Updated efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: Integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001

Abstract

Purpose: Entrectinib is a systemic and CNS-active, potent inhibitor of TRKA/B/C and ROS1. Primary data from integrated efficacy and safety analyses (6 mo follow-up) from clinical trials have shown that entrectinib is a promising option for pts with NTRK+ solid tumors; blinded independent central review (BICR) objective response rate (ORR) was 57.4% (95% CI 43.2-70.8). We show longer follow-up data from this integrated analysis. Methods: Pts with locally advanced/metastatic NTRK+ solid tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) Phase 1/2 entrectinib trials (ALKA [EudraCT 2012-000148- 88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) were included. Tumors were assessed after 4 wks (Cycle 1) then every 8 wks. Scans underwent BICR using RECIST v1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Secondary endpoints included overall survival (OS); ORR and DOR in pts with and without baseline CNS disease; intracranial (IC) ORR and DOR in pts with baseline CNS disease; safety. Results: There were 54 adults in the efficacy-evaluable population with advanced/metastatic NTRK+ solid tumors, including pts with baseline CNS metastases. As of Oct 30, 2018 (additional 5 mo follow-up), BICR ORR was 59.3% (95% CI 45.0-72.4); complete responses n=4 (7.4%). Median BICR DOR was 12.9 mo (95% CI 7.9-NE) and median OS was 23.9 mo (95% CI 16.8-NE). Per baseline CNS status, BICR ORR was 58.3% (95% CI 27.7-84.8) and 59.5% (95% CI 43.3-74.4) and median DOR was NE (95% CI 4.2-NE) and 12.9 mo (95% CI 7.9-NE) for pts with (n=12) and without (n=42) CNS disease, respectively. IC ORR was 54.5% (95% CI 23.4-83.3) and median IC DOR by BICR was NE (95% CI 6.7-NE). Entrectinib was well tolerated with a safety profile consistent with previously reports; there were no new or unexpected safety findings. Conclusions: In line with the primary data, these results at an additional 5 mo of follow-up show that entrectinib induced clinically meaningful, durable systemic and intracranial responses in pts with NTRK+ solid tumors.