Clinical Utility of Cell-Free DNA for the Detection of <i>ALK</i> Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non-Small Cell Lung Cancer.

Abstract

<b>Purpose:</b> Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (<i>ALK)</i> gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify <i>ALK</i> fusions and actionable resistance mechanisms without an invasive biopsy.<b>Patients and Methods:</b> The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected <i>ALK</i> 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.<b>Results:</b> Identified fusion partners included <i>EML4</i> (85.4%), <i>STRN</i> (6%), and <i>KCNQ, KLC1, KIF5B, PPM1B</i>, and <i>TGF</i> (totaling 8.3%). Forty-two <i>ALK</i>-positive patients had no history of targeted therapy (cohort 1), with tissue <i>ALK</i> molecular testing attempted in 21 (5 negative, 5 positive, and 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 to 3 <i>ALK</i> 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 <i>EGFR-</i>activating mutations, an <i>ALK</i> fusion was identified on progression (cohort 4; 4 <i>STRN</i>, 1 <i>EML4;</i> one both <i>STRN</i> and <i>EML4</i>); five harbored <i>EGFR</i> T790M.<b>Conclusions:</b> In this cohort of cfDNA-detected <i>ALK</i> fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. <i>Clin Cancer Res; 24(12); 2758-70. ©2018 AACR</i>.