2-year data confirm benefit of nivolumab regimen for advanced gastric, esophageal cancers
The addition of nivolumab to chemotherapy showed durable benefit for treatment-naive patients with advanced gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, 2-year data from the CheckMate 649 study showed.
However, results of the randomized phase 3 study showed the combination of nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) did not significantly improve survival compared with chemotherapy.
“Nivolumab plus chemotherapy continues to demonstrate clinically meaningful benefit [as first-line treatment], and it is nice to have these additional 12 months of follow-up data,” Yelena Y. Janjigian, MD, oncologist and chief of the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, said during a presidential symposium presentation at the virtual ESMO Congress. “These data have already changed practice for patients with metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.”
The CheckMate 649 study included adults with advanced or metastatic HER2-negative gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma enrolled regardless of PD-L1 expression.
In one analysis, researchers randomly assigned 1,581 patients to the anti-PD-1 antibody nivolumab plus chemotherapy (n = 789) or chemotherapy alone (n = 792). Researchers dosed nivolumab at 360 mg every 3 weeks or 240 mg every 2 weeks, and chemotherapy consisted of XELOX every 3 weeks or FOLFOX every 2 weeks.
A second analysis included 813 patients. Researchers assigned 409 of them to nivolumab plus the anti-CTLA-4 antibody ipilimumab (n = 409) or chemotherapy alone (n = 404). Patients assigned the combination received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for four doses, followed by 240 mg nivolumab every 2 weeks.
Previously reported data based on 12-month follow-up showed the addition of nivolumab to chemotherapy conferred significant OS and PFS benefits among patients with a combined positive score (CPS) of 5 or greater for PD-L1 tumor expression.
At ESMO, Janjigian reported data based on median follow-up of 24 months.
Results showed sustained improvement in OS with the addition of nivolumab to chemotherapy among patients with PD-L1 CPS of 5 or greater (median, 14.4 months vs. 11.1 months; HR = 0.7; 95% CI, 0.61-0.81), as well as among all randomly assigned patients (median, 13.8 months vs. 11.6 months; HR = 0.79; 95% CI, 0.71-0.88).
Researchers also reported a sustained PFS benefit among patients with PD-L1 CPS of 5 or greater (median, 8.1 months vs. 6.1 months; HR = 0.7; 95% CI, 0.6-0.81) and among all randomly assigned patients (median, 7.7 months vs. 6.9 months; HR = 0.79; 95% CI, 0.7-0.89).
Researchers observed no OS benefit with the nivolumab-ipilimumab combination compared with chemotherapy among patients with PD-L1 CPS of 5 or greater (median, 11.2 months vs. 11.6 months; HR = 0.89; 96.5% CI, 0.71-1.1) or all randomly assigned patients (median, 11.7 months vs. 11.8 months; HR = 0.91; 96.5% CI, 0.77-1.07). Results also showed no PFS benefit with nivolumab-ipilimumab vs. chemotherapy among patients with PD-L1 CPS of 5 or greater (median, 2.8 months vs. 6.3 months; HR = 1.42; 95% CI, 1.14-1.76) or all randomly assigned patients (median, 2.8 months vs. 7.1 months; HR = 1.66; 95% CI, 1.4-1.95).
Researchers reported no new safety signals with the nivolumab-chemotherapy and nivolumab-ipilimumab combinations.
“Longer follow-up data for nivolumab plus chemotherapy further support its use as a new standard first-line treatment [for these patient populations],” Janjigian said.
Perspective
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For more than a decade, platinum-based chemotherapy was the standard of care for patients with metastatic gastric adenocarcinoma. Median survival ranged between 9 months and 11 months. CheckMate 649 brought remarkable progress in the care of patients with HER2-negative gastric adenocarcinoma, shifting the median survival to longer than 12 months.
This abstract highlights that the survival benefit of chemotherapy plus nivolumab is sustained with longer follow-up.
However, CheckMate 649 also had a third arm, ipilimumab plus nivolumab. This arm was intended to test the efficacy of chemotherapy-free treatment for patients with advanced gastric cancer. Results revealed that ipilimumab plus nivolumab failed to improve OS or response rate compared with chemotherapy. It is important to point out that the combination of ipilimumab and nivolumab in this study used the higher dose of ipilimumab (3 mg/kg), which is known to be associated with higher toxicity than the “flip dose” ipilimumab-nivolumab. Interestingly, the percentage of patients who experienced treatment-related adverse events in the ipilimumab-nivolumab arm is lower than in the chemotherapy and chemotherapy-nivolumab arms (80% vs. 95% vs. 90%, respectively). Therefore, lack of benefit in the chemotherapy-free arm (ipilimumab-nivolumab) is unlikely to be due to toxicity and signifies the vital role of chemotherapy for gastric cancer. Conversely, lack of benefit from ipilimumab-nivolumab and the added benefit of nivolumab with chemotherapy confirms that gastric adenocarcinoma is only modestly immune-sensitive and requires the contribution of other therapeutic interventions to control the disease.
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