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Supplemental Figure 3 from Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers

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posted on 2023-03-31, 20:32 authored by Michael Offin, Hira Rizvi, Megan Tenet, Andy Ni, Francisco Sanchez-Vega, Bob T. Li, Alexander Drilon, Mark G. Kris, Charles M. Rudin, Nikolaus Schultz, Maria E. Arcila, Marc Ladanyi, Gregory J. Riely, Helena Yu, Matthew D. Hellmann

pre-EGFR-TKI TMB by TP53 co-mutation and incidence of TP53 co-mutation by tertile (low/intermediate vs high)

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NCI of the NIH

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ARTICLE 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 EGFR 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. EGFR wild-type lung adenocarcinoma samples were used for comparison. Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82–17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 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, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.See related commentary by Cheng and Oxnard, p. 899