Various Mechanisms May Inform Nivolumab Use in Gastroesophageal Cancer

Nivolumab-based therapies showed improved efficacy vs chemotherapy in hypermutated and Epstein-Barr virus–positive gastroesophageal tumors.

The decision to treat patients with nivolumab (Opdivo)-based therapies vs chemotherapy alone in patients with gastroesophageal cancer may be informed by anti–PD-1 and anti–CTLA-4 mechanisms, according to results from an exploratory analysis of the phase 3 CheckMate 649 trial (NCT02872116) published in Nature Medicine.¹

Among patients eligible for whole-exome sequencing (WES; n = 889); 5% had Epstein-Barr virus (EBV)–positive disease, 60% had a high chromosomal instability score and were classified as chromosomally instable (CIN), 31% had a low chromosomal instability score and classified as genomically stable (GS), and 5% had high total mutational burden (TMB) and were classified as hypermutated.

The hypermutated subtype saw the greatest overall survival (OS) benefit with nivolumab-based regimens vs chemotherapy (nivolumab/chemotherapy; HR, 0.37; 95% CI, 0.15-0.90; nivolumab/ipilimumab [Yervoy]; HR, 0.27; 95% CI, 0.07-1.06). Additionally, benefit was observed with nivolumab/chemotherapy vs chemotherapy alone in those with EBV (HR, 0.61; 95% CI, 0.26-1.45) and GS (HR, 0.70; 95% CI, 0.52-0.94) subtypes; a lesser benefit was reported in those with the CIN subtype (HR, 0.92; 95% CI, 0.74-1.13).

Additionally, an HR of 0.81 (95% CI, 0.61-1.08) was observed in the CIN subtype with nivolumab/ipilimumab vs chemotherapy alone. The HRs in the EBV and GS subtypes were 0.76 (95% CI, 0.22-2.64) and 1.01 (95% CI, 0.70-1.46), respectively.

Furthermore, among WES-evaluable patients treated with nivolumab/chemotherapy, 8% were identified as TMB-high. In the TMB-high tumor subtype group, the benefit with nivolumab/chemotherapy vs chemotherapy alone was higher (HR, 0.48; 95% CI, 0.25-0.91) compared with the TMB-low tumor subtype group (HR, 0.85; 95% CI, 0.72-1.00). Additionally, in those treated with nivolumab/ipilimumab, an OS benefit was in the TMB-high subtype (HR, 0.31; 955 CI, 0.10-0.95).

An enriched OS benefit was observed in patients receiving nivolumab/chemotherapy with microsatellite instability–high (MSI-H) tumors as well (HR, 0.34; 95% CI, 0.16-0.74); this benefit was further observed with nivolumab/ipilimumab (HR, 0.28; 95% CI, 0.08-0.92). Additionally, compared with the overall population (HR, 0.69; 95% CI, 0.60-0.79), patients with microsatellite stable (MSS) tumors had a similar OS benefit (HR, 0.79; 95% CI, 0.71-0.89).

“This exploratory biomarker analysis from the CheckMate 649 study identified patient populations with gastric, gastroesophageal junction and esophageal adenocarcinoma that seem to derive greater OS benefit from first-line nivolumab/chemotherapy or potential benefit from nivolumab/ipilimumab vs chemotherapy,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, wrote in the publication with study coinvestigators.¹ “The pattern of biomarkers identified in this analysis suggests a role for overlapping (anti–PD-1) and distinct (anti–CTLA-4) mechanisms from these immunotherapy regimens. Additional prospective clinical studies are needed to determine if these predictive biomarkers hold clinical utility for treatment selection.”

Patients in the phase 3 trial were randomly assigned 1:1:1 to receive nivolumab/chemotherapy (n = 789), nivolumab/ipilimumab (n = 409), or chemotherapy alone (n = 833).² Treatment in the chemotherapy only arm consisted of 130 mg/m² of oxaliplatin on day 1 and 1000 mg/m² of capecitabine twice daily from days 1 to 14 (XELOX) every 3 weeks or 85 mg/m² of oxaliplatin, 400 mg/m² of leucovorin, and 400 mg/m² of fluorouracil (FU) on day 1 and 1200 mg/m² of FU daily on days 1 and 2 (FOLFOX) every 2 weeks.

Treatment in the nivolumab/chemotherapy arm consisted of either 360 mg of nivolumab plus the same XELOX regimen every 3 weeks or 240 mg of nivolumab plus the same FOLFOX regimen every 2 weeks. Patients in the nivolumab/ipilimumab arm received 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles followed by 240 mg of maintenance nivolumab every 2 weeks.

Baseline tumor tissue and matched whole-blood samples were processed and underwent next-generation sequencing, with further sequence alignment and variant calling performed. Paired reads were aligned to the reference genome and sorted. PD-L1 expression was assessed at baseline via fresh biopsy specimens or archival tumor tissue, and TMB was assessed in patients with sufficient WES to pass quality control.

The dual primary end points of the study were OS and progression-free survival (PFS) in patients with a PD-L1 combined positive score (CPS) of 5 or higher. Secondary end points included OS in those with a PD-L1 CPS of 1 or higher, 10 or higher, and among all patients; blinded-independent central review-assessed PFS in the 3 previously specified groups, and ORR.

References

1. Shitara K, Janjigian YY, Ajani J, et al. Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial. Nat med. Published online March 7, 2025. doi:10.1038/s41591-025-03575-0
2. Janjigian YY, Moehler MH, Ajani JA, 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