Abstract P3-10-11: Entrectinib in NTRK fusion-positive breast cancer: Integrated analysis of patients enrolled in STARTRK-2, STARTRK-1 and ALKA-372-001
Authors: Blakely Collin , Tourneau Christophe Le , Lu Janice , Waqar Saiama N. , Huang Xinhui , Day Bann-mo , Simmons Brian , Barve Minal 
Published: March 2020

Abstract
Background Fusions involving the neurotrophic tropomyosin receptor kinase (NTRK) gene family NTRK1, NTRK2, and NTRK3 lead to the expression of chimeric rearrangements in the TRK tyrosine kinase proteins (TRKA, TRKB, and TRKC, respectively) with constitutively active kinase function. NTRK fusions act as oncogenic drivers, and are potential therapeutic targets across a broad range of tumor types including breast cancer. Entrectinib is a CNS-active, oral, potent inhibitor of TRKA/B/C, ALK and ROS1 designed to cross the blood-brain-barrier. Here we present integrated efficacy data from three trials of entrectinib in NTRK fusion-positive solid tumors focusing on a small cohort of patients with breast cancer, and safety data from the integrated safety population.
Methods Patients with locally advanced/metastatic NTRK fusion-positive tumors (with or without baseline CNS disease) confirmed by nucleic acid-based methods were enrolled in three global phase 1/2 entrectinib trials at &gt;150 sites in 15 countries (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]). Disease burden was assessed per blinded independent central review (BICR) using RECIST v1.1 after cycle 1 (4 weeks) then every 8 weeks thereafter. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by BICR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
Results The total efficacy-evaluable population comprised 54 adult patients with advanced/metastatic NTRK fusion-positive tumors; within this population 10 different tumor types and &gt;19 histopathologies were identified. In the overall integrated analysis population, responses to treatment with entrectinib occurred in all tumor types and included 4 complete responses (7.4%). The ORR by BICR was 57.4% (95% CI 43.2-70.8), and median (95% CI) DOR, PFS, and OS were 10.4 (7.1-not estimable [NE]), 11.2 (8.0-14.9), and 20.9 (14.9-NE) months, respectively. In the cohort of 6 patients with NTRK fusion-positive breast cancer, the median age was 63 years (range 36-67 years). Three patients reported prior systemic therapies (6, 4 and 1 prior therapies). The majority of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 (66.7%). Two patients had investigator-assessed CNS metastases at baseline; 1 patient (16.7%) had previously received radiotherapy in the brain 2-6 months prior to treatment with entrectinib. ORR by BICR was 83.3% (95% CI 35.9-99.6); 2 were complete responses, 3 were partial responses, and 1 patient had missing/unevaluable data. Median (95% CI) DOR, PFS, and OS were: 12.9 (4.2- NE), 10.1 (5.1-NE), and NE (5.1-NE) months, respectively. The integrated safety population comprised 355 patients who received ≥1 dose of entrectinib, of which 60.5% of patients had grade 1 or 2 treatment-related adverse events (TRAEs), 27.6% had grade 3, 3.4% had grade 4, and there were no grade 5 TRAEs. The most frequently reported TRAEs were dysgeusia (41.4%), fatigue (27.9%), dizziness (25.4%) and constipation (23.7%). TRAEs led to dose reductions in 27.3%, interruptions in 25.4% and discontinuations in 3.9% of patients.
Conclusion In this integrated analysis of global multicenter clinical trials, entrectinib was well tolerated and induced clinically meaningful, durable responses in patients with NTRK fusion-positive breast cancer.
Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.
Citation Format: Collin Blakely, Christophe Le Tourneau, Janice Lu, Saiama N. Waqar, Xinhui Huang, Bann-mo Day, Brian Simmons, Minal Barve. Entrectinib in NTRK fusion-positive breast cancer: Integrated analysis of patients enrolled in STARTRK-2, STARTRK-1 and ALKA-372-001 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-11.