Nivolumab regimen superior to chemotherapy alone in advanced gastric, esophageal cancers
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Nivolumab plus chemotherapy increased PFS and OS compared with chemotherapy alone among previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, study results showed.
The findings of the randomized phase 3 CheckMate 649 study, presented at ESMO Virtual Congress 2020, represent a potential new standard first-line treatment option for these patients, according to researchers.
“CheckMate 649 is mainly a study of first-line therapy, because as we know, standard first-line chemotherapy for advanced or metastatic HER2-negative gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma results in poor OS, mostly less than 1 year,” Markus Moehler, MD, professor of medicine at Johannes-Gutenberg University Clinic in Germany, said during a press conference. “We have already seen data for checkpoint inhibitors in phase 2 trials, and this study is now the largest randomized, global phase 3 study of [these agents] in the first line for these patients.”
Nivolumab (Opdivo, Bristol Myers Squibb), a PD-1 inhibitor, already has been approved for renal cell carcinoma.
Researchers conducted the open-label CheckMate 649 study to compare nivolumab plus chemotherapy or nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) with chemotherapy alone among adults with advanced or metastatic HER2-negative gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, regardless of PD-L1 expression.
The current analysis includes the 1,581 patients randomly assigned to nivolumab plus chemotherapy (n = 789) or chemotherapy alone (n = 792). Patients received nivolumab at doses of 360 mg every 3 weeks or 240 mg every 2 weeks.
Moehler and colleagues reported the primary endpoints of OS at a prespecified interim analysis and PFS at final analysis of the nivolumab combination vs. chemotherapy-only groups among patients with a combined positive score (CPS) for PD-L1 tumor expression of 5 or greater.
With minimum follow-up of 12 months, patients in the combination group with a PD-L1 CPS of 5 or greater (n = 473) demonstrated significantly longer median OS (14.4 months vs. 11.1 months; HR = 0.71; 95% CI, 98.4%, 0.59-0.86) and median PFS (7.7 months vs. 6.1 months; HR = 0.68; 95% CI, 98% CI, 0.56-0.81) than patients with a PD-L1 CPS of 5 or greater who received chemotherapy alone (n = 482).
Researchers also observed significantly longer median OS with the combination among patients with a PD-L1 CPS of 1 or greater (14 months vs. 11.3 months; HR = 0.77; 99.3% CI, 0.64-0.92) and in the overall population (13.8 months vs. 11.6 months; HR = 0.8; 99.3% CI, 0.68-0.94).
No new safety signals were identified.
Among patients with a PD-L1 CPS of 5 or greater, a greater proportion in the combination group experienced treatment-related adverse events (95% vs. 88%), grade 3 to grade 4 events (59% vs. 44%), and events leading to treatment discontinuation (38% vs. 25%) or death (2% vs. < 1%)
“[This trial] achieved statistical significance for both primary endpoints and all formally tested secondary endpoints,” Moehler said. “[This combination] represents a new potential standard first-line treatment for patients with these malignancies.”
Perspective
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Syma Iqbal, MD
Two first-line, potentially practice-changing studies in advanced/metastatic esophagogastric cancer were presented at ESMO this year. For the first time in many years, therapy for advanced disease is taking a step forward and the addition of immunotherapy has made an impact on the treatment of this most difficult disease.
CheckMate 649 — the largest randomized, global phase 3 trial of a PD-1 inhibitor in the first-line setting — is evaluating chemotherapy (fluoropyrimidine/oxaliplatin) vs. chemotherapy plus nivolumab and a third arm of nivolumab with ipilimumab. Moehler and colleagues presented data on the chemotherapy-alone vs. chemotherapy-nivolumab groups.
The second trial, KEYNOTE-590, is a randomized, phase 3, double-blind, placebo-controlled study that evaluated pembrolizumab (Keytruda, Merck) plus chemotherapy (5-FU/cisplatin) vs. chemotherapy alone in advanced esophageal cancer in the first-line setting.
Both studies met their primary endpoints and provided statistically significant, clinically meaningful improvements in outcome for patients with advanced/metastatic esophagogastric cancers. These data will lead to a change in the first-line standard of care.
The nuances will be in how these combinations receive their indication. It is thought that approximately 30% to 40% patients have a PD-L1 CPS greater than 5, but the enriched population of CheckMate 649 had 60% with that level of PD-L1 expression. This may have affected the results for those subgroups evaluated, including all patients and those with a CPS greater than 1. We still need data for the third arm of the combination of nivolumab with ipilimumab.
In KEYNOTE-590, the majority of patients had squamous cell cancer, yet the overall population still achieved benefit. Further details about PD-L1 CPS are still to be presented, as well as data about the adenocarcinoma population.
Clearly, these trials will have an impact on care, but we will see how these are incorporated into practice as the only biomarker or predictor of outcome, PD-L1 CPS, is not enough. Further, these trials will affect the conduct of ongoing studies and will challenge investigators as to how to move forward. For now, this success after years of just fluoropyrimidine/platinum is welcome.
Reference:
- Kato K, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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Moehler M, et al. Abstract LBA6_PR. Presented at European Society of Medical Oncology Virtual Congress; Sept. 19-21, 2020.
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