Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase ALK gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without biopsy. Experimental Design: The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ,KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 - 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. Conclusions: In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression.

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