Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with <i>EGFR</i>-Mutant Lung Cancers.

Abstract

Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. We identified all patients with metastatic <i>EGFR</i> exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. <i>EGFR</i> wild-type lung adenocarcinoma samples were used for comparison. Among 153 patients with <i>EGFR</i>-mutant lung cancer, TMB was lower compared with EGFR wild-type (<i>n</i> = 1,849; median 3.77 vs. 6.12 mutations/Mb; <i>P</i> < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with <i>EGFR</i>-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; <i>P</i> = 0.0008) and OS (HR, 0.40; <i>P</i> = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, <i>P</i> = 0.006; OS, <i>P</i> = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, <i>P</i> = 0.01; HR = 0.50, <i>P</i> = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; <i>P</i> = 0.008). TMB is negatively associated with clinical outcomes in metastatic patients with <i>EGFR</i>-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.<i>See related commentary by Cheng and Oxnard, p. 899</i>.