Tucatinib's journey from clinical development to clinical practice: New horizons for HER2-positive metastatic disease and promising prospects for brain metastatic spread.

Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice.

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Declaration of Competing Interest CCr reports personal fees for consulting, advisory role and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead and Pfizer. All the competing interests were outside the submitted work. CCo has no potential conflicts of interest to disclose. MDL reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos; support for attending meetings and/or travel from Gilead, Novartis, Roche, AstraZeneca; fees for participation on a Data Safety Monitoring Board or Advisory Board from Pfizer, AstraZeneca, Sanofi, Seagen, Novartis, Ipsen, Roche, Pierre-Fabre, Daiichi-Sankyo, GSK. All the competing interests were outside the submitted work. GB is a consultant and/or advisory board member for Amgen, AstraZeneca, Chugai, Daiichi Sankyo, EISAI, Eli Lilly, Genomic Health, Merck Sharp & Dohme, Neopharm, Novartis, Pfizer, Roche and Sanofi. All the competing interests were outside the submitted work. BP has no potential conflicts of interest to disclose. SC reports current presidency of the Italian Association of Medical Oncology (AIOM). All the competing interests were outside the submitted work. LC has no potential conflicts of interest to disclose. GA has no potential conflicts of interest to disclose. PC reports personal fees from Novartis, Eli Lilly, AstraZeneca, Tesaro, Daiichi Sankyo, and Gilead, revealing Genomics, BMS, and Roche. All the competing interests were outside the submitted work. FDM has no potential conflicts of interest to disclose. AG has no potential conflicts of interest to disclose. VG reports personal fees from Eli Lilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, and Eisai. All the competing interests were outside the submitted work. LV has no potential conflicts of interest to disclose. LL has no potential conflicts of interest to disclose. PM declares grants to his Institution from Roche, BMS, Pfizer, Incyte, Novartis, Takeda, MSD, Pierre Fabre; personal payments from Roche, BMS, MSD, Novartis, Pfizer, Pierre Fabre; personal support for congress attendance from BMS, Roche; is President of the Italian Foundation of Personalized Medicine, of AIOM Servizi s.r.l., of the Steering and Verification Board of the ’Regina Elena’ National Cancer Institute. All the competing interests were outside the submitted work. FP reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris; research funding from AstraZeneca, Eisai, Roche. All the competing interests were outside the submitted work. GV has no potential conflicts of interest to disclose. LDM reports institutional grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead; personal consulting fees from Eli Lilly; personal honoraria for lectures, presentations, speakers bureau, manuscript writing or educational events from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, Agendia, Stemline; support for attending meetings and/or travel from Roche, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca; personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, Astrazeneca, Agendia, GSK, Seagen. All the competing interests were outside the submitted work. SDP reports personal fees for consulting or advisory role from Roche, Novartis, Pfizer, Lilly, Celgene, AstraZeneca/MedImmune, Seattle Genetics, Daiichi Sankyo/AstraZeneca, MSD. All the competing interests were outside the submitted work. GC reports personal fees for consulting, advisory role and speakers’ bureau from Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung and Daiichi Sankyo; honoraria from Ellipses Pharma and fees for travel and accommodations from Roche/Genentech and Pfizer. All the competing interests were outside the submitted work.