O-3 Efficacy and safety of entrectinib in NTRK fusion-positive gastrointestinal cancers: Updated integrated analysis of three clinical trials (STARTRK-2, STARTRK-1 and ALKA-372-001)

Abstract

Gene fusions of NTRK (neurotrophic receptor tyrosine kinase) 1/2/3 result in the expression of chimeric TRKA/B/C proteins with constitutively active kinase activity that have oncogenic potential across a range of tissues. Entrectinib is a CNS-active, potent TRKA/B/C inhibitor. In a preliminary analysis of data from three phase 1/2 trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267), entrectinib demonstrated clinically meaningful, durable antitumor activity and a manageable safety profile in adults with NTRK fusion-positive (NTRK-fp) gastrointestinal cancers. We present updated data in a larger cohort of patients with NTRK-fp solid tumors, focusing on patients with gastrointestinal cancers. Patients with locally advanced/metastatic NTRK-fp solid tumors (with or without baseline CNS disease) confirmed by nucleic-acid-based methods were enrolled in ALKA-372-001, STARTRK-1 or STARTRK-2, across >150 sites in 15 countries. Tumor assessments, performed at the end of cycle 1 (4 weeks) and every 8 weeks thereafter, were done by blinded independent central review (BICR) using RECIST v1.1. Primary endpoints (per BICR) were objective response rate (ORR) and duration of response (DoR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. At the updated data cut-off (31 October 2018), the total efficacy-evaluable population comprised 74 adult patients with 12 different NTRK-fp tumor types and >25 histologies. In the overall integrated analysis population, ORR per BICR was 63.5% (47 of 74 patients); this included five complete and 42 partial responses. Responses occurred in all tumor types except neuroblastoma (n=1). Median DoR, PFS and OS were 12.9 (95% CI 9.3–not estimable [NE]), 11.2 (95% CI 8.0–15.7) and 23.9 (95% CI 16.0–NE) months, respectively. The cohort of patients with NTRK-fp gastrointestinal cancers comprised 12 adults (1 cholangiocarcinoma; 7 colorectal carcinomas; 3 pancreatic cancers; 1 other) aged 31–75 (median 59.5) years; half of them were male and 75% were white. Eight (66.7%) patients reported one (n=2), two (n=4) or three (n=2) prior lines of therapy. The majority of patients (91.6%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. No patient had investigator-assessed CNS metastases at baseline or received prior treatment for CNS disease. After a median follow-up time of 20.4 months, ORR by BICR was 50.0% (95% CI 21.1–78.9); all partial responses. Median (95% CI) DoR, PFS, and OS were: 12.9 (7.1–15.1), 7.1 (2.4–16.0), and 16.0 (11.2–NE) months, respectively. The integrated safety population comprised of 504 patients who received ≥1 dose of entrectinib. Most (58.7%) treatment-related adverse events (TRAEs) were grade 1/2; 28.6% were grade 3, 3.2% were grade 4, and there were two grade 5 TRAEs (one sudden death; one cardiac arrest). The most frequently reported TRAEs were dysgeusia (39.7%), fatigue (31.5%), dizziness (27.2%) and constipation (24.0%). TRAEs led to dose reductions in 24.6% of patients, interruptions in 27.0% and discontinuations in 4.6%. In this updated analysis, entrectinib continues to demonstrate a high level of clinical benefit for patients with NTRK-fp solid tumors, and a manageable safety profile, including patients with a variety of gastrointestinal cancers.