Abstract 202TiP
Background
HER3-DXd, a first-in-class HER3 directed antibody drug conjugate, has demonstrated clinically meaningful antitumor activity in heavily pre-treated HER2-negative (HER2-) metastatic breast cancer (BC) across a broad range of HER3 expression levels. TOT-HER3 aims to generate translational data and to explore potential predictive biomarkers of HER3-DXd activity. Recently, the results from Part A of the trial showed that one dose of HER3-DXd is associated with clinical response, increased immune infiltration and proliferation suppression in hormone receptor positive (HR+)/HER2- early BC (EBC) (Prat et al. ESMO Breast 2022). Based on these results, TOT-HER3 trial will further investigate the biological activity of HER3-DXd across different BC subtypes.
Trial design
This is a window-of-opportunity, multicenter, pre-operative trial designed to evaluate the biological activity of a single dose of HER3-DXd in multiple BC cohorts. Pre-/post-menopausal women, or men with untreated, primary operable EBC (≥1 cm by ultrasound/MRI) and local Ki67≥10% are eligible. In Part A, 78 patients were enrolled and categorized based on baseline ERBB3 mRNA levels. Patients received one dose of HER3-DXd (6.4 mg/kg). A Part B, including two additional cohorts, is now planned. The first cohort will enroll 20 patients with HR+/HER2- EBC and the second one 15 patients with triple-negative EBC. Patients will receive a single dose of HER3-DXd (5.6 mg/kg). Pre- and post-treatment (C1D21) biopsy and longitudinal blood samples will be obtained for the exploration of primary and correlative endpoints. The primary objective of the part A was to evaluate the mean change in the CelTIL score (Nuciforo P., Annals Oncol 2018) between pre- and post-treatment tumor samples. Secondary objectives in the overall trial population and in part B include: variation in CelTIL score between paired tumor samples; overall response rate at C1D21; correlation between CelTIL change and baseline expression of ERBB3 and HER3 IHC; ERBB3 and HER3 dynamics; CelTIL variation across PAM50 subtypes; safety; and additional pharmacokinetic, genomic and circulating biomarkers.
Clinical trial identification
EudraCT: 2019-004964-23. NCT04610528, Initial Release: 10/27/2020.
Editorial acknowledgement
Legal entity responsible for the study
SOLTI innovative cancer research.
Funding
Daiichi Sankyo Inc.
Disclosure
M. Oliveira: Financial Interests, Personal, Advisory Board: Roche, GSK, PUMA Biotechnology, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Seattle Genetics, Novartis, MSD, Guardant Health, Pfizer, AstraZeneca, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Genentech, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, Zenith Epigenetics; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research. J.M. Cejalvo Andujar: Financial Interests, Institutional, Invited Speaker: Pfizer, Novartis. M. Margeli Vila: Financial Interests, Institutional, Research Grant: Pfizer, nanoStringTranslational Research Request and Celgene; Financial Interests, Personal, Advisory Board: Novartis, Lilly; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Lilly; Financial Interests, Personal, Other, • Travel expences and congress assistance: GILEAD, Pfizer, Roche. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: pharmaMar, roche, Lilly, Pfyzer, Novartis, Gilead, AstraZeneca, Daichii, Seagen, GSK, bayer; Financial Interests, Personal, Invited Speaker: pharmaMar, Roche, Lilly, Pfyzer, Novartis, Eisai, Gilead, AstraZeneca, Daichii, Seagen, Esteve, roche. M.J. Vidal Losada: Financial Interests, Personal, Other, personal honoraria: Pfizer, Novartis, Roche, AstraZeneca and Daiichi Sankyo; Financial Interests, Personal, Other, travel, accommodations and expenses: Roche and Pfizer; Financial Interests, Personal, Advisory Role: Roche and Novartis. S. Pernas Simon: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daichii-Sankyo. G. Villacampa Javierre: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK. A. Santhanagopal: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.