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

Open AccessPublished:November 08, 2022DOI:
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      We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab-combination for NSCLC among patients in the phase 3 KEYNOTE-189 (, NCT02578680; nonsquamous) and KEYNOTE-407 (, NCT02775435; squamous) trials.


      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 (WES) in patients with available tumor and matched normal DNA. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.


      Among patients with evaluable data from WES 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 (PFS) 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 ≥175 compared with tTMB <175 mutations/exome in KEYNOTE-189 (OS, HR: 0.64 [95% CI, 0.38‒1.07] and 0.64 [95% CI, 0.42‒0.97], respectively) and KEYNOTE-407 (OS, HR: 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.


      These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest utility for tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.



      AUC (area under the concentration‒time curve), AUROC (area under the receiver operating characteristic), CTLA-4 (cytotoxic T lymphocyte antigen 4), GEP (gene expression profile), HR (hazard ratio), ICI (immune checkpoint inhibitors), NSCLC (non‒small-cell lung cancer), OS (overall survival), ORR (objective response rate), PD-(L)1 (programmed death (ligand) 1), PFS (progression-free survival), TPS (tumor proportion score), tTMB (tissue tumor mutational burden), WES (whole-exome sequencing)