The clinical treatment of breast cancer with leptomeningeal metastasis is extremely challenging, with patients surviving only a few months. Currently, intrathecal medication is the main treatment for leptomeningeal metastasis, but it comes with a high risk of bleeding and infection; finding effective systemic treatment drugs has been a hot topic of research in recent years. At the 46th San Antonio Breast Cancer Symposium (SABCS 2023) held recently, Professor Marta Vaz Batista from the Doutor Fernando Fonseca EPE Hospital in Portugal reported the results from Cohort 5 of the Phase II DEBBRAH study, which evaluated the efficacy and safety of T-DXd (trastuzumab deruxtecan) in patients with HER2-positive and HER2-low Advanced Breast Cancer (ABC) with brain metastasis (BM) and/or Leptomeningeal Carcinomatosis (LMC).
Study Introduction
Trastuzumab Deruxtecan in patients with HER2-positive or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study
Background:
About 5%-15% of patients with advanced breast cancer (ABC) develop leptomeningeal carcinomatosis (LMC), which is usually associated with a decrease in survival rate and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown significant activity both inside and outside the skull, and thus, is widely used in clinical settings. The DEBBRAH study is evaluating the efficacy and safety of T-DXd in patients with HER2-positive and HER2-low ABC who have brain metastasis (BM) and/or LMC. This report includes the results from Cohort 5, which consists of patients with pathologically confirmed LMC.
Methods:
The DEBBRAH study (NCT04420598), a single-arm, open-label, phase II trial with five cohorts, was conducted across 18 research centers in Spain and Portugal. It enrolled 39 patients aged 18 and over, who had undergone multiple treatments for HER2-positive or HER2-low ABC, with stable disease, disease progression, or untreated BM and/or LMC across five cohorts: (1) HER2-positive ABC with no progression of BM after radiotherapy and/or surgery; (2) asymptomatic, untreated BM in HER2-positive or HER2-low ABC; (3) HER2-positive ABC with BM progression after local treatment; (4) HER2-low ABC with BM progression after local treatment; (5) HER2-positive or HER2-low ABC with cytologically positive LMC in the cerebrospinal fluid. Patients were administered T-DXd intravenously at a dose of 5.4 mg/kg every 21 days until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint for Cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS) as assessed by RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions), overall response rate, clinical benefit rate (CBR); and safety and tolerability assessed according to the NCI-CTCAE v.5.0 standards. The OS was tested using the maximum likelihood estimation method (H0: median OS ≤ 2 months; H1: median OS ≥ 6 months). The results were evaluated with the goal of achieving 80% power at a one-sided α level of 0.05 with 7 patients.
Results:
From April 14, 2021, to April 5, 2022, Cohort 5 included 7 patients. The median age was 57 years (range, 42-69 years), with 3 patients (42.9%) being HER2-positive, and 6 patients (85.7%) having extracranial metastases, of which 2 (28.6%) had brain metastasis (BM), and 3 patients (42.9%) had their disease under control. The median number of prior treatments for advanced disease was 4 (range, 1-8), with no patients receiving prior local therapy related to the central nervous system. As of the data cut-off date (April 4, 2023), the median follow-up time was 12 months (range, 2.5-18.6 months). The median duration of treatment was 9.0 months (range, 2.1-18.6 months).
2 patients (28.6%) were still receiving treatment: one HER2-positive and one HER2-low patient at 18.6 months and 12.0 months, respectively. The median overall survival (OS) was 13.3 months (95% CI, 5.7-NA, P<0.001), achieving the primary endpoint. Among the 5 patients with disease progression, none experienced intracranial progression. There were 4 patients (57.1%) with extracranial progression and 1 patient (14.3%) with clinical deterioration. No objective responses were observed, but 5 out of 7 patients had prolonged disease stabilization (≥24 weeks), with an overall Clinical Benefit Rate (CBR) of 71.4% (95% CI, 29.0-96.3), and the median Progression-Free Survival (PFS) according to RECIST v.1.1 was 8.9 months (95% CI, 4.9-NA).
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 infections (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most common hematological TEAEs. No cases of interstitial lung disease/pneumonia were reported. Four out of 7 patients (57.1%) experienced serious TEAEs unrelated to treatment, and one case of treatment-related serious TEAE (Grade 3 nausea) was reported. No treatment-related deaths were reported.
Conclusion:
T-DXd demonstrated promising activity in patients with HER2-positive and HER2-low leptomeningeal carcinomatosis (LMC) that was pathologically confirmed and previously untreated, without raising new safety concerns. These findings warrant further research to address the unmet needs in treating these challenging conditions.
Researcher Comments
Oncology Frontier: Could you please introduce the results of Cohort 5 from the DEBBRAH study that you reported at the conference?
Professor Marta Vaz Batista: DEBBRAH is a single-arm, open-label, phase II study with five cohorts. In this study, we included 7 patients with advanced HER2-positive and HER2-low breast cancer, and the results showed a median overall survival of 33.3 months. Notably, as of the data cut-off date in April this year, 2 patients were still under treatment. Additionally, the median progression-free survival was 8.9 months, showing favorable outcomes.
Oncology Frontier: How about the safety of T-DXd in patients with HER2-positive or HER2-low leptomeningeal cancer? Are there any adverse reactions that need particular attention during application?
Professor Marta Vaz Batista: Despite the small scale of this trial, we did not identify any new safety risks associated with the use of T-DXd. Some controllable cases were observed in other cohorts, but no instances of pneumonitis occurred in this cohort. Overall, the safety profile is consistent with that observed in larger trials.
Oncology Frontier: Which patients with brain metastases in the DEBBRAH study could benefit from T-DXd treatment? In your opinion, what advantages does T-DXd have that make it beneficial for patients with HER2-positive or HER2-low leptomeningeal cancer?
Professor Marta Vaz Batista: Although our focus was on patients with leptomeningeal carcinomatosis, we have previously reported the results for patients with brain metastases. This trial included patients with stable brain metastases after local treatment, patients with progression of brain metastases after local treatment, and untreated patients with HER2-positive or HER2-low, showing significant effects. For instance, in Cohort 1, which evaluated patients with stable disease after local treatment, the primary endpoint of progression-free survival reached 13.3 months. The overall response rate in other cohorts was about 40%-50%, consistent with studies like tucatinib. Notably, T-DXd showed efficacy both inside and outside the brain, indicating its ability to penetrate and act within the central nervous system.
Marta Vaz Batista
Doutor Fernando Fonseca EPE Hospital , Portugal
