Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study

Keun Wook Lee (Coresponding Author), Eric Van Cutsem, Yung Jue Bang, Charles S. Fuchs, Iveta Kudaba, Marcelo Garrido, Hyun Cheol Chung, Jeeyun Lee, Hugo R. Castro, Joseph Chao, Zev A. Wainberg, Z. Alexander Cao, Deepti Aurora-Garg, Julie Kobie, Razvan Cristescu, Pooja Bhagia, Sukrut Shah, Josep Tabernero, Kohei Shitara, Lucjan Wyrwicz

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab-chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+ chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non-MSI-H subgroup, 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. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with firstline pembrolizumab-based therapy in patients with advanced gastric/ gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.

Original languageEnglish
Pages (from-to)3489-3498
Number of pages10
JournalClinical Cancer Research
Issue number16
Publication statusPublished - 15 Aug 2022
Externally publishedYes

Field of Science*

  • 3.2 Clinical medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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