The CheckMate 649 trial found that nivolumab plus chemotherapy lead to a median OS of 14.3 months vs 10.3 months for chemotherapy alone in several gastrointestinal cancers.
Results from the CheckMate 649 trial (NCT02872116) demonstrated that nivolumab (Opdivo) plus chemotherapy elicited a notable, long-term increase to overall survival (OS) when compared with chemotherapy alone in the first-line treatment of Chinese patients with gastroesophageal junction (GEJ) cancer, advanced gastric cancer, or esophageal adenocarcinoma.1
Updated data presented at the 2025 Gastrointestinal Cancers Symposium demonstrated that, at a minimum follow-up of 61.2 months for the Chinese population treated during the study, nivolumab plus chemotherapy (n = 99) generated a median OS of 14.3 months (95% CI, 11.5-16.5) compared with 10.3 months (95% CI, 8.1-12.1) for chemotherapy alone (n = 109; HR, 0.63; 95% CI, 0.46-0.85). The 60-month OS rates were 20% and 7%, respectively.
Among patients with a PD-L1 combined positive score (CPS) of at least 5, those in the nivolumab arm (n = 75) achieved a median OS of 15.5 months (95% CI, 11.9-21.1) vs 9.6 months (95% CI, 8.09-12.1) for patients in the chemotherapy arm (n = 81; HR, 0.57; 95% CI, 0.40-0.82). The respective 60-month OS rates were 24% and 8%.
The OS benefit with nivolumab plus chemotherapy was consistent across prespecified subgroups in the Chinese population.
In the overall population, the median progression-free survival (PFS) was 8.3 months (95% CI, 6.2-12.4) for the nivolumab arm vs 5.6 months (95% CI, 4.2-6.8) for the chemotherapy alone arm (HR, 0.57; 95% CI, 0.41-0.80). In the population with a PD-L1 CPS of at least 5, the median PFS was 8.5 months (95% CI, 6.0-14.0) and 4.3 months (95% CI, 4.1-6.5) for nivolumab plus chemotherapy and chemotherapy alone, respectively (HR, 0.51; 95% CI, 0.34-0.76).
“These extended follow-up results align with the overall CheckMate 649 trial population, reinforcing nivolumab plus chemotherapy as the standard first-line treatment for Chinese patients with advanced gastric cancer, GEJ cancer, [or] esophageal adenocarcinoma,” lead study author Lin Shen, MD, and colleagues wrote in a poster presentation of the data.
Shen is vice president of Clinical Oncology at Beijing Cancer Hospital and Peking University, as well as deputy director at Beijing Institute for Cancer Research in China.
In April 2021, the FDA approved nivolumab combined with select types of chemotherapy for the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, based on prior data from CheckMate 649.2
CheckMate 649 Overview
The randomized, open-label, global phase 3 study enrolled patients with previously untreated, unresectable, advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma.1 Patients were not permitted to have HER2-positive disease, and an ECOG performance status of 0 to 1 was required.
Patients were randomly assigned in a 1:1:1 fashion. In the first experimental arm, patients received nivolumab at 360 mg in combination with XELOX (oxaliplatin and capecitabine) once every 3 weeks; or nivolumab at 240 mg plus FOLFOX (oxaliplatin, leucovorin, and fludarabine) once every 2 weeks. In the control arm, patients received chemotherapy alone in the form of XELOX once every 3 weeks or FOLFOX once every 2 weeks. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or end of study.
The study also included a second experimental arm where patients received nivolumab at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg once every 3 weeks for 4 cycles, followed by nivolumab alone at 240 mg once every 2 weeks.
Stratification factors included PD-L1 expression (≥1% vs <1%), region (Asia vs United States/Canada vs rest of world), ECOG performance status (0 vs 1), and chemotherapy regimen (XELOX vs FOLFOX).
Blinded independent central review–assessed PFS and OS in the population of patients with a PD-L1 CPS of at least 5 served as the trial’s dual primary end points. Secondary end points included OS and PFS in the overall population, the population of patients with a PD-L1 CPS of at least 1, and the population of patients with a PD-L1 CPS of at least 10; and overall response rate (ORR).
Baseline Characteristics for the Chinese Population
Shen and colleagues noted that the baseline characteristics for Chinese patients enrolled on the study were balanced across the nivolumab plus chemotherapy and chemotherapy arms.
Among patients with a PD-L1 CPS of at least 5, the median age was 61 years (range, 23-77) in the nivolumab arm vs 60 years (range, 29-85) in the chemotherapy alone arm. The majority of patients were male (nivolumab arm, 64%; chemotherapy alone arm, 70%), had an ECOG performance status of 1 (76%; 70%), had gastric cancer (89%; 86%), had a tumor cell PD-L1 expression of less than 1% (77%; 73%), had metastatic disease (99%; 99%), had at least 2 organs with metastases (84%; 84%), and had micro satellite stable disease (100%; 98%). Liver metastases were reported at baseline in 55% of patients in the nivolumab arm vs 48% of patients in the control arm. The rates of peritoneal metastases at baseline were 15% and 12%, respectively.
In the nivolumab arm, 15% of patients received FOLFOX, and 85% were given XELOX. These rates were 13% and 87%, respectively, in the control arm.
At the May 28, 2024, data cutoff, no Chinese patients in either arm were ongoing study treatment. Fifty-four percent of patients in the nivolumab arm received subsequent therapy compared with 61% of patients in the chemotherapy alone arm; chemotherapy was the most common subsequent therapy for both groups. Five percent of patients in the experimental arm received subsequent immunotherapy vs 10% of patients in the chemotherapy alone arm.
Additional Efficacy and Safety Data for the Chinese Population
In the overall population, the ORR was 66% (95% CI, 55%-76%) in the nivolumab arm vs 45% (95% CI, 35%-56%) in the chemotherapy alone arm. In the experimental arm, the complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 17%, 49%, 25%, and 9%, respectively. These respective rates were 8%, 37%, 30%, and 14% in the control arm.
The median duration of response (DOR) in the overall population was 12.5 months (95% CI, 7.2-17.7) for the nivolumab arm vs 5.6 months (95% CI, 4.4-8.3) for the chemotherapy alone arm.
In the PD-L1 CPS of at least 5 population, the ORR was 68% (95% CI, 56%-79%) in the nivolumab arm vs 48% (95% CI, 36%-60%) in the chemotherapy alone arm. The respective CR, PR, SD, and PD in the nivolumab arm were 19%, 49%, 23%, and 9%. These respective rates were 11%, 37%, 25%, and 17% in the control arm. The median DOR in this population was 12.5 months (95% CI, 7.2-23.4) and 6.9 months (95% CI, 3.9-8.5) for the experimental and control arms, respectively.
The OS, PFS, and ORR benefits with the nivolumab regimen were consistent across different PD-L1 CPS subgroups.
Among all randomly assigned patients in the experimental arm, patients who responded to nivolumab plus chemotherapy (n = 49) experienced a median OS of 21.5 months (95% CI, 15.3-38.7) compared with 9.0 months (95% CI, 7.6-14.0) for those who had SD or PD (n = 33; HR, 0.36; 95% CI, 0.22-0.58). In the chemotherapy arm, responders (n = 42) achieved a median OS of 14.5 months (95% CI, 11.2-21.3) vs 9.1 months (95% CI, 6.5-12.0) for non-responders (n = 34; HR, 0.42; 95% CI, 0.26-0.69).
In the population of patients with a PD-L1 CPS of at least 5, those who responded to nivolumab plus chemotherapy (n = 40) had a median OS of 23.3 months (95% CI, 14.3-41.9) vs 11.5 months (95% CI, 7.5-15.6) for those who did not respond to the experimental regimen (n = 23; HR, 0.40; 95% CI, 0.23-0.71). In the chemotherapy arm, the median OS was 13.1 months (95% CI, 9.0-21.3) for responders (n = 33) vs 9.1 months (95% CI, 6.5-12.1) for non-responders (n = 22; HR, 0.41; 95% CI, 0.22-0.74).
No new safety signals with nivolumab plus chemotherapy were reported with longer-term follow-up. Any-grade treatment-related adverse effects (TRAEs) occurred in 99% of patients in the nivolumab arm vs 94% of patients in the control arm. The rates of grade 3/4 TRAEs were 66% and 50%, respectively. Serious any-grade TRAEs were reported in 26% of patients in the experimental arm vs 13% of patients in the chemotherapy alone arm. The respective rates of grade 3/4 serious TRAEs were 19% and 10%.
The most common grade 3/4 TRAEs reported in the nivolumab arm included decreased neutrophil count (17%), decreased platelet count (7%), thrombocytopenia (7%), decreased white blood cell count (6%), anemia (6%), and neutropenia (6%).
In the chemotherapy alone arm, the most frequent grade 3/4 TRAEs comprised decreased platelet count (11%), decreased neutrophil count (11%), neutropenia (8%), and vomiting (5%).
TRAEs led to treatment discontinuation in 51% of patients in the nivolumab arm vs 26% of patients in the chemotherapy alone arm. Four treatment-related deaths (4%) were reported in the experimental arm vs 1 treatment-related death (1%) in the control arm.
Notably, grade 3/4 TRAEs with potential immunologic etiology occurred in no more than 7% of Chinese patients in the nivolumab plus chemotherapy arm across organ categories; no grade 5 events occurred in either arm.