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.

Fig. 1

Flow chart of liquid biopsy samples used in the study. ^aFive samples were unavailable for testing. ^b16 samples were unavailable for testing. ^cTwo samples were excluded per FDA request.

Fig. 2

Primary resistance detected by F1L CDx, in patient ctDNA. Each column represents a single patient, with the genomic alterations indicated with non‐grey lines. Grey lines represent no alteration detected. Each sample was assayed a single time. Statistical analysis was carried out using Fisher’s exact test. (A) Patients with NTRK‐fp solid tumours; (B) Patients with ROS1‐fp NSCLC. CR, complete response; CRC, colorectal cancer; MASC, mammary analogue secretory carcinoma; N/A, not applicable; NE, non‐evaluable; PR, partial response; SD, stable disease.

Fig. 3

Acquired resistance mutations detected by F1L CDx, in patient ctDNA. Each paired column represents a single patient at two timepoints (pre‐treatment and end of study), with the genomic alterations indicated with a non‐grey line. Grey lines represent no alteration detected. Each sample was assayed a single time. Statistical analysis was carried out using Fisher’s exact test. (A) Patients with NTRK‐fp solid tumours; (B) Patients with ROS1‐fp NSCLC. CR, complete response; CRC, colorectal cancer; MASC, mammary analogue secretory carcinoma; NE, non‐evaluable; PR, partial response; SD, stable disease.

Fig. 4

Mechanisms of acquired resistance to TKIs in NTRK‐fp solid tumours and ROS1‐fp NSCLC: (A) On‐target resistance; (B) Off‐target resistance. Black square indicates clinical resistance observed following treatment with therapeutic. ^aDual mutation. ^bFunctional domain/structure not reported/unknown. ^cSpecific mutation unknown/not reported. ^dReported in patients with ALK fusion‐positive lung cancer only. ^eComplete genomic profile of transformed SCLC not fully elucidated. ALK, anaplastic lymphoma kinase; BDNF, brain‐derived neurotrophic factor; C, crizotinib; DFG, Asp‐Phe‐Gly motif; E, entrectinib; KIT, KIT proto‐oncogene, receptor tyrosine kinase; KRAS, Kirsten rat sarcoma virus; L, larotrectinib; MET, mesenchymal epithelial transition; NGF, nerve growth factor beta; NRAS, neuroblastoma RAS viral (v‐ras) oncogene homolog; NTF‐3, Neurotrophin‐3; TKI, tyrosine kinase inhibitor; Trk, tropomyosin receptor kinase.