Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases

Abstract

Background: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models.

Patients and methods: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR).

Results: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively.

Conclusion: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases.

Clinical trial registration: NCT01921335.

Keywords: HER2-positive brain metastases; clinical trial; targeted therapy; tucatinib; tyrosine kinase inhibitor.

Conflict of interest statement

Disclosures OM has received institutional research funding from AbbVie, Array Biopharma, Genentech, Pfizer, Seattle Genetics, and has served as an consultant/advisory board member for AbbVie, Pfizer. JPL received research funding from Kazia Therapeutics. WTB received institutional research funding from Pfizer. SMT receives institutional research funding from Novartis, Genentech, Eli Lilly, Pfizer, Merck, Exelixis, Eisai, Bristol Meyers Squibb, AstraZeneca, Cyclacel, Immunomedics, Odonate, and Nektar. SMT has served as an advisor/consultant to Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, Daiichi Sankyo, OncoPep, Paxman, and NanoString. IK has received research support paid to his institution from Genentech/Roche and Pfizer, and honoraria from Bristol Meyers Squibb, Daiichi/Sankyo, MacroGenics, Context Therapeutics, Taiho Oncology, Genentech/Roche, and Seattle Genetics, and serves on Data Safety Monitoring Committees for Novartis and Merck. EPW serves as an advisor/consultant to Carrick Therapeutics, Genentech, Genomic Health, GSK, Jounce, Leap, Lilly, Merck, and Seattle Genetics, and receives institutional funding from Genentech and Merck. NUL has received research funding from Pfizer, Genentech, Seattle Genetics, Array Biopharma, Novartis, and Merck, and has served as a consultant/advisory board member for Genentech, Novartis, Seattle Genetics, Puma, and Daiichi Sankyo. LW is an employee of Seattle Genetics. RAF reports institutional funding from Eisai and Puma.

Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.