Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Marina C. Garassino, Shirish Gadgeel, Silvia Novello, Balazs Halmos, Enriqueta Felip, Giovanna Speranza, Rina Hui, Edward B. Garon, Hidehito Horinouchi, Shunichi Sugawara, Delvys Rodriguez-Abreu, Martin Reck, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, Bilal Piperdi, M. Catherine PietanzaLuis Paz-Ares

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (, NCT02578680; nonsquamous) and KEYNOTE-407 (, NCT02775435; squamous) trials. Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome. Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.

Original languageEnglish (US)
Article number100431
JournalJTO Clinical and Research Reports
Issue number1
StatePublished - Jan 2023


  • Biomarker
  • Metastatic non‒small-cell lung cancer
  • Pembrolizumab
  • Single-gene genetic alterations
  • Tissue tumor mutational burden

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine


Dive into the research topics of 'Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC'. Together they form a unique fingerprint.

Cite this