TY - JOUR
T1 - Tucatinib's journey from clinical development to clinical practice
T2 - New horizons for HER2-positive metastatic disease and promising prospects for brain metastatic spread
AU - Criscitiello, Carmen
AU - Corti, Chiara
AU - De Laurentiis, Michelino
AU - Bianchini, Giampaolo
AU - Pistilli, Barbara
AU - Cinieri, Saverio
AU - Castellan, Lucio
AU - Arpino, Grazia
AU - Conte, Pierfranco
AU - Di Meco, Francesco
AU - Gennari, Alessandra
AU - Guarneri, Valentina
AU - Visani, Luca
AU - Livi, Lorenzo
AU - Marchetti, Paolo
AU - Puglisi, Fabio
AU - Viale, Giuseppe
AU - Del Mastro, Lucia
AU - De Placido, Sabino
AU - Curigliano, Giuseppe
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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.
AB - 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.
KW - Brain metastasis
KW - Breast cancer
KW - Drug development
KW - HER2
KW - Innovation
KW - TKI
KW - Tucatinib
UR - http://www.scopus.com/inward/record.url?scp=85168814812&partnerID=8YFLogxK
U2 - 10.1016/j.ctrv.2023.102618
DO - 10.1016/j.ctrv.2023.102618
M3 - Review article
C2 - 37639757
AN - SCOPUS:85168814812
SN - 0305-7372
VL - 120
JO - Cancer Treatment Reviews
JF - Cancer Treatment Reviews
M1 - 102618
ER -