Nivolumab plus chemotherapy as standard first-line treatment option for patients with advanced gastric and oesophageal cancers
At ASCO GI 2022, Dr. Shitara presented expanded efficacy, safety and subgroup analyses of the randomised, phase III CheckMate 649 trial, evaluating nivolumab plus chemotherapy as a first-line treatment option for patients with advanced gastric or gastro-oesophageal junction cancer or oesophageal adenocarcinoma. With longer follow-up, nivolumab plus chemotherapy continued to demonstrate a clinically meaningful improvement in efficacy versus chemotherapy alone.
Standard first-line chemotherapy for advanced or metastatic HER2-negative gastric and gastro-oesophageal junction cancer (GC/GEJC) results in a poor median overall survival (OS) of less than one year. Nivolumab plus chemotherapy (NIVO + chemo) previously demonstrated superior OS vs. chemo in advanced GC/GEJC and oesophageal adenocarcinoma (EAC) after twelve months of minimum follow-up in CheckMate 649. Based on these results, the combination of NIVO + chemo is now approved as first-line treatment for patients with advanced GC/GEJC/EAC in many countries. At ASCO GI 2022, Dr. Shitara reported expanded analyses of NIVO + chemo vs. chemo with minimum follow-up of 24 months.
CheckMate 649 study design
In CheckMate 649, a total of 2,031 adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of PD-L1 expression. Patients with known HER2-positive status or an ECOG performance status ≥2 were excluded from the trial. Patients were randomised to receive nivolumab (360 mg Q3W) plus XELOX, or nivolumab (240 mg Q2W) plus FOLFOX (N= 789), nivolumab plus ipilimumab (N= 409), or XELOX/FOLFOX alone (N= 833). The two co-primary endpoints of the trial were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients with a PD-L1 combined positive score (CPS) of ≥ 5 for NIVO + chemo vs. chemo. Hierarchically tested secondary endpoints included OS in NIVO + chemo vs. chemo (PD-L1 CPS ≥ 1, then all randomised) and OS in NIVO + IPI vs. chemo (PD-L1 CPS ≥ 10).
Of 2,031 patients, 1,581 were randomised to NIVO + chemo or chemo and the baseline characteristics of these patients were well balanced across treatment arms. A clinically meaningful improvement in OS and PFS with NIVO + chemo vs. chemo was maintained with longer follow-up. Median OS in all randomised patients was 13.8 months with NIVO + chemo and 11.6 months with chemo alone (HR[95%CI]: 0.79[0.71-0.88]). OS favoured NIVO + chemo across key subgroups, including patients with poor prognostic factors such as high tumour burden, low albumin levels and liver metastases. When analysing the efficacy and response by PD-L1 subgroup, favourable hazard ratios for OS were maintained in all subgroups with NIVO + chemo vs. chemo. However, the OS benefit with NIVO + chemo was enriched at higher PD-L1 CPS cut-offs. Notably, the ORR was also higher across all PD-L1 subgroups. Furthermore, OS and ORR benefits were consistent with the all randomised population when excluding patients with MSI-H tumours. PFS2 (defined as time from randomisation to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy or death, whichever was earlier) favoured NIVO + chemo vs. chemo with a 25% reduction in the risk of death or disease progression on subsequent therapy (HR[95%CI]: 0.75[0.67-0.84]). The proportion of patients that was treated with any subsequent therapy was similar in both treatment arms (41% vs. 44% for NIVO + chemo and chemo alone, respectively). Finally, objective response rate was higher, responses were more durable and more deep responses were observed with NIVO + chemo vs. chemo alone, regardless of PD-L1 CPS ≥5 or <5.
No new safety signals were identified. The most common grade 3-4 treatment-related adverse events (TRAEs) in the NIVO + chemo arm included neutropenia (15%), decreased neutrophil count (11%) and anaemia (6%). The majority of the TRAEs with potential immunologic aetiology were grade 1 or 2. Grade 3 or 4 events were reported in ≤ 5% of patients with NIVO + chemo across organ categories.
With longer follow-up, nivolumab plus chemotherapy continued to demonstrate a clinically meaningful improvement in efficacy versus chemotherapy with an acceptable safety profile in patients with previously untreated advanced GC/GEJC/EAC. These data further support the use of nivolumab in combination with chemotherapy as a standard first-line treatment in this patient population.
Shitara K, Janjigian YY, Moehler MH, et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy, safety, and subgroup analyses from CheckMate 649. Presented at ASCO GI 2022; Abstract 240.