PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. (27th August 2018)

• Record Type: Journal Article
• Authors: Sabari, J K; Leonardi, G C; Shu, C A; Umeton, R; Montecalvo, J; Ni, A; Chen, R; Dienstag, J; Mrad, C; Bergagnini, I; Lai, W V; Offin, M; Arbour, K C; Plodkowski, A J; Halpenny, D F; Paik, P K; Li, B T; Riely, G J; Kris, M G; Rudin, C M; Sholl, L M; Nishino, M; Hellmann, M D; Rekhtman, N; Awad, M M; Drilon, A
• Is Part Of: Annals of oncology. Volume 29:Number 10(2018)
• Page Start: 2085
• Page End: 2091
• Publication Date: 2018-08-27
• Subjects: non-small-cell lung cancer -- MET exon 14 -- PD-L1 -- tumor mutational burden -- immunotherapy; Oncology -- Periodicals; 616.992
• DOI: 10.1093/annonc/mdy334
• Languages: English
• ISSNs: 0923-7534

Abstract

Abstract: Background: MET 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 carried out 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% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase ( P < 0.001, n = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase ( P < 0.001, n = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearman's rho=0.18, P = 0.069). In response-evaluable patients ( n = 24), the objective response rate was 17% (95% CI 6% to 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.