In the ASTRUM-007 study, double-blind, placebo-controlled, randomised phase III study, the efficacy and safety of first-line serplulimab plus chemotherapy administered every 2 weeks versus placebo plus chemotherapy were evaluated in patients with locally advanced or metastatic, PD-L1-positive (defined as a combined positive score [CPS] ≥ 1) oesophageal squamous cell carcinoma. In prespecified final analysis for progression-free survival (PFS) and interim analysis for overall survival (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. The findings are published by Dr. Jing Huang of the Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China and colleagues on 2 February 2023 in the Nature Medicine.
Oesophageal squamous cell carcinoma accounts for approximately 84% of all oesophageal cancers. Although 5-fluorouracil (5-FU) or paclitaxel plus cisplatin has been used in the first-line setting, PD1 inhibitors in combination with chemotherapy, administered every 3 or 4 weeks, showed improved efficacy compared with chemotherapy alone in phase III studies. The authors wrote in the background that a few randomised studies have demonstrated that survival of patients receiving chemotherapy regimens with shortened intervals between cycles was better than that of patients treated by standard chemotherapy in ovarian, breast and advanced colorectal cancers. The results from these studies and the fact that advanced or metastatic oesophageal squamous cell carcinoma progresses rapidly prompted the study team to modify the dose frequency to every 2 weeks.
PD-L1 overexpression is observed in up to 40% of oesophageal squamous cell carcinomas. Previously, 3 phase III studies in which PD1 inhibitors were tested as a second-line treatment in patients with oesophageal squamous cell carcinoma who were unselected for PD-L1 expression revealed modest activity, as shown by objective response rates (ORRs) ranging from 16.7 to 20.2%. Although the ORRs were unsatisfactory, further analysis from these studies revealed that the treatment outcome was better in patients with oesophageal squamous cell carcinoma with higher PD-L1 expression.
Several phase III randomised studies of first-line treatment in patients with advanced oesophageal squamous cell carcinoma have also demonstrated a positive association between PD-L1 expression and outcomes with PD1 inhibitors plus chemotherapy. In particular, KEYNOTE-590 revealed that patients with PD-L1 CPS ≥ 10 experienced greater treatment benefit than those with PD-L1 CPS < 10. Based on the findings of that study, pembrolizumab plus chemotherapy was approved in the US for the first-line treatment of locally advanced or metastatic oesophageal cancer regardless of PD-L1 expression. This combination is also recommended by the NCCN guidelines, but the evidence and consensus categories differ according to PD-L1 subgroup: category 1 for PD-L1 CPS ≥ 10 and category 2B for PD-L1 CPS < 10. However, the European Medicines Agency restricted the indication only to patients with PD-L1 CPS ≥ 10.
Serplulimab is a fully humanised, PD1 monoclonal antibody that showed promising antitumour activity and a manageable safety profile in various tumour types in phase II clinical studies. Furthermore, a phase III study of serplulimab plus chemotherapy in patients with untreated extensive-stage small cell lung cancer has reached its primary endpoint of OS. Another phase III study in patients with untreated locally advanced or metastatic squamous non-small cell lung cancer has also reached its primary endpoint of PFS.
A phase III ASTRUM-007 study assessed the efficacy and safety of serplulimab in combination with 5-FU plus cisplatin versus chemotherapy alone as a first-line treatment in patients with locally advanced or metastatic oesophageal squamous cell carcinoma with PD-L1 CPS ≥ 1. A total of 551 patients were randomised (2:1) to receive serplulimab 3 mg/kg or placebo on day 1, plus cisplatin 50 mg/m2 on day 1 and continuous infusion of 5- FU 1,200 mg/m2 on days 1 and 2, once every 2 weeks.
At the prespecified final analysis of PFS assessed by the blinded Independent Radiological Review Committee (IRRC), serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy with median PFS of 5.8 months and 5.3 months (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.48–0.75; p < 0.0001). At the prespecified interim analysis of OS, serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy with median OS of 15.3 months and 11.8 months (HR 0.68, 95% CI 0.53–0.87; p = 0.0020).
The treatment-related adverse events (TRAEs) observed in this study were consistent with those observed previously with serplulimab, cisplatin and 5-FU, with no new safety issues identified. Grade 3 or higher TRAEs occurred in 201 patients (53%) in the serplulimab plus chemotherapy group and 81 patients (48%) in the placebo plus chemotherapy group. A higher incidence of TRAEs 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.
Other planned secondary endpoints that were not reported in this manuscript, but that will be reported in the future are PFS, ORR and duration of response assessed by IRRC and by investigators based on iRECIST, pharmacokinetics and immunogenicity of serplulimab, quality-of-life assessment, the relationship between efficacy and microsatellite instability and the relationship between efficacy and tumour mutation burden.
The authors stated that they have included in this study only patients from China. However, the results might be extrapolated to patients with oesophageal squamous cell carcinoma outside China, as no differences were noted in terms of survival between Asian and non-Asian patients in the CHECKMATE-648 study.
The study was funded by Shanghai Henlius Biotech, Inc.
- Song Y, Zhang B, Xin D, et al. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nature Medicine; Published online 2 February 2023. DOI: https://doi.org/10.1038/s41591-022-02179-2