First-Line Nivolumab/Chemo Generates Long-Term Survival Benefits in Gastric/GEJ/Esophageal Cancer

Frontline nivolumab (Opdivo) in combination with chemotherapy elicited clinically meaningful long-term overall survival (OS) and progression-free survival (PFS) benefits compared with chemotherapy alone at 5 years of follow-up in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC), according to findings from the phase 3 CheckMate 649 trial (NCT02872116).1

The updated results shared during the 2025 Gastrointestinal Cancers Symposium showed that at a minimum follow-up of 60.1 months, the median OS was 14.4 months (95% CI, 13.1-16.2) with nivolumab plus chemotherapy vs 11.1 months (95% CI, 10.1-12.1) with chemotherapy alone (HR, 0.71; 95% CI, 0.61-0.81) in the subgroup of patients with a PD-L1 combined positive score (CPS) of 5 or higher. The 5-year OS rates were 16% and 6%, respectively. OS and PFS in this subgroup were the primary end points of the trial.

Across all patients randomly assigned to nivolumab plus chemotherapy or chemotherapy alone, the median OS at 5 years was 13.7 months (95% CI, 12.4-14.5) vs 11.6 months (95% CI, 10.9-12.5), respectively (HR, 0.79; 95% CI, 0.71-0.88). The 5-year OS rates across all patients were 12% and 6%, respectively.

The progression-free survival (PFS) benefit previously reported with the addition of nivolumab to chemotherapy was also maintained with longer follow-up. Among patients with a PD-L1 CPS of at least 5, the median PFS at 5 years was 8.3 months (95% CI, 7.0-9.4) in the investigative arm vs 6.1 months (95% CI, 5.6-6.9) in the control arm (HR, 0.71; 95% CI, 0.61-0.82). Across all randomly assigned patients, the 5-year median PFS was 7.8 months (95% CI, 7.1-8.6) vs 6.9 months (95% CI, 6.7-7.2), respectively (HR, 0.79; 95% CI, 0.71-0.89).

Five-year response data highlighted the durability of the clinically meaningful activity of the nivolumab combination in this frontline setting. The objective response rate (ORR) in the CPS of at least 5 subgroup was 60% in the nivolumab plus chemotherapy arm compared with 45% in the control arm. The median duration of response (DOR) was 9.6 vs months 7.0 months, respectively. Among all patients, the ORR was 58% vs 46%, respectively, and the median DOR was 8.5 months vs 6.9 months, respectively.

“To our knowledge, these results represent the longest follow-up in a phase 3 trial of a PD-1 inhibitor plus chemo in advanced gastric cancer/GEJ cancer/ esophageal adenocarcinoma and continue to support nivolumab plus chemotherapy as standard first-line treatment,” said presenting author Yelena Y. Janjigian, MD, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.

In April 2021, the FDA approved nivolumab for use in combination with select types of chemotherapy in the frontline treatment of this patient population based on earlier findings from CheckMate 649.2

About the CheckMate 649 Trial

The open-label, randomized, global phase 3 CheckMate 649 trial enrolled patients with previously untreated, unresectable, advanced or metastatic gastric cancer/GEJ cancer/ esophageal adenocarcinoma. Eligible patients had no known HER2 positivity and an ECOG performance status of 0 or 1.

Study enrollment occurred at 175 hospitals and cancer centers across 29 countries. Patients were randomly assigned in a 1:1:1 ratio to receive 1 of the following treatment cohorts:

• Nivolumab at 360 mg plus oxaliplatin at 130 mg/m2 on day 1 and capecitabine at 1000 mg/m2 twice daily from days 1 to 14 (XELOX regimen) every 3 weeks or nivolumab at 240 mg plus oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, and fluorouracil (FU) at 400 mg/m2 on day 1 and FU at 1200 mg/m2 daily on days 1 and 2 (FOLFOX regimen) every 2 weeks (n = 789)
• XELOX every 3 weeks or FOLFOX every 2 weeks (control arm; n = 833)
• Nivolumab at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at 240 mg every 2 weeks (n = 409)

At the 2025 Gastrointestinal Cancers Symposium, Janjigian shared 5-year data for the nivolumab plus chemotherapy arm and the control arm of chemotherapy alone. Baseline characteristics between these 2 arms were well balanced. Among patients in the nivolumab arm, the median age was 62 years (range, 18-88), 68% were male, 77% were not Asian, and 58% had an ECOG performance status of 1. The primary tumor location at initial diagnosis across all patients in this arm was gastric cancer (70%), GEJ cancer (17%), and esophageal adenocarcinoma (13%).

Among patients in the control arm, the median age was 61 years (range, 21-90), 71% were male, 78% were not Asian, and 57% had an ECOG performance status of 1. The primary tumor location at initial diagnosis across all patients in this arm was gastric cancer (70%), GEJ cancer (16%), and esophageal adenocarcinoma (14%).

This study also enrolled patients with signet ring cell carcinoma (nivolumab arm, 18%; control arm, 17%), metastatic disease (96%; 95%), liver metastases (38%; 40%), peritoneal metastases (24%; 24%), tumor cell PD-L1 expression of at least 1% (16%; 16%), and microsatellite instability–high status (3%; 3%). During the study, 54% and 53% of patients in these respective arms received FOLFOX, and 46% and 47% of patients in these respective arms received XELOX.

The dual primary end points were OS and PFS in the subset of patients with a PD-L1 CPS of 5 or higher. Secondary end points comprised OS in those with a PD-L1 CPS of 1 or higher and in the all-randomized population; OS in patients with a PD-L1 CPS of 10 or higher; blinded independent central review–assessed PFS in patients with a PD-L1 CPS of 10 or higher, 1 or higher, and in the all-randomized population; and ORR. Safety and quality of life served as exploratory end points of the trial. The data cutoff date for the results presented at the 2025 Gastrointestinal Cancers Symposium was May 28, 2024.

There were no new safety signals observed with the extended follow-up, according to Janjigian. The most common grade 3/4 treatment-related adverse events (TRAEs) in the nivolumab plus chemotherapy arm were neutropenia (16%), decreased neutrophil counts (11%), anemia (6%), and increased lipase levels (6%). In the chemotherapy-alone arm, the most common grade 3/4 TRAEs were neutropenia (13%), decreased neutrophil counts (9%), diarrhea (3%), peripheral neuropathy (3%), anemia (3%), and vomiting (3%).

References

1. Janjigian Y, Moehler M, Ajani J, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649. J Clin Oncol. 2025;43(suppl 4):398. doi:10.1200/JCO.2025.43.4_suppl.398
2. FDA approves first immunotherapy for initial treatment of gastric cancer. FDA. April 16, 2021. Accessed January 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer