Abstract 353TiP
Background
Tucatinib (TUC), approved in the US for metastatic HER2+ breast cancer (MBC), including patients (pts) with brain metastases (BM), is an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. Ado-trastuzumab emtansine (T-DM1), approved for treatment (tx) of pts with HER2+ MBC after trastuzumab (Tras) and a taxane, has led to significant improvements in progression-free survival (PFS) and overall survival (OS). Still, further 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 (Borges 2018). Common AEs included nausea (72%), diarrhea (60%), and fatigue (56%); mostly grade 1/2. Median PFS was 8.2 months and the objective response rate (ORR) in pts with measurable disease (n=34) was 47%. Sixty percent of pts treated with TUC + T-DM1 had BM at baseline and showed a brain specific response rate (RECISTv1.1) of 36% in pts with measurable BM (14/30). This encouraging clinical activity, including in pts with BM, provides rationale for a randomized trial to further evaluate this combination.
Trial design
HER2CLIMB-02 is a randomized, double-blind, placebo-controlled phase III study to evaluate efficacy and safety of TUC + T-DM1 in pts with unresectable locally advanced or metastatic HER2+ breast cancer; ∼460 pts will be randomized 1:1 to receive 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Pts must have had prior tx with Tras and a taxane in any setting, be ≥18 yrs, with an ECOG ≤1 and histologically confirmed HER2+ MBC. Prior tx with any investigational anti-HER2 or anti-EGFR agent or HER2 TKI is not permitted. Prior pertuzumab tx is allowed, but not required. Baseline brain MRIs are required for all pts; pts with stable, progressing, or untreated BM not requiring immediate local therapy are eligible. While on tx, radiographic disease evaluations (RECISTv1.1) will occur every 6 weeks for the first 24 weeks, and then every 9 weeks. The primary endpoint is PFS per investigator, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US and planned for Canada, the EU and the Asia/Pacific region.
Clinical trial identification
NCT03975647.
Editorial acknowledgement
Medical writing assistance was funded by Seattle Genetics, Inc., and provided by Amanda Blaker, PhD, of MMS Holdings, Inc.
Legal entity responsible for the study
Seattle Genetics.
Funding
Seattle Genetics.
Disclosure
S.A. Hurvitz: Research grant/Funding (institution): Ambryx; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer; 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; Research grant/Funding (institution): 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. L.T. Vahdat: Honoraria (institution), Advisory/Consultancy: Berg Pharma; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Honoraria (institution), Advisory/Consultancy: Osmol Therapeutics; Honoraria (institution), Advisory/Consultancy: Polyphor; Honoraria (institution), Advisory/Consultancy: R Pharm; Advisory/Consultancy: Concarlo; Advisory/Consultancy: Athenex. N. Harbeck: Advisory/Consultancy, Speaker Bureau/Expert testimony: Daiichi Sankyo; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Roche. A.C. Wolff: Full/Part-time employment: Johns Hopkins Kimmel Cancer Center,Breast & 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; 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. S. Loi: Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy, Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Novartis; Advisory/Consultancy: G1 Therapeutics; Research grant/Funding (institution): 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; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Seattle Genetics; Shareholder/Stockholder/Stock options: BMS; Shareholder/Stockholder/Stock options: AstraZeneca. 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), Research grant/Funding (self), Research grant/Funding (institution): Eisai; Honoraria (self): Takeda; 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: Board of directors: Japan Breast Cancer Research Group Association (JBCRG). 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: Ipsen; 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; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Syndax; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi. L. Walker: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Patents as inventor via status as employee of Seattle Genetics: Seattle Genetics. E. Rustia: Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Seattle Genetics. V. Borges: Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Abbott/AbbVie; Research grant/Funding (institution): Millenium. All other authors have declared no conflicts of interest.