The first report from the DEBBRAH trial, sponsored and designed by MEDSIR, and funded Daiichi Sankyo/AstraZeneca, show encouraging intracranial and extracranial activity of trastuzumab deruxtecan (T-DXd), along with generally manageable toxicity, and maintained quality of life for pretreated patients with stable or active HER2-positive brain metastases (BMs). Of note, this is the first trial to demonstrate T-DXd activity in patients with progressing BMs after prior local therapy.
While HER2-targeted agents have improved outcomes for patients with HER2-positive breast cancer, challenges of discovering therapies that cross the blood brain barrier to deliver therapeutic levels to the central nervous system remain. Both the DESTINY-Breast01 and DESTINY-Breast03 trials demonstrated intracranial response and long-lasting activity of T-DXd in HER2-positive advanced breast cancer (ABC) patients, although did not allow inclusion of patients with active BMs. Therefore, the DEBBRAH trial was designed to determine the efficacy and safety of T-DXd in HER2-positive ABC patients with stable or progressing BMs after local therapy, and asymptomatic untreated BMs, with the last two groups usually excluded from participation in most clinical trials.
Specifically, patients in the study were enrolled into 5 cohorts based on HER2 status and central nervous system involvement:
· Cohort 1: HER2-positive ABC and stable BMs after local treatment with radiotherapy and/or surgery
· Cohort 2: HER2-positive or HER2-low ABC and asymptomatic untreated BMs
· Cohort 3: HER2-positive ABC and progressing BMs after local treatment with radiotherapy and/or surgery
· Cohort 4: HER2-low ABC and progressing BMs after local treatment with radiotherapy and/or surgery
· Cohort 5: HER2-positive or HER2-low ABC and untreated leptomeningeal carcinomatosis
The trial has a single-arm, open-label, five-cohort, phase II study design and recruitment was conducted across 18 sites in Spain and Portugal (ClinicalTrials.gov identifier NTC04420598). Preliminary results were first selected for presentation in a Spotlight Session at the 2021 San Antonio Breast Cancer Symposium and now the results from cohorts 1, 2, and 3 have been endorsed through publication in the prestigious Neuro-Oncology.
The group of patients with HER2-positive ABC included 21 pretreated women, whose median age was 53 years (range 36–77). Eight of the 21 patients were still on treatment at data cut-off, with the primary reasons for discontinuation including progressive disease (33.3%), adverse events (19%), and consent withdrawal (9.5%).
In Cohort 1, at 16 weeks, seven of the eight patients (87.5%) were alive without progressive disease. In Cohort 2, two of the four patients (50%) had partial intracranial response, and no patients had experienced intracranial progressive disease. Four of the nine patients (44.4%) in Cohort 3 experienced intracranial partial responses; with one patient having stable disease lasting >24 weeks, three patients had stable disease <24 weeks, and one patient having progressive disease. The intracranial overall response rate for patients with active brain metastases in Cohorts 2 and 3 was 46.2%.
In terms of safety and tolerability, the most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). There were only two patients that experienced grade 1 interstitial lung disease/pneumonitis, a serious adverse event associated with T-DXd. Of relevance, overall quality of life of most patients did not deteriorate at six months of treatment, suggesting that T-DXd may have served to preserve the global health status of pretreated patients.
While larger studies are required to validate these results, this study demonstrated that T-DXd is safe and effective and will provide another drug option to HER2-positive ABC patients with both stable and active BMs.
Analysis for this trial is still ongoing, and results from cohorts 2 (groups of patients with HER2-low ABC), 4, and 5 are still pending. Contact us for more information about this trial.
