Results of a patient-level pooled analysis of three studies of trastuzumab deruxtecan in HER2-positive breast cancer with active brain metastasis

Abstract

Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibody-drug conjugates has been reported, but the size of individual studies has been small. Therefore, this patient-level pooled analysis was conducted.

Patients and methods: This is a patient-level pooled analysis of the prospective phase II DEBBRAH and TUXEDO-1 trials and the retrospective DFCI/Duke/MDACC cohort. Patients with evaluable active BMs (defined as newly diagnosed and untreated or progressing with measurable tumor-related size after previous local therapy) from HER2-positive breast cancer (BC) and treated with trastuzumab deruxtecan (T-DXd) included in these studies were eligible. The primary endpoint was intracranial objective response rate (ORR-IC) by Response Assessment in Neuro-Oncology (RANO)-BM criteria.

Results: Overall, 37 patients were assessable for intracranial response assessment. BMs progressing after prior local therapy were present in 64.9% of patients. The median patient age was 49.1 years. All patients had received prior trastuzumab and the median number of prior systemic treatment lines was 3 (0-13). The pooled ORR-IC by RANO-BM criteria was 64.9% [95% confidence interval (CI) 47.5% to 79.8%] with low heterogeneity observed between the studies included. The clinical benefit rate by RANO-BM was 81.1% (95% CI 64.8% to 92.0%). The median progression-free survival was 13.3 months (95% CI 8.4-22.6 months) and the median overall survival was 22.5 months (95% CI 14.9 months-not achieved) with high heterogeneity between studies and numerically longer in patients with few prior treatment lines. Quality of life remained stable throughout treatment, with no new safety concerns.

Conclusions: This patient-level pooled analysis of DEBBRAH, TUXEDO-1, and the DFCI/Duke/MDACC cohort indicates clinically relevant intracranial activity of T-DXd in patients with active HER2-positive BC, BMs, and extensive systemic pretreatment. The results therefore support the use of T-DXd when clinically indicated irrespective of BMs.

Keywords: HER2-positive breast cancer; active brain metastases; systemic therapy; trastuzumab deruxtecan.

Figure 1

CONSORT diagram. BM, brain metastasis; CONSORT, Consolidated Standards of Reporting Trials; QoL, quality of life; RANO, Response Assessment in Neuro-Oncology.

Figure 2

Response rate. Best response in patients with active brain metastases. (A) Response rate by individual patients. Best response in patients assessable for intracranial response by RANO-BM criteria (n = 37). 1 = TUXEDO; 2 = DFCI/Duke/MDACC; 3 = DEBBRAH. (B) Intracranial response rate overall and by trials. CI, confidence interval; CR, complete response; DFCI/Duke/MDACC, Dana-Farber Cancer Institute, Duke Cancer Institute, and MD Anderson Cancer Center; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; SD, stable disease.

Figure 3

PFSand OS. PFS in all patients (A) and by number of prior treatment lines (B) (n = 37) (months). OS in all patients (C) and by number of prior treatment lines (D) (n = 37) (months). CI, confidence interval; NA, not achieved; OS, overall survival; PFS, progression-free survival.

Figure 3

PFSand OS. PFS in all patients (A) and by number of prior treatment lines (B) (n = 37) (months). OS in all patients (C) and by number of prior treatment lines (D) (n = 37) (months). CI, confidence interval; NA, not achieved; OS, overall survival; PFS, progression-free survival.