFS was assessed in accordance with RECIST v1.1 by the IRRC.

Fig. 3. Kaplan–Meier estimates of OS.

a, All randomized patients. For serplulimab + CF, n = 368, median OS 15.3 months (95% CI, 14.0–18.6 months). For placebo + CF, n = 183, median OS 11.8 months (95% CI, 9.7–14.0 months). HR, 0.68; 95% CI, 0.53–0.87; P = 0.0020. b, Patients with PD-L1 expression level of 1 ≤ CPS < 10. For serplulimab + CF, n = 206, median OS 14.2 months (95% CI, 11.5–15.3 months). For placebo + CF, n = 104, median OS 11.4 months (95% CI, 9.2–14.0 months). HR, 0.74; 95% CI, 0.54–1.03; P = 0.066. c, Patients with PD-L1 CPS ≥ 10. For serplulimab + CF, n = 162, median OS 18.6 months (95% CI, 15.3–20.9 months). For placebo + CF, n = 79, median OS 13.9 months (95% CI, 8.3–18.2 months). HR, 0.59; 95% CI, 0.40–0.88; P = 0.0082. Tick marks, data censored on the last known survival date.

Fig. 4. Survival by patient subgroups.

a,b, Forest plot analysis of PFS (a) and OS (b) in prespecified and post-hoc (smoking status) subgroups in the ITT population for patients receiving serplulimab plus chemotherapy (n = 368) versus placebo plus chemotherapy (n = 183). PFS was assessed in accordance with RECIST v1.1 by the IRRC. The Cox proportional hazards model with Efron’s method of tie handling was used to assess the magnitude of the treatment difference between groups. Sex was recorded by the investigators according to the identity information provided by the patients.

Extended Data Fig. 1. Kaplan–Meier estimates of progression-free survival assessed by investigators in the ITT population.

Tick marks represent data censored at the time of last valid tumor assessment. Progression-free survival was assessed per the Response Evaluation Criteria in Solid Tumors version 1.1 by investigators. CF = cisplatin and 5-fluorouracil. CI = confidence interval. CPS = combined positive score. HR = hazard ratio. PD-L1 = programmed death ligand 1.