The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis

Med. 2025 Jan 10;6(1):100502. doi: 10.1016/j.medj.2024.08.001. Epub 2024 Sep 11.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / mortality
  • Breast Neoplasms* / pathology
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Camptothecin / therapeutic use
  • Female
  • Humans
  • Immunoconjugates / adverse effects
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use
  • Meningeal Carcinomatosis* / drug therapy
  • Meningeal Carcinomatosis* / secondary
  • Middle Aged
  • Progression-Free Survival
  • Receptor, ErbB-2* / metabolism
  • Trastuzumab* / adverse effects
  • Trastuzumab* / pharmacology
  • Trastuzumab* / therapeutic use

Substances

  • Trastuzumab
  • Receptor, ErbB-2
  • trastuzumab deruxtecan
  • ERBB2 protein, human
  • Camptothecin
  • Immunoconjugates
  • Antineoplastic Agents, Immunological

Associated data

  • ClinicalTrials.gov/NCT04420598