Gastric cancer (GC), including gastroesophageal junction cancer (GEJC), is a major health problem, and better treatments are needed to improve patient outcomes. Until recently, the first-line treatment for HER2-negative GC and GEJC included combination chemotherapy (chemo); however, overall survival (OS) has remained below 1 year. Initial results from the large, global, randomized, phase III CheckMate 649 study at 12-month follow up showed that the addition of nivolumab (nivo) to XELOX or FOLFOX chemo provides clinically meaningful OS improvement and progression-free survival (PFS) benefit compared with chemo alone, along with durable responses and a manageable safety profile. These practice-changing data led to the FDA approval of nivo/chemo combination as first-line therapy for GC, GEJC, and esophageal adenocarcinoma.

At the 2021 ESMO Congress, Dr. Yelena Janjigian (Memorial Sloan Kettering Cancer Center, New York, NY, USA) presented further results from the CheckMate 649 study, including the 24-month follow-up data of the nivo/chemo combination, and first results of nivo/ipilimumab (nivo/ipi) combination vs. chemo. In total, 2031 patients were randomized to one of the three treatment arms, with fewer patients in the nivo/ipi arm since the data monitoring committee (DMC) recommended stopping enrolment due to higher toxicity and early deaths. Updated results showed a sustained improvement in median OS with nivo/chemo compared with chemo in patients with PD-L1 combined positive score (CPS) ≥5 (14.4 vs. 11.1 months; hazard ratio [HR], 0.7) and all randomized patients (13.8 vs. 11.6 months; HR, 0.79). Similarly, PFS benefit was maintained with longer follow-up: in patients with PD-L1 CPS ≥5, median PFS was 8.1 months with nivo/chemo vs. 6.1 months with chemo (HR, 0.7), and for all randomized patients, median PFS was 7.7 vs. 6.9 months (HR, 0.79), respectively. Furthermore, the overall response rate (ORR) remained higher, and the duration of responses was longer with nivo/chemo. Patients with high microsatellite instability (MSI-H) and microsatellite stable (MSS) cancers both benefited from treatment with nivo/chemo in terms of longer median OS and higher ORR; however, the magnitude of benefit was greater in MSI-H patients, with an impressive median OS of nearly 40 months.

Conversely, there was no OS benefit with nivo/ipi vs. chemo in patients with PD-L1 CPS ≥5 (11.2 vs. 11.6 months; HR, 0.89; P=0.2302). In addition, no PFS benefit was seen with this combination. Although ORR was lower with nivo/ipi than with chemo (27% vs. 47%), those patients who did respond had a longer duration of response. Nivo/ipi also showed efficacy in patients with MSI-H tumors (median OS not reached vs. 10 months with chemo), but the number of patients was low. There were no new safety signals identified in either treatment arm. Serious treatment-related adverse events (TRAEs) were highest with the nivo/ipi combination (23%). Grade 3-4 of potentially immune-mediated AEs occurred in ≤5% of patients with nivo/chemo and ≤12% of patients with nivo/ipi.

Dr. Janjigian concluded that the longer follow-up data for the nivo/chemo combination further support its use as a new standard first-line therapy in patients with advanced GC/GEJC/esophageal adenocarcinoma. A discussant of the trial, Dr. Florian Lordick (University Cancer Center Leipzig, Leipzig, Germany), called the results “a big step forward in gastric cancer therapy.” He highlighted the survival differences between patients with PD-L1 CPS ≥5 compared with PD-L1 CPS <5. His take-home message was that “nivolumab in combination with fluoropyrimidine- and platinum-based combination chemo should be the new standard of care for the first-line treatment of patients with HER2-negative advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma whose tumors express PD-L1 with a CPS ≥5.”

Reference:
Janjigian Y, et al. ESMO 2021; Abstract LBA7