First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
Mené sur 1 581 patients atteints d'un adénocarcinome de l'oesophage, d'un cancer gastrique ou de la jonction oeso-gastrique de stade avancé ou métastatique, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout du nivolumab à une chimiothérapie de première ligne
Background : First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a medianoverall survival (OS) of less than 1 year. We aimed to evaluate first-line programmedcell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction,and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone. Methods : In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolledadults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric,gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patientswere randomly assigned (1:1:1 while all three groups were open) via interactive webresponse technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks orleucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab,or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review,in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more.Safety was assessed in all patients who received at least one dose of the assignedtreatment. This study is registered with ClinicalTrials.gov, NCT02872116. Findings : From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility,we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy[n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was13·1 months (IQR 6·7–19·1) for nivolumab plus chemotherapy and 11·1 months (5·8–16·1)for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvementsin OS (hazard ratio [HR] 0·71 [98·4% CI 0·59–0·86]; p<0·0001) and PFS (HR 0·68 [98% CI 0·56–0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPSof five or more (minimum follow-up 12·1 months). Additional results showed significantimprovement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one ormore and all randomly assigned patients. Among all treated patients, 462 (59%) of782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patientsin the chemotherapy alone group had grade 3–4 treatment-related adverse events. Themost common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea,and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab pluschemotherapy group and four (1%) deaths in the chemotherapy alone group were consideredto be treatment-related. No new safety signals were identified. Interpretation : Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefitand an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction,or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standardfirst-line treatment for these patients.
The Lancet 2021