Association of ALK resistance mutations by EML4-ALK variant (v3 vs. non-v3) in ALK+ non-small cell lung cancer (NSCLC).

Abstract

9010 Background: ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant. Methods: We analyzed samples from 634 unique NSCLC patients (704 samples) with tumors harboring ALK rearrangements ( ALK+) detected using hybrid-capture based genomic profiling performed on DNA isolated from FFPE tissue specimens (676 samples) or ctDNA isolated from blood (28 samples) during the course of clinical care. Results: Of the 634 ALK+ cases, we identified 200 (32%) EML4- ALKv1 (E13; A20), 50 (8%) EML4-ALKv2 (E20; A20), 204 (32%) EML4- ALKv3 (E6; A20), 78 (12%) other EML4-ALK, and 102 (16%) non- EML4 ALK rearrangements. Despite relatively equal frequency of EML4-ALK v1 and v3 in this dataset, the presence of a known ALK resistance mutation (n = 40 cases) was significantly associated with v3 as compared to v1 (P < 0.0002). G1202R mutation in particular was significantly associated with EML4-ALK v3 versus v1 (P < 0.002), and as compared to all non-v3 (P = 0.02). The tumor mutation burden (TMB) was generally low (median v1: 1.8, v3: 2.5, non-v3: 1.8 mutations/Mb), and although significantly different between v1 and v3 (P = 0.0008) and v3 and non-v3 (P = 0.003), the difference is not expected to be clinically relevant. Available ALK+ cases with paired pre- and post-treatment samples tested for a single patient will also be evaluated by ALKfusion variant, as well as for novel non-ALK mechanisms of acquired resistance, including a case with MET kinase domain duplication acquired post-ALK targeted therapy. Conclusions: The use of tissue and blood-based next generation sequencing allows for detection of the specific ALK fusion partner, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance and inform the selection of ALK inhibitor therapy. [Table: see text]