Extended Analysis Finds Sustained Efficacy of Nivolumab Combo in GI Subtype

Results from the CheckMate 649 trial showed continued efficacy at 5 years in the nivolumab combination for patients with gastric/GEJ/esophageal cancer.

An overall survival (OS) benefit was observed with first-line nivolumab (Opdivo) plus chemotherapy compared with chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC), based on results from the 5-year follow-up data from the phase 3 CheckMate 649 trial (NCT02872116) presented at the 2025 ASCO Gastrointestinal Cancer Symposium.1

The updated results 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 progression-free survival (PFS) in this subgroup were the primary end points of the trial.

Across all patients randomized to nivolumab/chemotherapy or the control arm of 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% vs 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 ≥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 randomized 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 ≥5 subgroup was 60% in the nivolumab/chemo arm compared with 45% in the control arm. The median duration of response (mDOR) was 9.6 vs months 7.0 months, respectively. Among all patients, the ORR was 58% vs 46% and the mDOR was 8.5 vs 6.9 months, respectively.

“To our knowledge, these results represent the longest follow-up in a phase 3 trial of a programmed death-1 inhibitor plus chemo in advanced GC/GEJC/EAC, 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 April 2021, the FDA approved nivolumab for use in combination with select types of chemotherapy for 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/EAC. 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 randomized in a 1:1:1 ratio to one of the following treatment cohorts:

• Nivolumab (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 GI Symposium, Janjigian shared 5-year data for the nivolumab/chemo arm and the control arm of chemotherapy alone. Baseline characteristics between these 2 arms were well balanced. Across both arms, the median age was about 62 years, 70% of patients were male, three-quarters of patients were non-Asian, and about 58% of patients had an ECOG performance status of 1. The primary tumor location at initial diagnosis across all patients was 70% gastric cancer, about 16% GEJ, and about 14% EAC.

Around 18% of patients in each arm had signet ring cell carcinoma, 96% had metastatic disease, 40% had liver metastases, and 24% had peritoneal metastases. Sixteen percent of patients in each arm had tumor cell PD-L1 expression ≥1% and 3% had microsatellite instability high status. About 54% of patients in each arm received FOLFOX and 46% 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 the all-randomized population; OS in those with a PD-L1 CPS of 10 or higher; blinded independent central review–assessed PFS in those with a PD-L1 CPS of 10 or higher, 1 or higher, and the all-randomized population; and ORR. Safety and quality of life served as the exploratory end points of the trial. The data cutoff data for the results presented at the GI 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 count (11%), anemia (6%), and increased lipase (6%). In the chemotherapy-alone arm, the most common grade 3/4 TRAEs were neutropenia (13%), decreased neutrophil count (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. News release. FDA. April 16, 2021. Accessed January 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer