Gastrointestinal Cancers Exhibit Clear Benefit With Addition of Nivolumab to Chemotherapy, Regardless of TMB Status

Results of CheckMate 649 trial show consistently improved outcomes across advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma when nivolumab is administered in combination with chemotherapy.

Nivolumab (Opdivo) plus chemotherapy boosted overall survival (OS) vs chemotherapy alone in patients with advanced gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC) across all tumor mutational burden (TMB) expression levels, according to findings from the phase 3 CheckMate 649 study (NCT02872116) that were presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting.

It was noted, however, that higher degrees of benefit were observed in small population of patients with TMB-high tumors, according to Ming Lei, PhD, scientific director of Translational Medicine at Bristol Myers Squibb, who presented to data.

The median OS for all TMB evaluable patients (n = 685) was 14.3 months in those who received nivolumab plus chemotherapy vs 12.1 months for patients who received chemotherapy alone (HR, 0.79; 95% CI, 0.67-0.93). Median OS for patients who had TMB-high tumors (n = 57) favored the nivolumab combination showing 24.6 months compared with 12. 6 months with chemotherapy alone (HR, 0.48; 95% CI, 0.257-0.93). The median OS for patients with TMB-low tumors (n = 628) was 13.7 months vs 12.1 months in patients who received the nivolumab combo and chemotherapy alone, respectively (HR, 0.83; 95% CI, 0.70-0.99).

The CheckMate 649 (NCT02872116) is a randomized phase 3 study. The investigators enrolled 2031 patients with previously untreated, unresectable, advanced, or metastatic GC, GEJC, or EAC 1:1:1 to receive nivolumab treatment plus chemotherapy, administering either 360 mg or 240 mg of nivolumab, chemotherapy alone, or 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab (Yervoy) 3 times a week for 4 weeks followed by 240 mg of nivolumab twice a week. The dual primary end points were OS and progression-free survival (PFS; PD-L1 combined positive score [CPS] ≥ 5). The secondary end points were OS with PD-L1 CPS of at least 1, OS with PD-L1 CPS of at least 10, PFS with a PD-L1 CPS of at least 10, and overall response rate (ORR). The exploratory end points were safety, quality of life, and biomarkers. The minimum follow up at data cutoff was 24.0 months in the nivolumab plus chemotherapy arm.

Investigators defined tissue TMB as the total number of somatic missense mutations, assessed by whole exome sequencing of baseline tumor tissue and matching blood. TMB-high was defined as 199 mutations/exome or more. TMB-low was defined as less than 199 mutations/exome. Gene expression signatures (GES) was assessed by RNA sequencing of baseline tumor tissue.

In the all-randomized cohort (n = 1581), patients were 68% male, 40% were 65 years or older, and 76% were non-Asian in the nivolumab plus chemotherapy group, whereas patients in the chemotherapy-only group were 71% male, 38% were 65 years or older, and 76% were non-Asian. GC was the most common tumor location, appearing in 70% of both patient arms. Sixty and 61% of patients had a PD-L1 CPS of 5 or greater in the nivolumab plus chemotherapy arm and chemotherapy alone arm, respectively. A majority of patients were microsatellite stable in both arms (88% and 86%, respectively).

Lower HRs were seen with TMB-high status in the nivolumab combination in patients with PD-L1 CPS of 5 or greater and with PD-L1 CPS of less than 5. Investigators noted that this group had a small sample size and wide CIs, thus limiting this result’s interpretation.

OS benefit in patients in the nivolumab plus chemotherapy arm was observed across 4-gene inflammatory GES subgroups: all evaluable (n = 809), high (n = 270), medium (n = 269), and low (n = 270). These results were consistent in patients with PD-L1 CPS of 5 or greater and with PD-L1 CPS of less than 5.

OS also favored patients in the nivolumab plus chemotherapy arm across most stroma-related and angiogenesis GES subgroups. Investigators added that lower stroma-related and angiogenesis GES seemed to be associated with lower HRs for the nivolumab plus chemotherapy arm vs the chemotherapy-alone arm. This observation was consistent in patients with PD-L1 CPS of 5 or greater and in patients with PD-L1 CPS of less than 5.

The investigators concluded that the biomarkers reported in the exploratory analyses of this study will need to be confirmed in future studies.


Lei M. CT023 - Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 biomarker analyses. Presented at: AACR Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Accessed April 10, 2022.

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