Adding Opdivo (nivolumab) to standard first-line chemotherapy significantly extends overall survival and delays disease progression or death in adults with inoperable advanced HER2-negative stomach cancer, esophageal adenocarcinoma, or gastroesophageal junction (GEJ) cancer, compared with chemotherapy alone, according to interim data from the CheckMate-649 Phase 3 trial.
Notably, survival benefits were seen across several patient groups, regardless of the PD-L1 levels — the amount of the PDL1 protein on cancer cells — in their tumors.
Bristol Myers Squibb’s Opdivo is the first PD-1 immune checkpoint inhibitor that, when combined with chemo, improves overall survival and delays disease progression in patients with these types of stomach and esophageal cancers.
“CheckMate-649 recently became the first global study in over a decade to demonstrate a significant overall survival benefit over chemotherapy in the first-line setting of non-HER2 positive gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, highlighting the potential of Opdivo plus chemotherapy to become a new standard of care for these patients, regardless of their tumor location,” Ian M. Waxman, MD, Bristol Myers Squibb’s development lead of gastrointestinal cancers, said in a press release.
These data “will be discussed with global health authorities as we strive to bring this important new treatment option to patients in need,” Waxman added.
The findings were presented in “Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study,” a presentation given at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, held recently online.
Chemotherapy is the current first-line standard of care for people with these advanced, HER2-negative, upper gastrointestinal cancers.
“While it has been an important treatment option for these patients, chemotherapy alone is associated with a marginal survival benefit of often less than one year from the time a patient’s treatment is initiated,” said Markus Moehler, MD, who presented the data.
“Innovative treatments are urgently needed,” for these patients “as there are currently no approved immunotherapy options in the first-line setting,” added Moehler, also a professor of gastrointestinal oncology at Johannes-Gutenberg University Medical Center, in Germany.
Opdivo works by blocking the interaction between the PD-1 receptor in T-cells and its ligand PD-L1 in cancer cells, a mechanism commonly used by the cancer cells to evade immune attacks. By preventing this interaction, Opdivo boosts anti-cancer responses and promotes cancer cell death. Tumors with high PD-L1 levels tend to respond better to Opdivo.
CheckMate-649 (NCT02872116) is the largest randomized, global Phase 3 clinical trial of a PD-1 checkpoint inhibitor therapy in the first-line setting of people with stomach and esophageal cancers conducted to date.
It was designed to compare the benefits of Opdivo, in combination with either Yervoy (ipilimumab) or chemotherapy, against chemotherapy alone in some 2,000 adults with inoperable, advanced or metastatic, HER2-negative stomach cancer, esophageal adenocarcinoma, or GEJ cancer.
Yervoy, also marketed by Bristol-Myers Squibb, is an immune checkpoint inhibitor that targets CTLA-4, a protein involved in another immune evasion mechanism.
The trial’s main goals are to assess whether combining Opdivo with chemo was superior to chemotherapy alone at prolonging overall and progression-free survival in patients whose tumors showed at least moderate PD-L1 levels — or who showed PD-L1 production in at least 5% of cells in their tumors.
A total of 1,581 patients, including 955 (60%) with at least moderate PD-L1 levels, were randomly assigned to receive either a combination of Opdivo and chemotherapy, or chemotherapy alone, for two years or until disease progression or unacceptable toxicity.
Opdivo was given at a dose of either 240 mg every two weeks or 360 mg every three weeks, consistent with the chemotherapy regimen — FOLFOX every two weeks or XELOX every three weeks.
At a minimum follow-up of one year, results showed that adding Opdivo to chemotherapy significantly lowered the risk of death by 29% and the risk of disease progression or death by 32% in patients with moderate or higher PD-L1 levels, meeting both of the trial’s main goals.
In particular, the combination therapy prolonged the lives of these patients from a median of 11.1 months to 14.4 months, and the time they lived without signs of disease progression from 6.1 to 7.7 months.
Notably, the Opdivo combo also significantly reduced the risk of death among participants whose tumors produced any level of PD-L1 (by 23%) and among all treated patients, regardless of their PD-L1 status (by 20%)
The safety profile of the combination treatment was consistent with the known profiles of each therapy, with no new safety concerns identified.
A modestly greater proportion of patients treated with the Opdivo combo reported serious treatment-related adverse events (22% vs. 12% in the chemotherapy group), and more of those discontinued treatment due to such adverse events (36% vs. 24%).
