Introduction: Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma are among the most aggressive malignancies, particularly in their advanced stages. The CheckMate 649 trial previously established nivolumab plus chemotherapy as a superior first-line treatment compared to chemotherapy alone. With five years of follow-up, this latest analysis provides crucial insights into long-term survival, disease progression, and safety outcomes in Chinese patients. Given that nivolumab plus chemotherapy has been approved in over 50 countries as a first-line treatment, this updated evaluation assesses whether its benefits remain sustained over time in this population.Background
The CheckMate 649 trial demonstrated a clinically meaningful improvement in survival when nivolumab was added to chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). Consistent with the broader trial population, the Chinese subgroup analysis showed significant benefits. After four years of follow-up, nivolumab plus chemotherapy continued to show a long-term survival advantage, with more durable responses compared to chemotherapy alone and no new safety signals. This five-year follow-up further evaluates efficacy and safety outcomes, focusing on overall survival (OS), progression-free survival (PFS), and subgroup outcomes based on PD-L1 expression, ECOG performance status, and baseline disease characteristics.
Methods
CheckMate 649 (NCT02872116) is a global, randomized, open-label, phase 3 trial comparing nivolumab plus chemotherapy to chemotherapy alone in patients with previously untreated advanced or metastatic GC/GEJC/EAC. Patients were randomly assigned to receive either nivolumab 360 mg every three weeks in combination with XELOX or FOLFOX chemotherapy, or chemotherapy alone. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 Combined Positive Score (CPS) ≥5. Secondary endpoints included OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, as well as the objective response rate (ORR). The study enrolled 208 Chinese patients, of whom 156 (75%) had PD-L1 CPS ≥5. Baseline characteristics were well-balanced across treatment groups. The median follow-up duration was 61.2 months, ensuring a robust long-term evaluation.
Results
The five-year follow-up confirms that nivolumab plus chemotherapy sustains a survival advantage over chemotherapy alone in Chinese patients with advanced GC/GEJC/EAC.
Overall Survival (OS)
For Chinese patients with PD-L1 CPS ≥5, the median overall survival was 15.5 months in the nivolumab plus chemotherapy arm versus 9.6 months in the chemotherapy-alone arm (HR = 0.57; 95% CI: 0.40-0.82). In all randomized Chinese patients, the median OS was 14.3 months with nivolumab plus chemotherapy versus 10.3 months with chemotherapy alone (HR = 0.63; 95% CI: 0.46-0.85). Kaplan-Meier survival curves demonstrated a clear separation favoring nivolumab, highlighting its long-term survival benefit. Progression-Free Survival (PFS) For Chinese patients with PD-L1 CPS ≥5, the median PFS was 8.5 months in the nivolumab group versus 4.3 months in the chemotherapy-alone group (HR = 0.51; 95% CI: 0.34-0.76). In all randomized Chinese patients, the median PFS was 8.3 months with nivolumab plus chemotherapy versus 5.6 months with chemotherapy alone (HR = 0.57; 95% CI: 0.41-0.80). These results confirm long-term disease control with nivolumab.
Objective Response Rate (ORR)
The ORR was significantly higher in the nivolumab plus chemotherapy group compared to chemotherapy alone. For PD-L1 CPS ≥5, the ORR was 68% with nivolumab plus chemotherapy versus 48% with chemotherapy alone. Among all randomized Chinese patients, the ORR was 66% with nivolumab plus chemotherapy versus 45% with chemotherapy alone. The median duration of response (DOR) was 12.5 months with nivolumab compared to 6.9 months with chemotherapy alone. These findings reinforce nivolumab’s role in achieving long-lasting responses.
Subgroup Analysis
The overall survival benefit was consistent across multiple predefined subgroups. Patients with higher PD-L1 CPS scores derived the greatest survival advantage. Patients with PD-L1 CPS ≥5 had the longest survival benefit (median OS = 15.5 months with nivolumab versus 9.6 months with chemotherapy, HR = 0.58). Patients with ECOG 0 had longer survival outcomes than those with ECOG 1. Liver metastases patients also benefited from nivolumab therapy. Additionally, an analysis of overall survival by best response at week 18 revealed that patients who achieved complete or partial responses (CR/PR) had significantly longer survival than those with stable or progressive disease.
Safety and Tolerability
No new safety signals emerged with long-term nivolumab treatment. The most common grade 3-4 treatment-related adverse events (TRAEs) occurred in 5% of Chinese patients. In the nivolumab plus chemotherapy group, the most frequent adverse events were neutrophil count reduction (17%), platelet reduction (7%), thrombocytopenia (7%), anemia (6%), and neutropenia (6%). In the chemotherapy-alone group, common events included platelet reduction (11%), neutropenia (8%), and vomiting (5%). Serious TRAEs occurred in 26% of nivolumab-treated patients versus 19% in the chemotherapy-alone group. Treatment-related discontinuations were slightly higher in the nivolumab arm (20%) compared to chemotherapy (11%). Treatment-related deaths were rare but observed in 4 patients in the nivolumab group versus 1 in the chemotherapy-alone group.
Conclusions
The five-year follow-up of CheckMate 649 reinforces nivolumab plus chemotherapy as the standard first-line treatment for Chinese patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma. Patients with PD-L1 CPS ≥5 derive the most significant benefits, showing prolonged overall survival, improved progression-free survival, and higher objective response rates compared to chemotherapy alone. Kaplan-Meier survival curves consistently favor nivolumab plus chemotherapy, confirming its long-term durability of response. The safety profile remains manageable, with no unexpected long-term adverse effects. These results align with previous findings, further validating nivolumab as a transformative therapy in this setting. The persistence of clinical benefits after five years of follow-up solidifies nivolumab’s role in changing the treatment paradigm for advanced GC/GEJC/EAC.
References CheckMate 649 Trial Data – ASCO Gastrointestinal Cancers Symposium 2025. Lin Shen et al. Five-Year Survival Outcomes in Chinese Patients, ASCO GI 2025.
