Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases.

Journal Article (Editorial)

PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff. CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.

Full Text

Duke Authors

Cited Authors

  • Kabraji, S; Ni, J; Sammons, S; Li, T; Van Swearingen, AED; Wang, Y; Pereslete, A; Hsu, L; DiPiro, PJ; Lascola, C; Moore, H; Hughes, M; Raghavendra, AS; Gule-Monroe, M; Murthy, RK; Winer, EP; Anders, CK; Zhao, JJ; Lin, NU

Published Date

  • January 4, 2023

Published In

Volume / Issue

  • 29 / 1

Start / End Page

  • 174 - 182

PubMed ID

  • 36074155

Pubmed Central ID

  • PMC9811155

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-22-1138


  • eng

Conference Location

  • United States