Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND

In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB.

PATIENTS AND METHODS

HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized.

RESULTS

Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events.

CONCLUSIONS

With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure GC: consultancy with Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen Inc.; honoraria from Ellipses Pharma; research funding/grants from Merck; speaker’s bureau with Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen Inc.; travel from Pfizer and Roche/Genentech. VM: consultancy with Amgen, Daiichi Sankyo, Eisai, Gilead, Hexal, Lilly, Nektar, Roche, and Seagen Inc.; honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Genomic Health, Lilly, MSD Oncology, Nektar, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche, Seagen Inc., Tesaro, and Teva; speaker’s bureau with Novartis, Roche, and Seagen Inc.; travel from Daiichi Sankyo, P Value Communications, and Roche. VB: consultancy with Seagen Inc.; research funding/grants from AstraZeneca, Genentech, Olema Oncology, Oncosec, Pfizer, and Seagen Inc. EH: consultancy with Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and Seagen Inc.; research funding/grants from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen Inc., Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, Stemcentrx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxikon, Amgen, Akesobio Australia, and Shattuck Labs. SH: equity ownership in Ideal Implant, ROM Tech; research funding/grants from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, CytomX, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GlaxoSmithKline, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pfizer, Medivation, BioMarin, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seagen Inc., Zymeworks, and Phoenix Molecular Designs, Ltd.; travel from Lilly. SL: consultancy and advisory board membership with AbbVie, Amgen, AstraZeneca, Bayer Bristol-Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, G1 Therapeutics, GlaxoSmithKline, Gilead, Lilly, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche/Genentech, Seagen Inc., and Silverback; honoraria from AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Roche/Genentech, and Samsung; research funding/grants from AbbVie, AstraZeneca, Celgene, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche/Genentech, and Seagen Inc.; patents/royalties: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, vm Scope GmbH; employee of GBG Forschungs GmbH; other (non-financial – medical writing) with Daiichi Sankyo, Gilead, Novartis, Pfizer, Puma, Roche/Genentech, and Seagen Inc. RM: consultancy with AstraZeneca, Genentech/Roche, Novartis, Puma, and Seagen Inc.; honoraria from AstraZeneca, Genentech, Novartis, Puma, and Seagen Inc.; research funding/grants from AstraZeneca, Daiichi Sankyo, EMD Serono, Genentech/Roche, Pfizer, and Seagen Inc.; travel from Genentech and Seagen Inc. AO: advisory board membership with AstraZeneca, Roche/Genentech, and Seagen Inc.; honoraria from Daiichi Sankyo, Lilly, Pfizer, and Seagen Inc.; research funding/grants from Pfizer and Roche/Genentech; travel from AstraZeneca, Daiichi Sankyo, LEO Pharma, and Lilly. EP: consultancy with Biotheranostics, Mylan Novartis, Pfizer, Puma, and R-pharm; honoraria from Mylan Novartis, Pfizer, Puma, and R-pharm; research funding/grants from AbbVie, Cascadian, Corcept, Genentech, Hoosier Cancer Research Network, Immunogenicity, Merck, Novartis, and Seagen Inc.; speaker’s bureau with OncLive Clinical Congress Consultants; travel from Amgen, Genentech, Merck, Novartis, and Tesaro. DC: consultancy with and research funding from Novartis, Roche, and Seagen Inc. LAC: advisory board membership (all uncompensated) from Eisai, Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AZ, Daiichi Sankyo, Aptitude Health, and Exact Sciences; royalty sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme (immediate family member); research funding/grants (to institution) from AbbVie, NanoString, Novartis, Seagen Inc., Syndax, and Veracyte; other (uncompensated relationships) with Aptitude Health, AstraZeneca/Daiichi Sankyo, Exact Sciences, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, Novartis, and Sanofi. KG: consultancy with AstraZeneca, Ayala, Bristol-Myers Squibb, Genentech, Genomic Health, Gilead, Janssen, Lilly, Merck, Mylan, NanoString, Novartis, Pfizer, and Roche; honoraria from AstraZeneca, Merck Sharp & Dohme, Pfizer, Novartis, and Lilly; research funding/grants from AstraZeneca, Bristol-Myers Squibb, Pfizer, and Roche. GNH: consultancy with, research funding/grants, and travel from Novartis. IK: advisory board membership with AMAG Pharma and Freeline Therapeutics; consultancy with AstraZeneca, Bristol-Myers Squibb, Context Therapeutics, Daiichi Sankyo, Genentech/Roche, Ionis Pharma, Macrogenics, Merck, Novartis, Seagen Inc., and Taiho; employment with AMAG Pharma and Freeline Therapeutics; equity ownership: AMAG Pharma, Freeline Therapeutics, and Vertex; honoraria from AstraZeneca, Celltrion, and Genentech/Roche; research funding/grants from Genentech and Pfizer. SL: consultancy with AbbVie, Amgen, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, GlaxoSmithKline, Immunomedics, Lilly, Medscape, Merck, Novartis, Pfizer, Pierre Fabre, Puma, Samsung, and Seagen Inc.; honoraria from Chugai Pharma; Patent Pending EP14153692.0; research funding/grants from AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics, Myriad Genetics, Novartis, Pfizer, Pierre Fabre, Roche, Seagen Inc., and Vifor Pharma. MP: consultancy and honoraria from Genentech/Roche and Seagen Inc. DS: corporate board membership with BioMarin; consultancy with Lilly, Novartis, Pfizer, and Seagen Inc.; equity ownership in Amgen, BioMarin, Merck Sharp & Dohme, Pfizer, Seagen Inc., Vertex, TORL BioTherapeutics, and 1200 Pharma; honoraria and speaker’s bureau from Novartis; research funding/grants from Novartis, Pfizer, and Seagen Inc.; travel from Novartis and Pfizer. JR: employment and equity ownership with Seagen Inc. WF: employment and equity ownership with Seagen Inc. EW: Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Gilead, GlaxoSmithKline, Jounce, Leap, Lilly, Seagen Inc., Syros Pharma, and Zymeworks; honoraria from Genentech/Roche and Genomic Health; research funding/grants from AstraZeneca and Genentech; other relationship with InfiniteMD.