Abstract PS11-05: Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study

Abstract Background: Leptomeningeal carcinomatosis (LMC) occurs in approximately 5-15% of patients (pts) with advanced breast cancer (ABC) and is associated with poor survival and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity, leading to its widespread clinical use. DEBBRAH is evaluating the efficacy and safety of T-DXd in pts with HER2[+] and HER2-low ABC with a history of brain metastases (BM) and/or LMC. Here, we report results from cohort 5 that included pts with pathologically confirmed LMC. Methods: DEBBRAH (NCT04420598) is a single-arm, open-label, five-cohort, phase 2 study conducted across 18 sites in Spain and Portugal. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC and LMC with positive cerebrospinal fluid cytology. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response, clinical benefit rate (CBR) according to RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions); and safety and tolerability as per NCI-CTCAE v.5.0. OS was tested with the maximum likelihood exponential method (H0: median OS ≤2 months; H1: median OS≥6 months). We estimate that 7 pts are needed to attain an 80% power at the nominal level of one-sided α of 0.05. Results: Between Apr 14, 2021, and Apr 5, 2022, 7 pts were allocated into cohort 5. Median age was 57 (range, 42–69) years, 3 (42.9%) pts were HER2[+], 6 (85.7%) pts had synchronous extracranial metastases, 2 of whom (28.6%) also presented BM, and 3 (42.9%) pts had measurable disease. Median number of previous lines of therapy for advanced disease was 4 (range, 1-8) and no patient received prior local treatment for central nervous system involvement. At data cut-off (Apr 4, 2023), median follow-up was 12 months (range, 2.5-18.6). Median duration of treatment was 9.0 months (range, 2.1-18.6). Two (28.6%) pts remained on treatment: 1 HER2[+] and 1 HER2-low, after 18.6 and 12.0 months, respectively. Median OS rate was 13.3 months (95% CI, 5.7-NA, p< 0.001) meeting the primary endpoint. Among 5 pts with disease progression, none had intracranial progression. A total of 4 (57.1%) pts presented extracranial progression and 1 (14.3%) patient had clinical worsening. No objective responses were observed, but 5 out of 7 pts had prolonged stabilization (≥24 weeks) for an overall CBR of 71.4% (95% CI, 29.0-96.3) and a median PFS of 8.9 months (95% CI, 4.9-NA) according to RECIST v.1.1. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were nausea (57.1%; 14.3% G3), fatigue (42.9%; 0% G3), vomiting (42.9%; 0% G3), headache (42.9%; 0% G3), and urinary tract infection (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most frequent hematological TEAEs. No cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 4 (57.1%) of 7 pts, and 1 patient experienced a related serious TEAE (nausea G3). No treatment-related deaths were reported. Conclusions: T-DXd showed promising activity with no new safety concerns in HER2[+] and HER2-low pts with previously untreated, pathologically confirmed LMC. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. Citation Format: Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez-Castedo, Fabriccio Racca, Salvador Blanch, Manuel Ruíz - Borrego, Adela Fernández, María Fernández-Abad, Vega Iranzo, Maria Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofía Braga, Javier Cortés. Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-05.