Phase 3 CheckMate-649 Study Sees Promising Survival Benefit with Frontline Nivolumab, Chemo Combo

September 22, 2020

The combination of nivolumab (Opdivo) and chemotherapy led to a statistically significant survival benefit among previously untreated patients with PD-L1–positive advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

The phase 3 CheckMate-649 study demonstrated that first-line treatment with the combination of nivolumab (Opdivo) and chemotherapy led to a statistically significant survival benefit among previously untreated patients with PD-L1–positive advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC) versus chemotherapy alone.

Presented during the 2020 ESMO Virtual Congress, the study indicated that at a minimum follow-up of 12 months, the median overall survival (OS) was 14.4 months with nivolumab plus chemotherapy (95% CI, 13.1-16.2) versus 11.1 months with chemotherapy alone (95% CI, 10-12.1) in patients with a PD-L1 combined positive score (CPS) of 5 or greater (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001), translating to a 29% reduction in the risk of death with the combination.

Additionally, in this population, the combination led to a 32% reduction in the risk of disease progression or death compared with chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.81; < .0001).

“In the first-line therapy of patients with metastatic gastric cancer or GEJ cancer, [standard treatment] is chemotherapy with mostly a doublet consisting of fluoropyrimidine and platinum,” said Salah-Eddin Al-Batran, MD, director of the Institute of Clinical Cancer Research in Frankfurt, Germany, during a press conference ahead of the Congress. “For [EAC], the treatment is similar, but options are even [more limited]. The prognosis is poor, and median survival is below 12 months in most [cases].”

In the trial, a total of 1,581 patients were randomized 1:1 to receive 360 mg of nivolumab plus XELOX every 3 weeks or 240 mg of nivolumab plus FOLFOX every 2 weeks (n = 789) versus XELOX or FOLFOX alone (n = 792). A total of 60% of patients had a PD-L1 CPS of 5 or greater.

OS and progression-free survival served as dual primary end points of the trial. Secondary end points consisted of OS in all randomized patients and those with a PD-L1 CPS of 1 or greater.

In patients with a PD-L1 CPS of 1 or greater, the median OS was 14 months with the combination (95% CI, 12.6-15) versus 11.3 months with chemotherapy alone (95% CI, 10.6-12.3; HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001).

Among all randomized patients, the median OS was 13.8 months (95% CI, 12.6-14.6) versus 11.6 months (95% CI, 10.9-12.5), respectively (HR, 0.80; 99.3% CI, 0.68-0.94; P = .0002).

Regarding safety, nivolumab plus chemotherapy elicited an expected toxicity profile, and no new safety signals were reported. Among patients with a PD-L1 CPS of 5 or greater, any-grade treatment-related adverse effects (TRAEs) occurred in 95% of patients treated with nivolumab plus chemotherapy (n = 468) versus 88% of patients treated with chemotherapy alone (n = 465). Grade 3 or 4 TRAEs were observed in 59% and 44% of patients, respectively.

Additionally, 38% of patients discontinued the combination due to TRAEs versus 25% of patients treated with chemotherapy alone.

In the combination arm, 8 patients died due to treatment-related toxicity compared with 4 patients in the chemotherapy-alone arm.

“I believe that nivolumab plus chemotherapy will represent a new potential standard first-line treatment for patients with advanced gastric cancer, GEJ cancer, and EAC,” said Markus Moehler, MD, PhD, lead study author and head of Gastrointestinal Oncology at the Mainz University Clinic in Mainz, Germany, during the press conference. “In contrast to earlier studies with other checkpoint inhibitors, we see that the [survival] curves do not cross, and there is a clear separation of the curves [after 1 year].”

An additional arm of the study evaluating the combination of nivolumab plus ipilimumab (Yervoy) will be reported at an upcoming medical meeting.

Reference:

Moehler M. Shitara K, Garrido M, et al. 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. Ann Oncol. 2020;31(4). Abstract: LBA6_PR.