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

Racial differences in characteristics and prognoses between Asian and white patients with nonsmall cell lung cancer receiving atezolizumab: An ancillary analysis of the POPLAR and OAK studies

“…Approximately, 10% of western patients are never smokers, compared to >30% of Asian patients, in accordance with the demographic findings of the current study . Asian patients are also more likely to have EGFR mutations and EGFR ‐mutated patients have lower TMB levels than wild‐type EGFR patients . The lower bTMB in Asian patients compared to white patients in the current study (median bTMB: 6 vs .…”

“…22 Asian patients are also more likely to have EGFR mutations 23 and EGFR-mutated patients have lower TMB levels than wild-type EGFR patients. 24 The lower bTMB in Asian patients compared to white patients in the current study (median bTMB: 6 vs. 8 mutations/Mb) may have been partly driven by the influence of EGFR mutation status. Similarly, PD-L1 expression was significantly associated with wild-type EGFR and smoking status, which could explain the higher incidence of negative PD-L1 expression in Asian patients in this study.…”

Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

“…It is possible that the number of reads for NGS analysis was not sufficient to conclude the presence of a copy number gain for MET as a result of the small volume of plasma (2 mL) used for the analysis. The number of somatic alterations has previously been shown to be increased at the time of acquired resistance to EGFR‐TKI treatment compared with baseline in paired tumor samples . A diverse clonal architecture of genetic alterations including truncal alterations such as those of TP53 or CTNNB1 has been identified in tumor samples obtained from patients with EGFR ‐mutated lung cancer .…”

“…The number of somatic alterations has previously been shown to be increased at the time of acquired resistance to EGFR-TKI treatment compared with baseline in paired tumor samples. 32 A diverse clonal architecture of genetic alterations including truncal alterations such as those of TP53 or CTNNB1 has been identified in tumor samples obtained from patients with EGFR-mutated lung cancer. 27,33 In the present study, mutation of TP53 was frequently detected in cfDNA at both baseline and disease progression.…”

Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

“…The factors that drive these differences are poorly understood. Potential tumor and patient factors include EGFR co-alterations, for example, MET [26,27] and SNPs around drug binding sites [28]. Off-target kinase inhibition may therefore have increasing importance (Table 1), with osimertinib, for example, having activity against HER2/4, ALK, BLK, and BRK [29].…”