The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis
- PMID: 39265579
- DOI: 10.1016/j.medj.2024.08.001
The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis
Abstract
Background: Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD.
Methods: This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile.
Findings: At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed.
Conclusions: T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition.
Funding: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.
Keywords: HER2 low; HER2 positive; Translation to patients; advanced breast cancer; leptomeningeal carcinomatosis; phase 2 trial; trastuzumab deruxtecan.
Copyright © 2024. Published by Elsevier Inc.
Conflict of interest statement
Declaration of interests M.V.B. reports participating in a consulting/advisory board for AstraZeneca; participating as an invited speaker for Daiichi Sankyo and Nutricia; and receiving travel fees from AstraZeneca, Daiichi Sankyo, Pfizer, and GSK. J.M.P.-G. reports having a consulting or advisory role for Lilly, Roche, Eisai, Daiichi Sankyo, AstraZeneca, and Seattle Genetics; receiving travel compensation from Roche; and employment at MEDSIR. J.A.G.-S. declares consultative and advisory services for Seagen, AstraZeneca, Daiichi Sankyo, Novaris, Gilead, and Menarini; consultancy/speaker fees from Celgene, Eli Lilly, EISAI, MSD, Exact Sciences, Tecnofarma, Nolver (Adium), Asofarma, and Roche; institution and research funding from AstraZeneca; and travel support from Gilead, AstraZeneca, and Daiichi Sankyo. M.R.-B. reports serving as a consultant to Roche and Puma and receiving honoraria from Roche/Genentech, Pfizer, and Novartis. M.F.-A. reports participating in an advisory board for Seagen and Daiichi Sankyo-AstraZeneca and speakers’ bureau from Novartis and Lilly. M.G. reports receiving honoraria from Roche, Novartis, Gilead, and Daiichi Sankyo and travel compensation from Roche, Pfizer, and Daiichi Sankyo. G.M. is a full-time employee at MEDSIR. D.A.-L. is a full-time employee at MEDSIR. J.P.-E. is a full-time employee at MEDSIR. M.S.-C. reports participating in an advisory board for Optimapharm, Ability Pharma, and MD Anderson and is a full-time employee at MEDSIR. A.L.-C. reports receiving research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daiichi Sanyo; consulting or advisory roles for Lilly, Roche, Pfizer, and Novartis; speakers’ bureaus from Lilly, AstraZeneca, and Merck Sharp & Dohme; travel support from Roche, Pfizer, and AstraZeneca; and stock or other ownership of MEDSIR and Initia-Research. S.B. reports participating in a consulting/advisory board for Daiichi Sankyo, AstraZeneca, Novartis, and Roche; participating as an invited speaker for Daiichi Sankyo, AstraZeneca, Novartis, and Roche; and receiving travel fees from Daiichi Sankyo, AstraZeneca, Novartis, and Roche. J.C. reports serving as a consultant/advisor to Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, and Expres2ion Biotechnologies; receiving honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; research funding to the Institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; stock of MEDSIR, Nektar Pharmaceuticals, and Leuko (relative); travel, accommodations, and expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead; and the following patents: (1) “Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent,” Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde, WO 2014/199294 A, ISSUED; and (2) “Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy,” Aleix Prat, Antonio Llombart, Javier Cortés, US 2019/0338368 A1, LICENSED.
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