67TiP - HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Background

Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US for use in combination with trastuzumab (Tras) and capecitabine for treatment (tx) of patients (pts) with metastatic HER2+ breast cancer (MBC), including pts with brain metastases (BM), who received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-Tras emtansine (T-DM1), approved for tx of HER2+ MBC after Tras and a taxane, has improved progression-free survival (PFS) and overall survival (OS). Improvements are needed, including pts with active BM. A phase Ib trial evaluated TUC (300 mg PO BID) with T-DM1 in 50 pts with HER2+ MBC who received prior tx with Tras and a taxane; 60% of pts had BM at baseline (Borges 2018). Common AEs, mostly grade 1/2, were nausea (72%), diarrhea (60%), and fatigue (56%). Median PFS was 8.2 months and objective response rate (ORR) in pts with measurable disease (n=34) was 47%. Brain specific response rate (RECISTv1.1) in pts with measurable BM (n=14) was 36%. This encouraging clinical activity, including in pts with BM, provides rationale to evaluate this combination.

Trial design

HER2CLIMB-02 is a global, randomized, double-blind, placebo-controlled, phase III study enrolling pts with centrally confirmed HER2+, unresectable, locally advanced, or MBC previously treated with Tras and taxane (in any setting), and ECOG ≤1. ∼460 pts will be randomized 1:1 for 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Prior tx with investigational anti-HER2 or anti-EGFR agent or HER2 TKI is not permitted. Prior pertuzumab tx is permitted. Baseline brain MRIs are required; pts with stable, progressing, or untreated BM not requiring immediate local therapy are eligible. On tx response assessments per RECISTv1.1 occur every 6 wks for the 1st 24 wks, and then every 9 wks. Primary endpoint is PFS per investigator assessment, with OS and ORR as key secondary endpoints. Enrollment is ongoing in North America, EU, and will include Japan, South Korea, Singapore, and Australia.

Clinical trial identification

NCT03975647; 2019-005017-39.

Legal entity responsible for the study

Seattle Genetics, Inc.

Funding

Seattle Genetics, Inc.

Disclosure

N. Masuda: Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Eli-Lilly; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Kyowa-Kirin; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Daiichi Sankyo; Full/Part-time employment: National Hospital Organization Osaka National Hospital, Dept. of Surgery, Breast Oncology; Officer/Board of Directors: Japan Breast Cancer Research Group Association Board of Directors. S. Hurvitz: Research grant/Funding (institution): Ambryx; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Biomarin; Research grant/Funding (institution): Cascadian Therapeutics; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Dignitana; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): OBI Pharma; Advisory/Consultancy, Research grant/Funding (institution), medical writing: Pfizer; Research grant/Funding (institution): Pieris Pharma; Research grant/Funding (institution): Puma Biotech; Research grant/Funding (institution): Radius Health; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, medical writing: Roche; Research grant/Funding (institution): Bayer. L. Vahdat: Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics, Inc.; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy, Research grant/Funding (institution): Polyphor; Advisory/Consultancy: Berg Pharma; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution), Other: Roche; Research grant/Funding (institution), Other: Arvinas; Research grant/Funding (institution): Polyphor; Research grant/Funding (institution): Oncotherapy Biosciences; Licensing/Royalties, A patent on bone marrow derived progenitor and relapse: No company. N. Harbeck: Advisory/Consultancy, Speaker Bureau/Expert testimony: Daiichi Sankyo; Advisory/Consultancy: Seattle Genetics, Inc.; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Officer/Board of Directors: West German Study Group. A.C. Wolff: Full/Part-time employment: John Hopkins Kimmel Cancer Center, Breast and Ovarian Cancer Program. S.M. Tolaney: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Celldex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Nektar; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Nanostring; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Paxman; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Puma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics, Inc.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Odonate; Honoraria (self), Advisory/Consultancy: Silverback Therapeutics; Honoraria (self), Advisory/Consultancy: G1 Therapeutics; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Anthenex; Honoraria (self), Advisory/Consultancy: Oncopep; Honoraria (self), Advisory/Consultancy: Kyowa Kirin Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Daiichi-Sankyo; Research grant/Funding (institution): Exelixis. S. Loi: Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy, Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Novartis; Advisory/Consultancy: GlaxosmithKline; Advisory/Consultancy: G1 Therapeutics; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Bristol-Meyers Squibb; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Merck; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Roche-Genentech; Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Pfizer; Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics, Inc.; Shareholder/Stockholder/Stock options: AstraZeneca. J. O'Shaughnessy: Honoraria (self): AbbVie; Honoraria (self): Agendia; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi-Sankyo; Honoraria (self): Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genomic Health; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Grail; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Heron; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Immunomedics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ispen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Jounce; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Myriad; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Odonate Therapeutics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Puma Biotech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Samsung; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics, Inc.; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Syndax; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi. D. Xie: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics, Inc.; Shareholder/Stockholder/Stock options: Metlife. L. Walker: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Seattle Genetics, Inc.. E. Rustia: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics, Inc.. V.F. Borges: Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics, Inc.; Research grant/Funding (self): Abbot/AbbVie; Research grant/Funding (institution): Millenium.