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

Purpose: 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. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R mutant lung cancers treated with first/second generation EGFR tyrosine kinase inhibitors (TKIs) with pre-treatment large panel 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 (WT) lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR mutant lung cancer, TMB was lower compared to EGFR wild-type (n=1849) (median 3.77 vs. 6.12 mutations/Mb, p<0.0001) with a broad range (0.82-17.9). EGFR mutant lung cancer patients whose tumors had TMB in the upper tertile had shorter TTD (HR=0.46, p=0.0008) and OS (HR=0.40, p=0.006) compared to 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 to high TMB (HR=0.57, p=0.01; HR=0.50, p=0.02, respectively). In paired pre-treatment and post-progression samples, TMB was increased at resistance (median 6.56 vs 3.42 mutations/Mb, p=0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic EGFR mutant lung cancer patients treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.

https://ift.tt/2LkSKzn