PD-L1 Expression, Tumor Mutational Burden, and Response to Immunotherapy in Patients with MET exon 14 Altered Lung Cancers

Abstract

BackgroundMET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized.Patients and Methods Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was performed and TMB was calculated by estimation from targeted next-generation sequencing panels.Results We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1-49%, and ≥50% was 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers were lower than that of unselected non-small cell lung cancers (NSCLCs) in both independently-evaluated cohorts: 3.8 vs 5.7 mutations/megabase (p < 0.001, n = 78 vs 1,769, Cohort A), and 7.3 vs 11.8 mutations/megabase (p < 0.001, n = 62 vs 1,100, Cohort B). There was no association between PD-L1 expression and TMB (Spearman rho = 0.18, P = 0.069). In response-evaluable patients (n = 24), the objective response rate was 17% (95% CI 6-36%) and the median progression free survival was 1.9 months (95% CI 1.7 – 2.7). Responses were not enriched in tumors with PD-L1 expression ≥ 50% nor high TMB.Conclusion A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.