Effect of Tumor Mutational Burden on Clinical Efficacy of First-Line Pembrolizumab in Advanced Gastric/GEJ Adenocarcinoma

According to an exploratory analysis of data from the KEYNOTE-062 trial, there may be an association between tumor mutational burden (TMB) and the clinical efficacy of pembrolizumab-based treatment in the first line for patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma.

The phase 3 KEYNOTE-062 trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic gastric/GEJ cancer with a programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 between September 18, 2015, and May 26, 2017. Patients were randomized in a 1:1:1 ratio to treatment with pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy plus placebo (n = 250). The primary end points were overall survival (OS) and progression-free survival (PFS) in patients with a PD-L1 CPS ≥ 1, or ≥ 10

In this exploratory analysis, those patients from the KEYNOTE-062 trial who had evaluable tumor mutational data (n = 306) were included to evaluate the association between TMB and clinical outcomes and OS. TMB was assessed using FoundationOne CDx. For assessment of TMB clinical utility, the prespecified cutoff of was 10 mutations per megabase (mut/Mb).

Of the 306 patients with TMB data available, 107 were treated with pembrolizumab, 100 were treated with pembrolizumab and chemotherapy, and 99 were treated with chemotherapy. Across all treatment groups, there was a 16% prevalence of TMB ≥ 10 mut/Mb. Of those patients with a TMB ≥ 10 mut/Mb, 44% had high microsatellite instability tumors.

There was a significant association found between TMB and clinical outcomes in those patients treated with pembrolizumab and pembrolizumab plus chemotherapy (objective response rate, PFS, and OS; P < .05). This association was not seen for patients treated with chemotherapy. In addition, there were improved clinical outcomes (objective response rate, PFS, and OS) seen in those patients treated with pembrolizumab, in both the monotherapy and pembrolizumab plus chemotherapy groups, with a TMB ≥ 10 mut/Mb.

Study authors added that when patients with high microsatellite instability tumors were excluded, “both the positive association between clinical outcomes with pembrolizumab or pembrolizumab + chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated.”

Source:

Lee KW, Van Cutsem E, Band YJ, et al. Association of tumor mutational burden with efficacy of pembrolizumab ± chemotherapy as first-line therapy for gastric cancer in the phase III KEYNOTE-062 study. Clin Cancer Res. Published online July 6, 2022. doi:10.1158/1078-0432.CCR-22-0121