Pre- and post-treatment blood-based genomic landscape of patients with ROS1 or NTRK fusion-positive solid tumours treated with entrectinib

Abstract

Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion-positive (-fp) solid tumours and ROS1-fp non-small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non-invasive in vitro next-generation sequencing (NGS)-based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK-fp or ROS1-fp tumours and assessed the genomic landscape pre- and post-entrectinib treatment. Among evaluable pre-treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA⁺ F1L CDx⁺ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx⁺ and F1L CDx^- samples in ROS1-fp (5.6 vs. 17.3 months) but not NTRK-fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue-based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.

Keywords: NTRK; ROS1; F1L CDx; genomic profiling; resistance.