Author of

• 16549

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  P1.02 - Poster Session with Presenters Present (ID 454)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16606

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    P1.02-057 - Clinical Utility of ctDNA for Detecting ALK Fusions and Resistance Events in NSCLC: Analysis of a Laboratory Cohort (ID 6247)

    14:30 - 14:30  |  Author(s): N.E. Ihuegbu
    • Abstract

    Background:
    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.
    
    Methods:
    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.
    
    Results:
    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: BRAF[V600E], MET[E14skip], KRAS[G12], KRAS[G13], HRAS[Q61], EGFR[E330K], KIT[amp], BRAF[amp]. 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 EGFR[T790M], but the presence of an ALK fusion may represent further subclonal evolution following the selective pressure of an EGFR inhibitor.
    
    Conclusion:
    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.