P1.02-057 Clinical Utility of ctDNA for Detecting ALK Fusions and Resistance Events in NSCLC: Analysis of a Laboratory Cohort

Abstract

Advanced NSCLC patients whose tumors harbor ALK fusions benefit from first line treatment with ALK inhibitors (ALKi). However, insufficient tissue for testing (QNS) occurs ∼25% of the time. Patients treated with ALKi ultimately progress. Historically, identification of the resistance mechanism/s required repeat tumor biopsy. Circulating tumor DNA (ctDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without a repeat biopsy. The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 57 patients (2/2015-6/2016) with 58 ctDNA-detected ALK fusions. G360 is a CLIA-laboratory ctDNA test that detects point mutations in 70 genes and select amplifications, fusions and indels. Available records were reviewed to characterize patients at baseline and at progression. Identified fusion partners included EML4 (n=51, 88%), STRN (7%), KLC1 (3%), KIF5B (2%). Thirty patients had no history of targeted therapy (new diagnosis or no prior genotyping, “cohort 1”); 23 patients were drawn at ALKi progression (“cohort 2”). In 6 samples, the patients’ clinical status was unknown. Three additional cases had ALK resistance mutations (F1174C, F1269A/I1171T, D1203N) detected in ctDNA but no fusion detected; historical tissue testing was ALK+. Conversely, in cohort 1, 10 (33%) were tissue QNS (7) or tissue ALK negative (3) while 4 (13%) were tissue ALK+ and 16 (54%) had unknown tissue status. As expected, no documented or putative resistance mechanisms were identified in cohort 1, although TP53 mutations were identified in 43%. Among 18 patients progressing on an ALKi, 7 (39%) contained 1 (4 patients), 2 (1 patient) or 3 (2 patients) ALK resistance point mutations (F1174C/V: 3 occurrences; G1202R: 3; L1196M: 3; G1128A: 1; L1189F: 1; I1171T: 1). Additional events co-occurring in the resistance cohort included 1 each of: BRAFV600E, METE14skip, KRASG12, KRASG13, HRASQ61, EGFRE330K, KITamp, BRAFamp. 5 EGFR-mutant NSCLC cases at progression harbored ALK fusions (4 STRN, 2 EML4; 1 patient had both) representing 1% of all EGFR-mutant progressing NSCLC cases in the G360 database. Four of these patients also harbored EGFRT790M, but the presence of an ALK fusion may represent further subclonal evolution following the selective pressure of an EGFR inhibitor. These results add to the growing body of literature demonstrating that comprehensive ctDNA assays provide a non-invasive means of detecting targetable alterations in the first line when tissue is QNS as well as detecting known and novel resistance mechanisms that may inform treatment decisions at progression.