After 3 years of follow-up, nivolumab plus chemotherapy continued to demonstrate clinically meaningful overall survival (OS) improvement in patients with unresectable advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma, with sustained separation of the Kaplan-Meier curves, higher OS rates, continued progression-free survival (PFS) benefit, and more durable responses in patients whose tumours expressed PD-L1 combined positive score (CPS) ≥5 and in the overall population.
OS benefit was also observed across subgroups, including in patients with poor prognostic factors, such as liver metastases. The magnitude of OS benefit was substantially greater in patients with microsatellite instability-high (MSI-H) tumours. CheckMate 649 has the longest follow-up data, including OS, for first-line treatment with anti–PD1 plus chemotherapy for patients with gastro-oesophageal cancer according to Dr. Yelena Y. Janjigian of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, NY, US, and colleagues who published the findings on 21 February 2024 in the JCO.
Previously at 12.1-month minimum follow-up, nivolumab plus chemotherapy demonstrated improvement in all efficacy measures, including superior OS (hazard ratio [HR] 0.71, 98.4% confidence interval [CI] 0.59 to 0.86]; p < 0.0001) and PFS by blinded independent central review (BICR; HR 0.68, 98% CI 0.56 to 0.81; p < 0.0001) versus chemotherapy in patients with PD-L1 CPS ≥5. Nivolumab plus chemotherapy also showed significant improvement in OS, along with PFS benefit versus chemotherapy in the overall population, and an acceptable safety profile.
Based on the results from the CheckMate 649, first-line nivolumab plus chemotherapy has been approved for the treatment of unresectable advanced, HER2-negative gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma in over 50 countries. Dual primary endpoints for the nivolumab plus chemotherapy versus chemotherapy arms were OS and PFS by BICR per RECIST v1.1, in patients whose tumours expressed PD-L1 CPS ≥5.
Patients with previously untreated advanced or metastatic gastro-oesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the HR for OS for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI 0.61 to 0.81) and 21% versus 10% of patients were alive at 36 months. The HR for PFS was 0.70 (95% CI 0.60 to 0.81) and 36-month PFS rates were 13% versus 8%.
The objective response rate (ORR) per BICR was 60% (95% CI 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI 40 to 50) with chemotherapy. Median duration of response was 9.6 months (95% CI 8.2 to 12.4) versus 7.0 months (95% CI 5.6 to 7.9).
Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. OS benefit was also observed across subgroups, including in patients with poor prognostic factors, such as liver metastases. The magnitude of OS benefit was substantially greater in patients with MSI-H tumours, and the survival benefit in the population with microsatellite stable tumours was consistent with the overall population.
A trend toward improved health-related quality-of-life with nivolumab plus chemotherapy versus chemotherapy alone was maintained over time. Although baseline Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) total scores were similar between the nivolumab plus chemotherapy and chemotherapy arms for patients with PD-L1 CPS ≥5 and the overall population, the least squares mean difference between treatment arms continued to favour nivolumab plus chemotherapy at most time points. FACT-Ga GP5 questionnaire results continued to indicate more patients reporting not being bothered at all or being bothered a little bit by side effects from treatment with nivolumab plus chemotherapy versus chemotherapy.
The data from this 3-year follow-up support a notion that adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.
The findings were previously presented in part at the ASCO Gastrointestinal Cancers Symposium (San Francisco, CA, US, 23-25 January 2023.
The study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company. Dako participated in collaborative development of the PD-L1 IHC 28-8 pharmDx assay.
Reference
Janjigian YY, Ajani JA, Moehler M, et al. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. JCO; Published online 21 February 2024. DOI: https://doi.org/10.1200/JCO.23.0160