Nivolumab plus chemotherapy as standard first-line treatment option for patients with advanced gastric and oesophageal cancers
At ESMO 2021, Dr. Janjigian presented updated results of the randomised, phase III CheckMate 649 trial evaluating nivolumab plus chemotherapy as a first-line treatment option for patients with advanced gastric or gastro-oesophageal junction cancer or oesophageal adenocarcinoma. In addition, the first results of the nivolumab plus ipilimumab vs. chemotherapy arms of this study were discussed.
Over the past decade, chemotherapy has remained the standard of care for first-line treatment of advanced or metastatic, HER2-negative gastric cancer and gastro-oesophageal junction cancer (GC/GEJC), resulting in poor overall survival (OS). However, nivolumab plus chemotherapy (NIVO + chemo) demonstrated superior OS vs. chemo in advanced GC/GEJC and oesophageal adenocarcinoma (EAC) in the CheckMate 649 study.
CheckMate 649 study design
In CheckMate 649, a total of 2,031 adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of PD-L1 expression. Patients with known HER2-positive status were excluded and all patients had an ECOG performance status of 0 or 1. Patients were randomised to receive nivolumab (360 mg Q3W) plus chemotherapy (XELOX), or nivolumab (240 mg Q2W) plus FOLFOX (N= 789), nivolumab plus ipilimumab (N= 409), or XELOX/FOLFOX alone (N= 833). The two co-primary endpoints of the trial were overall (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients with a PD-L1 combined positive score (CPS) of ≥ 5. Hierarchically tested secondary endpoints included OS in NIVO + chemo vs. chemo (PD-L1 CPS ≥ 1, then all randomised) and OS in NIVO + IPI vs. chemo (PD-L1 CPS ≥ 5, then all randomised). At ESMO 2021, Dr. Janjigian reported longer follow-up for the nivolumab + chemotherapy (NIVO + chemo) vs. chemotherapy alone comparison as well as the first results for NIVO + IPI vs. chemo.
At the time of the analysis, the minimum follow-up was 24.0 months in the NIVO + chemo arm and 35.7 months in the NIVO + IPI arm. Baseline characteristics were balanced across the arms and consistent with the PD-L1 CPS ≥ 5 population. In total, 42% of all patients randomised to NIVO + chemo vs. chemo and 47% to NIVO + IPI vs. chemo received subsequent treatment. The predominant subsequent treatment across all arms was chemotherapy while subsequent immunotherapy was received by 2-3% of patients in the NIVO-containing arms and 9-12% in the chemo arms.
With longer follow-up, a clinically meaningful improvement in OS with NIVO + chemo vs. chemo alone was maintained. In the PD-L1 CPS ≥5 population a 30% reduction in the risk of death (HR[95%CI]: 0.70[0.61-0.81]) and a 12% improvement in 24-month OS rate was reported. In the all randomised population there was a 21% reduction in the risk of death (HR[95%CI]: 0.79[0.71-0.88]) and a 9% improvement in 24-month OS rate. Furthermore, also the PFS benefit was maintained with NIVO + chemo vs. chemo with longer follow-up in both the PD-L1 CPS ≥5 and all randomised populations. Objective response rates remained higher and responses were more durable with NIVO + chemo vs. chemo.
The hierarchically tested secondary endpoint of OS with NIVO + IPI vs. chemo in patients with PD-L1 CPS ≥5 was not met (HR[96.5%CI]: 0.89[0.71-1.10], p= 0.2302). Therefore, OS in all randomised patients was not statistically tested. In addition, no PFS benefit was observed with NIVO + IPI vs. chemo in either the PD-L1 CPS ≥5 or in all randomised population. Although response rates were lower with NIVO + IPI vs. chemo, duration of response was longer in both the PD-L1 CPS ≥ 5 and in all randomised populations. A longer median OS and higher ORR was observed in all randomised patients with MSI-H tumours with NIVO + IPI vs. chemo, although the sample size was small. Finally, no new safety signals were identified with NIVO + chemo or NIVO + IPI.
With an additional twelve months of follow-up, NIVO + chemo continued to demonstrate improvement in OS, PFS and objective responses versus chemo alone in previously untreated patients with advanced GC/GEJC/EAC. In contrast, NIVO + IPI did not significantly improve OS vs. chemo in patients with PD-L1 CPS ≥5. No new safety signals were identified with NIVO + chemo or NIVO + IPI. Longer follow-up data for NIVO + chemo further support its use as a new standard first-line treatment in patients with advanced GC/GEJC/EAC.
Janjigian YY, Ajani JA, Moehler M, et al. Nivolumab (NIVO) Plus Chemotherapy (Chemo) or Ipilimumab (IPI) vs Chemo as First-Line (1L) Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophageal Adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Study. Presented at ESMO 2021; Abstract LBA7.