A new phase II clinical trial has demonstrated promising intracranial activity for trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced breast cancer and active brain metastases, addressing an important unmet need in this challenging patient population.
The DEBBRAH trial was a single-arm, open-label, five-cohort phase II study conducted across 21 sites in Spain and Portugal. The study was funded by Daiichi Sankyo and AstraZeneca, though the sponsors did not participate in data collection, analysis, interpretation or manuscript preparation. Results were published in January 2024 in the journal ESMO Open.
The primary purpose of the DEBBRAH trial was to evaluate the efficacy and safety of T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low advanced breast cancer. This article focuses specifically on the results for patients with HER2-low disease and active brain metastases, who were enrolled in cohorts 2 and 4 of the study.
A total of 12 patients with HER2-low advanced breast cancer and active brain metastases were included in this analysis - 6 patients in cohort 2 with asymptomatic untreated brain metastases and 6 patients in cohort 4 with progressing brain metastases after prior local therapy. Key inclusion criteria were: age ≥18 years, at least one measurable brain lesion ≥10 mm on MRI, ECOG performance status 0-1, normal liver and renal function, prior treatment with at least one chemotherapy regimen for advanced disease, and previous treatment with one endocrine therapy-based regimen for patients with hormone receptor-positive disease.
The median age of patients was 54 years (range 40-73). All patients were female and had at least three metastatic organ sites. Nine patients (75%) had hormone receptor-positive tumors and 10 patients (83.3%) had HER2 IHC 1+ expression. Patients were heavily pretreated, with a median of 4 prior lines of therapy for advanced disease (range 2-8).
Patients received T-DXd at a dose of 5.4 mg/kg intravenously once every 21 days until disease progression, unacceptable toxicity, withdrawal from study, or study completion. The primary endpoint was intracranial objective response rate (ORR-IC) sustained for at least 4 weeks based on investigator assessment using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
The results showed encouraging intracranial activity for T-DXd in this difficult-to-treat population. In cohort 2 (asymptomatic untreated brain metastases), the intracranial objective response rate was 50% (3 of 6 patients, 95% CI 11.8-88.2%). In cohort 4 (progressing brain metastases after local therapy), the intracranial objective response rate was 33.3% (2 of 6 patients, 95% CI 4.3-77.7%, p=0.033). All responders had partial responses.
The overall intracranial objective response rate across both cohorts was 41.7% (95% CI 15.2-72.3%). The intracranial clinical benefit rate, which includes complete response, partial response and stable disease for ≥6 months, was 66.7% in cohort 2 and 50% in cohort 4. The median time to intracranial response was 2.3 months (range 1.5-4.0) and the median duration of intracranial response was 7.2 months (range 2.8-16.8).
In terms of overall efficacy (intracranial plus extracranial), the objective response rate was 50% (95% CI 21.1-78.9%) and the clinical benefit rate was also 50%. The median progression-free survival was 5.4 months (95% CI 4.1-10.0 months). Overall survival data were still immature at the time of analysis.
The safety profile was generally consistent with previous studies of T-DXd. All patients experienced at least one treatment-emergent adverse event, with grade 3 events occurring in 16.7% of patients. The most common adverse events of any grade were fatigue (75%), nausea (58.3%), vomiting (33.3%), increased gamma-glutamyltransferase (33.3%), and anemia (33.3%). Three patients (25%) experienced grade 1 interstitial lung disease/pneumonitis. There were no grade 4 or 5 treatment-related adverse events.
The study had some important limitations, including its non-randomized single-arm design and small sample size. Additionally, because cohort 2 included both HER2-positive and HER2-low patients, the results for the HER2-low subgroup in that cohort are descriptive only without formal statistical analysis. The authors acknowledge that these findings are hypothesis-generating and require validation in larger cohorts.
Nevertheless, the researchers concluded that T-DXd demonstrated promising intracranial activity in heavily pretreated patients with HER2-low advanced breast cancer and active brain metastases. They note that this is an important unmet need, as patients with active brain metastases are often excluded from clinical trials and have limited treatment options.
The potential clinical impact of these findings is significant. Brain metastases occur in approximately 30% of patients with advanced breast cancer overall and are associated with poor prognosis. While the incidence of brain metastases is particularly high in HER2-positive and triple-negative breast cancer, the specific occurrence in HER2-low disease is not well described. Current management of HER2-low breast cancer with brain metastases relies largely on chemotherapy and/or radiotherapy.
T-DXd is already approved for HER2-positive and HER2-low advanced breast cancer based on previous pivotal trials. However, those studies included very few patients with brain metastases, particularly active brain metastases. The DESTINY-Breast04 trial, which led to approval in HER2-low disease, showed a consistent benefit for T-DXd over chemotherapy in a small subgroup of patients with stable brain metastases. But its efficacy in patients with active brain metastases had not been specifically assessed until now.
The intracranial response rates seen in this study (50% in untreated brain metastases and 33.3% in progressing brain metastases) are encouraging in this heavily pretreated population. For context, the overall response rate in the DESTINY-Breast04 trial in HER2-low metastatic breast cancer was 52.6% with T-DXd. The fact that similar response rates were seen intracranially in patients with active brain metastases is noteworthy.
Additionally, the median progression-free survival of 5.4 months is clinically meaningful in this population with poor prognosis, though it is shorter than the 9.9 months seen in the overall DESTINY-Breast04 population. This likely reflects the negative prognostic impact of active brain metastases.
The safety profile, including the rate of interstitial lung disease/pneumonitis, was generally consistent with larger studies of T-DXd, suggesting that patients with brain metastases may not be at substantially higher risk of toxicity. However, the small sample size limits definitive conclusions about safety.
If confirmed in larger studies, these results could potentially expand the use of T-DXd to patients with HER2-low advanced breast cancer and active brain metastases - a group that currently has very limited treatment options. This could significantly impact clinical practice, as these patients are often excluded from clinical trials and treatment decisions are frequently based on limited evidence.
The findings also highlight the importance of including patients with active brain metastases in clinical trials of new agents. The authors note that while several ongoing studies are evaluating T-DXd in HER2-low advanced breast cancer, they all exclude patients with active brain metastases. They argue that their results reinforce the need to include these patients in future trials.
It's worth noting that this study used the previous definition of HER2-low (IHC 1+ or IHC 2+/ISH-negative). Recent guidelines have redefined HER2-low as only IHC 1+, with IHC 2+/ISH-negative now classified as HER2-intermediate. However, the vast majority of patients in this study (83.3%) had IHC 1+ expression, so the results are still relevant under the new classification system.
In conclusion, this phase II study provides preliminary evidence of meaningful intracranial activity for T-DXd in patients with HER2-low advanced breast cancer and active brain metastases. While further research is needed to confirm these findings, they address an important knowledge gap and could potentially impact clinical practice in this challenging patient population. The results also underscore the feasibility and importance of including patients with active brain metastases in clinical trials of targeted therapies for advanced breast cancer.
References
Vaz Batista M, Pérez-García JM, Cortez P, et al. Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial. ESMO Open. 2024;9(9):103699. doi:10.1016/j.esmoop.2024.103699
