tTMB was graphed on a log 10 scale for the ROC curve. a p values were calculated using the Wald test and are one-sided for pembrolizumab-combination (a priori hypothesis that tTMB was positively associated with improved outcomes for pembrolizumab-combination) and two-sided for placebo-combination (no a priori hypothesis regarding the direction of the association between tTMB and outcomes) with significance level set at 0.05 and no multiplicity adjustment. Panels B and D provide p values for OS, PFS, and ORR in each respective study from logistic regression analysis. In panels A and C, the graph illustrates the area under the ROC curve for ORR. 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.īiomarker Metastatic non‒small-cell lung cancer Pembrolizumab Single-gene genetic alterations Tissue tumor mutational burden.Īssociation of tTMB with efficacy outcomes in ( A) and ( B) KEYNOTE-189 and ( C) and ( D) KEYNOTE-407. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. 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 and 0.64, respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74, respectively) versus placebo-combination. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.Īmong 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. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. 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. 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. 14 Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center, Universidad Complutense and Ciberonc, Madrid, Spain.13 Merck & Co., Inc., Rahway, New Jersey.12 LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.11 Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
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