High Tumor Mutational Burden in Rare and Complex EGFR Mutant Non-Small Cell Lung Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Classical EGFR mutant lung cancer with exon 19 deletions, exon 21 L858R and de novo exon 20 T790M mutations are associated with good response to tyrosine kinase inhibitors. In contrast, rare and complex mutations have uncertain or poor response to targeted therapy. Recent retrospective analyses have observed a potential benefit of rare and complex EGFR mutations from immunotherapy, in contrast to cancers harboring classical EGFR mutations. We hypothesized that a larger proportion of rare and complex EGFR mutant lung cancers may have molecular differences that would promote immune checkpoint blockade as a putative combination or alternative treatment. <h3>Materials/Methods</h3> Patients (pts) with nonsynonymous EGFR mutant lung cancers from two datasets (The Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium) were identified. Rare EGFR mutations were defined as non-sensitizing somatic mutations occurring within the tyrosine kinase (TK) domain of exons 18 through 21. Complex EGFR mutant cases (i.e., G719X + S768I) were tumors with two mutations within the TK region where at least one mutation was non-sensitizing. Tumor mutational burden (TMB) was calculated as the number of somatic mutations per million bases (human exome was estimated to be 38 Mb). High-TMB was denoted as a TMB over 10. Gene expression of PD-L1 was evaluated by RNA-sequencing as well as bioinformatic assessment of tumor purity, immune infiltration and stroma contribution within the tumor microenvironment using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumours using Expression data) algorithm. <h3>Results</h3> Of the 675 pts evaluated, 97 (14.3%) had tumors which harbored EGFR mutations. Patients with EGFR mutant tumors were more likely to be female (64 vs 48%, <i>P</i> = 0.006) and non-smokers (49 vs 12%, <i>P</i> < 0.001). Tumors from non-smokers were less likely to have high-TMB (<i>P</i> < 0.001). Twenty four of 97 (25%) EGFR mutant cancers had either rare (n = 12) or complex mutations (n = 12). Tumors with rare/complex EGFR mutations had a higher average TMB (5.4 compared to 2.3) and were significantly more likely to have a TMB over 10 (17% vs 1.4%, <i>P</i> = 0.003). 25% of rare EGFR mutant tumors (L861Q, E866K, K754I) had a TMB > 10 (<i>P</i> = 0.0003). There were no significant differences in PD-L1 expression (<i>P</i> = 0.46) or smoking history (<i>P</i> = 0.71) between classical and rare/complex EGFR mutant cancers. Tumors with rare EGFR mutations had significantly higher tumor purity (0.759 versus 0.459, <i>P</i> = 0.0038), and corresponding lower proportion of immune (<i>P</i> = 0.0045) and stromal cells (<i>P</i> = 0.0077). <h3>Conclusion</h3> Our data suggests that lung cancers harboring rare EGFR mutations may have mutation-specific dependencies that would make a non-significant proportion amenable to immunotherapy. While PD-L1 appears to be a poor biomarker, we observed an increase in high-TMB and distinct changes in the tumor microenvironment in rare EGFR mutant lung cancer.