Octs-03 a Multicenter, Open-Label, Single-Arm, Multicohort Phase Ii Clinical Trial of Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2 (Her2)-Positive and Her2-Low Advanced Breast Cancer (Abc) With Brain Metastases and/or Leptomeningeal Carcinomatosis (Lmc) – The Debbrah Study

Abstract The DEBBRAH study (NCT04420598) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, in patients with HER2-positive and HER2-low ABC with brain metastases (BM) and/or LMC. Forty-one patients aged ≥18 years were enrolled in 5 cohorts: (1) HER2-positive ABC with non-progressing BM after radiotherapy and/or surgery (n=8); (2) HER2-positive or HER2-low ABC with asymptomatic untreated BM (n=10); (3) HER2-positive ABC with progressing BM after local treatment (n=9); (4) HER2-low ABC with progressing BM after local treatment (n=7); (5) HER2-positive or HER2-low ABC and pathologically confirmed LMC (n=7). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. At the final analysis cut-off (4th April 2023), with a median follow-up of 15.2 months (range 2.1-30.1), three (7.3%) patients were still receiving T-DXd. In cohort 1, the 16-week progression-free survival rate was 87.5% (p0.001), meeting the primary endpoint, with seven out of eight patients alive without progressive disease 16 weeks after initiating treatment, demonstrating intracranial and extracranial activity. Among cohorts 2, 3 and 4, intracranial overall response rates ranged from 50% to 70%. In cohort 5, the median overall survival rate was 13.3 months, meeting the primary endpoint. The most common hematologic treatment adverse events (TEAEs) (≥10%) were anemia (31.7%; 0% G≥3), neutropenia (24.4%; 9.8% G≥3) and thrombocytopenia (17.1%; 4.9% G≥3). Fatigue (60.9%; 4.9% G≥3) and nausea (52.2%; 2.4% G≥3) were the most common non-hematologic TEAEs. One (2.4%) patient died due to drug-related pneumonitis. In conclusion, T-DXd showed impressive activity and was consistent with the known safety profile in patients with HER2-positive and HER2-low ABC with a history of BMs and/or LMC. These results justify Destiny Breast 12 and reinforce the need to include this patient population in clinical trials evaluating HER2-targeted agents.