5033 - Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive (NTRK-fp) Tumors: Pooled Analysis of STARTRK-2, STARTRK-1 and ALKA-372-001

Background

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions lead to the transcription of chimeric TRK proteins with overexpressed kinase function; this confers oncogenic potential across several tumor types. Entrectinib is a central nervous system (CNS)-active, potent inhibitor of TRKA/B/C and ROS1. We show integrated efficacy and safety analyses from entrectinib clinical trials.

Methods

Patients (pts) with locally advanced/metastatic NTRK-fusion positive (fp) tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after cycle 1 (4 wk) then every 8 wk. Scans underwent blinded independent central review (BICR) using RECISTv1.1. Primary endpoints: overall response rate (ORR); duration of response (DOR) by BICR. Secondary endpoints: progression-free survival (PFS), overall survival (OS) in pts with and without baseline CNS disease; safety.

Results

The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK-fp solid tumors (10 tumor types, >19 histopathologies), including pts with baseline CNS metastases. After 15.5 mo follow-up, BICR ORR was 57.4% (95% CI 43.2–70.8), complete responses n=4 (7.4%); responses seen in all tumor types. Median BICR DOR: 10.4 mo (95% CI 7.1–NR); median BICR PFS: 11.2 mo (95% CI 8.0–14.9); median OS: 20.9 mo (95% CI 14.9–NR). Per baseline CNS status (investigator assessed), median BICR PFS was 12.0 mo (95% CI 8.7–15.7) and 7.7 mo (95% CI 4.7–NR) for patients without (n=42) and with CNS disease (n=12), respectively. In the safety population (355 pts who received entrectinib across clinical trials), most treatment-related AEs were grade 1–2 and managed with dose reduction (27.3%); few pts discontinued (3.9%) due to treatment-related AEs.

Conclusions

In this multicenter, pooled analysis of global clinical trials, entrectinib was well tolerated overall and induced clinically meaningful, durable systemic responses in pts with NTRK-fp solid tumors, type agnostic, with and without CNS disease.

Clinical trial identification

EudraCT 2012-000148-88; NCT02097810; NCT02568267

Editorial Acknowledgement