JTO Clinical and Research Reports (Jan 2023)

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

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

Journal volume & issue
Vol. 4, no. 1
p. 100431

Abstract

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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 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, 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.

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