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

Abstract

<h3>Introduction</h3><p>We evaluated tissue tumor mutational burden (tTMB) and mutations in <em>STK11, KEAP1,</em> and <em>KRAS</em> as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (<a href="http://clinicaltrials.gov/">ClinicalTrials.gov</a>, NCT02578680; nonsquamous) and KEYNOTE-407 (<a href="http://clinicaltrials.gov/">ClinicalTrials.gov</a>, NCT02775435; squamous) trials.</p><h3>Methods</h3><p>This retrospective exploratory analysis evaluated prevalence of high tTMB and <em>STK11, KEAP1</em>, and <em>KRAS</em> mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and <em>STK11</em>, <em>KEAP1</em>, and <em>KRAS</em> 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.</p><h3>Results</h3><p>Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, <em>n</em> = 293; KEYNOTE-407, <em>n</em> = 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 <em>p</em> > 0.05) or placebo-combination (Wald test, two-sided <em>p</em> > 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 <em>KEAP1</em>, <em>STK11,</em> or <em>KRAS</em> mutation status.</p><h3>Conclusions</h3><p>These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, <em>STK11, KEAP1,</em> or <em>KRAS</em> mutation status as a biomarker for this regimen.</p>