Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial

Abstract

Background: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement.

Methods: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3.

Results: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. 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). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis.

Conclusions: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

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

Fig. 1

Patient enrollment and disposition at data cutoff. *Not reported in this article. Patient recruitment in cohorts 4 and 5 was ongoing at the time of data cutoff. ^†One patient reported an intraventricular hemorrhage related to disease progression as serious adverse event. The reason of discontinuation reported for this patient is progressive disease. Abbreviations: ABC, advanced breast cancer; BMs, brain metastases; HER2-LE, HER2-low; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.

Fig. 2

Waterfall plots of best response in patients of cohorts 1-3 with measurable (A) intracranial lesions by RANO-BM, (B) extracranial lesions by RECIST v1.1, and (C) overall lesions by RECIST v1.1. Data cutoff for this analysis was October 20, 2021. Dotted lines denote 30% decrease and 20% increase in tumor size cutoffs for PR and PD, respectively. *Patient was evaluated as SD despite the 60.9% increase in tumor size. The investigator considered there was radiation necrosis instead of PD. ^†Patient had a new brain lesion and was evaluated as PD despite an increase in tumor size <20% (13.6%). ^§Patient showed a 37.5% increase in extracranial lesions (PD) and a 15.8% reduction in intracranial lesions. Overall increase of tumor lesions was 8.6%. The patient was considered as having PD for extracranial lesions and SD for intracranial and for all lesions. ^¶Patient had a new lesion (liver) and was evaluated as PD despite an increase in tumor size <20% (3.5%). Abbreviations: 24w, 24 weeks; PD, progressive disease; PR, partial response; RANO-BM, Response Assessment in Neuro-Oncology Brain Metastases; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.