Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial

Abstract

Background: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet.

Methods: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts.

Results: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis.

Conclusions: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

Keywords: HER2-low; T-DXd; active brain metastases; advanced breast cancer; trastuzumab deruxtecan.

Figure 1

Patient enrollment and disposition at data cut-off. ABC, advanced breast cancer; BMs, brain metastases; HER2, human epidermal growth factor receptor 2; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy. ^∗Patient died as result of a pulmonary embolism and deep vein thrombosis unrelated to the study treatment.

Figure 2

Waterfall plots of best response in patients with HER2-low disease and measurable lesions in cohorts 2 and 4. (A) Intracranial best response by RANO-BM; (B) extracranial best response by RECIST v.1.1; (C) overall (intracranial + extracranial) best response by RECIST v.1.1. Data cut-off for this analysis is 5 January 2023. One patient for cohort 2 did not have extracranial measurable lesions and is not shown in panel (B). Dotted lines indicate a 30% reduction and 20% increase from baseline, which are the cut-off values used to determine partial response and progressive disease, respectively. HER2 protein expression by immunohistochemistry and hormone receptor status is reported at the bottom of the figures (positive versus negative). 24w, 24 weeks; HER2, human epidermal growth factor receptor 2; HR, hormone receptors; PD, progressive disease; PR, partial response; RANO-BM, Response Assessment in Neuro-Oncology Brain Metastases; SD, stable disease.