Among patients with advanced gastric and gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma (EAC), treatment with first-line Opdivo (nivolumab) plus chemotherapy demonstrated deep responses and an overall survival (OS) benefit versus chemotherapy alone, according to 5-year follow-up data from the phase 3 CheckMate 649 trial.
The updated results shared during the 2025 ASCO Gastrointestinal (GI) Cancers Symposium showed that at a minimum follow-up of 60.1 months, the median OS was 14.4 months with Opdivo plus chemotherapy versus 11.1 months with chemotherapy alone in 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 Opdivo plus chemotherapy or the control arm of chemotherapy alone, the median OS at 5 years was 13.7 months versus 11.6 months, respectively. The 5-year OS rates across all patients were 12% versus 6%, respectively.
The PFS benefit previously reported with the addition of Opdivo to chemotherapy was also maintained with longer follow-up. Among patients with a PD-L1 CPS of 5 or greater, the median PFS at 5 years was 8.3 months in the investigative arm versus 6.1 months in the control arm. Across all randomized patients, the 5-year median PFS was 7.8 months versus 6.9 months, respectively.
Glossary:
Median duration of response (mDOR): the length of time that a patient with a disease experiences a positive response to a treatment before their disease progresses again.
Objective response rate (ORR): patients who have a partial response or complete response to the treatment within a certain period of time.
Overall survival (OS): the average length of time patients are alive after the start of treatment.
Open label: a type of research where both the participants and researchers are aware of which treatment is being administered.
PD-L1 combined positive score (CPS): a method used in cancer pathology to assess the level of PD-L1 expression on tumor cells.
Progression-free survival (PFS): the length of time during and after treatment that a patient lives with the disease but it does not get worse.
Five-year response data highlighted the durability of the clinically meaningful activity of the Opdivo combination in this frontline setting. The objective response rate (ORR) in the CPS greater than or equal to 5 subgroup was 60% in the Opdivo plus chemo arm compared with 45% in the control arm. The median duration of response (mDOR) was 9.6 versus months 7.0 months, respectively. Among all patients, the ORR was 58% versus 46% and the mDOR was 8.5 versus 6.9 months, respectively.
There were no new safety signals observed with the extended follow-up, according to Janjigian. The most common grade 3 (severe) or 4 (life-threatening) treatment-related side effects in the Opdivo 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 or 4 treatment-related side effects were neutropenia (13%), decreased neutrophil count (9%), diarrhea (3%), peripheral neuropathy (3%), anemia (3%) and vomiting (3%).
“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 and EAC and continue to support [Opdivo] plus chemotherapy as standard first-line treatment,” said presenting author Dr. Yelena Y. Janjigian, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in New York, New York.
In April 2021, the FDA approved Opdivo for use in combination with select types of chemotherapy in the frontline treatment of this patient population based on earlier findings from CheckMate 649.
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 or 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 to one of the following treatment cohorts:
- Opdivo (360 milligrams, mg) plus oxaliplatin at 130 mg per square meter (mg/m2) on day 1 and capecitabine at 1000 mg/m2 twice daily from days 1 to 14 (XELOX regimen) every three weeks or Opdivo 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 two weeks (789 patients).
- XELOX every three weeks or FOLFOX every two weeks (833 patients).
- Opdivo at 1 mg per kilogram (kg) plus Yervoy (ipilimumab) at 3 mg/kg every three weeks for 4 cycles followed by Opdivo at 240 mg every two weeks (409 patients).
At the 2025 Symposium, Janjigian shared 5-year data for the Opdivo plus chemotherapy arm and the control arm of chemotherapy alone. Baseline characteristics between these two arms were well balanced. Across both arms, the median age was approximately 62 years, 70% of patients were male, three-quarters of patients were non-Asian and approximately 58% of patients had an ECOG performance status of 1. The primary tumor location at initial diagnosis across all patients was 70% gastric cancer, 16% GEJ and 14% EAC.
Approximately 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% or greater 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 was May 28, 2024.
References:
“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.” By Dr. Janjigian Y, et al. J Clin Oncol. 2025; suppl.398
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