Research in context
Evidence before this study
We searched PubMed on Nov 24, 2020, for English language articles, using the terms “gastric” OR “gastroesophageal junction” OR “esophagogastric junction” OR “esophageal adenocarcinoma” OR “oesophageal adenocarcinoma”, and “PD-1” OR “PD-L1,” and “first-line” OR “previously untreated” OR “treatment naive” in the title or abstract, with no time limits. To identify results from clinical trials that were not yet published in peer-reviewed journals, we also searched the American Society of Clinical Oncology and European Society for Medical Oncology congress websites for publications between Sept 1, 2018, and Dec 1, 2020, using the same key words. Our search identified 259 abstracts, from which we selected primary publications from randomised phase 3 studies of programmed cell death (PD)-1 or PD-ligand 1 (PD-L1) inhibitors in previously untreated patients with advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. Using these criteria, four studies with efficacy and safety data were identified: ATTRACTION-4, KEYNOTE-062, KEYNOTE-590, and JAVELIN Gastric 100. In the phase 3 ATTRACTION-4 study of previously untreated Asian patients with advanced gastric cancer or gastro-oesophageal junction cancer, nivolumab plus chemotherapy significantly improved progression-free survival (PFS) but not overall survival (OS) in the all-randomised population with a manageable safety profile. Similarly, in the global, phase 3 KEYNOTE-062 study, which enrolled patients whose tumours expressed PD-L1 with a combined positive score (CPS) of one or more, pembrolizumab plus chemotherapy did not provide superior OS benefit but provided a modest improvement in PFS and objective response with a manageable safety profile in patients with advanced or recurrent gastric cancer or gastro-oesophageal junction cancer expressing PD-L1 with a CPS of one or more or ten or more. In the phase 3 KEYNOTE-590 study of oesophageal cancer or gastro-oesophageal junction cancer (mainly squamous cell carcinoma histology), first-line pembrolizumab plus chemotherapy provided improved OS and PFS in advanced unresectable or metastatic gastro-oesophageal junction (Siewert type 1) or oesophageal adenocarcinoma in a subgroup analysis with a manageable safety profile. In the phase 3 JAVELIN Gastric 100 study of advanced gastric cancer and gastro-oesophageal junction cancer, avelumab maintenance after first-line chemotherapy did not show superior OS versus continued chemotherapy in the primary population of all randomly assigned patients or in patients with tumour cell PD-L1 expression of 1% or more.
Added value of this study
With nearly 1600 patients randomly assigned in the CheckMate 649 trial, nivolumab in combination with chemotherapy showed superior OS, along with PFS benefit, versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. To our knowledge, CheckMate 649 is the first global study to show superior OS with a median OS exceeding 1 year in the first-line setting for patients with non-human epidermal growth factor receptor 2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. The safety profile of nivolumab plus chemotherapy was consistent with the known safety profiles of the individual treatment components and no new safety signals were identified. Although grade 3–4 treatment-related adverse events and events leading to discontinuation were more frequent with nivolumab plus chemotherapy versus chemotherapy alone, the safety profile was acceptable in the context of the significant improvement in OS, along with PFS benefit, improved and durable objective responses, and maintained health-related quality of life.
Implications of all the available evidence
The CheckMate 649 trial addresses an important unmet need in previously untreated patients with gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, for whom no advances have been made in the past decade. Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone; this combination is now indicated in the USA as a first-line treatment in patients with advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma.