Discussion
esophageal cancer, tumor, death, ESCC, treatment-related adverse
TUMOR, OESOPHAGEAL CANCER, ADVERSE EVENTS, SOLID TUMORS, MICROSATELLITE INSTABILITY, SECONDARY, LUNG METASTASES, CPS, METASTASES
In this double-blind, placebo-controlled, randomized phase 3 study, we evaluated the efficacy and safety of first-line serplulimab plus chemotherapy versus placebo plus chemotherapy in patients with locally advanced or metastatic, PD-L1-positive (CPS ≥ 1) ESCC. In our prespecified final analysis for PFS and interim analysis for OS, the addition of serplulimab to cisplatin and 5-FU chemotherapy resulted in a significant improvement in both efficacy endpoints. In addition, the safety profile of serplulimab plus chemotherapy was manageable. Other planned secondary endpoints that were not reported in this manuscript but that will be reported in the future are PFS, ORR and DOR assessed by IRRC and by investigators based on immune-response evaluation criteria in solid tumors (iRECIST), pharmacokinetics and immunogenicity of serplulimab, quality-of-life assessment, the relationship between efficacy and microsatellite instability and the relationship between efficacy and tumor mutation burden. In this study, we demonstrate an improvement in survival with the addition of PD-1 blockade to chemotherapy administered every 2 weeks in a solely PD-L1-positive population with advanced ESCC.Anti-PD-1 antibodies have changed the systemic treatment of advanced esophageal cancer in recent years. In the first-line setting, results from five previous phase 3 studies showed that PD-1 inhibitors plus chemotherapy provided significant improvement in OS over chemotherapy alone in patients with advanced ESCCCisplatin plus 5-FU is commonly adopted in the first-line treatment of advanced ESCC, and different schedules for drug delivery exist for this combination. The dose intensities of cisplatin and 5-FU in our 2-week schedule were similar to those in the KEYNOTE-590 and CHECKMATE-648 trials, which used the same chemotherapy backboneThe expression of PD-L1, assessed with the 22C3, 28-8 or SP263 antibodies, has been considered a potential biomarker for efficacy in patients with advanced ESCC treated with anti-PD-1 antibodiesSerplulimab combined with cisplatin and 5-FU delivered every 2 weeks was well tolerated in our trial. The incidences of grade 3 or higher treatment-related adverse events, serious adverse events and adverse events leading to death were similar between the two treatment groups. A higher incidence of treatment-related adverse events leading to treatment discontinuation was observed in patients treated with serplulimab plus chemotherapy; this was probably related to the immune-related adverse events induced by serplulimab and a longer treatment duration in this group. Similar findings have also been reported in other controlled trials of PD-1 inhibitors in combination with chemotherapy in patients with ESCCOur study had some limitations. First, we included only patients from China; however, our results might be extrapolated to patients with ESCC outside China, as no differences were noted in terms of survival between Asian and non-Asian patients in the CHECKMATE-648 study. In addition, the presence of liver or lung metastases at baseline was not considered in stratification. These common visceral metastases are representative of tumor burden and may affect treatment outcomes. Furthermore, biomarkers other than PD-L1 expression were not investigated in our current analysis.In conclusion, first-line serplulimab in combination with chemotherapy significantly improved PFS and OS in patients with previously untreated, PD-L1-positive, locally advanced or metastatic ESCC, compared with chemotherapy alone, with a manageable safety profile.