Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: a systematic review and meta-analysis

Abstract

Background: Trastuzumab deruxtecan (T-DXd) has shown promising results in patients with breast cancer brain metastases (BCBMs). We conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of T-DXd in the human epidermal growth factor receptor 2 (HER2)-positive BCBM population.

Patients and methods: We searched PubMed, Embase, and Cochrane Library databases as well as American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and San Antonio Breast Cancer Symposium (SABCS) websites for clinical trials (CTs) and observational studies evaluating T-DXd in patients with HER2-positive BCBM. Heterogeneity was assessed with I² statistics. Random effects models were used for all statistical analyses, which were carried out using R software (version 4.2.2).

Results: Ten studies were included, six CTs (n = 189) and four observational studies (n = 130), with a total of 319 patients. The median progression-free survival was 15 months [95% confidence interval (CI) 13.9-16.1 months]. The objective response rate (ORR) was 61% (95% CI 52% to 70%), and the intracranial (IC)-ORR was 61% (95% CI 54% to 69%). No significant differences in ORR and IC-ORR were observed between CTs and observational studies (P = 0.31 and 0.58, respectively). The clinical benefit rate (CBR) was 80% (95% CI 52% to 94%), and the IC-CBR was 70% (95% CI 54% to 82%). The ORR was 68% (95% CI 57% to 77%) in the subgroup of patients with stable BMs and 60% (95% CI 48%-72%) in patients with active BM, with no significant difference between groups (P = 0.35).

Conclusions: Our systematic review and meta-analysis supports the IC activity of T-DXd in patients with stable BM and active BM.

Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) under the protocol number CRD42023422589.

Keywords: HER+; T-DXd; antibody-drug conjugate; brain metastases; breast cancer; human epidermal growth factor receptor 2; trastuzumab deruxtecan.

Figure 1

PRISMA flow diagram of study screening and selection. Green vertical boxes indicate each stage of the screening, and the horizontal boxes present more detailed information about the process, including the steps carried out in each stage. ASCO, American Society of Clinical Oncology; BCBM, breast cancer brain metastasis; ESMO, European Society for Medical Oncology; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SABCS, San Antonio Breast Cancer Symposium.

Figure 2

(A) ORR and (B) IC-ORR in patients with breast cancer and brain metastases.^,,,, , , , , , , , , , Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. Kabraji 2023 includes one HER-negative patient. For the ORR analysis, we incorporated data on the extracranial response from the Kabraji 2023. In Murphy 2023 and DESTINY-Breast01, data were available for only 21 and 17 patients, respectively. For the ORR of the DEBBRAH trial we used data from patients with IC or extracranial lesions. The analysis by Murphy 2023 includes one patient with leptomeningeal disease. HER, human epidermal growth factor receptor; IC, intracranial; ORR, objective response rate.

Figure 3

(A) Clinical benefit rate (CBR) and (B) intracranial (IC)-CBR in patients with breast cancer with brain metastases.^,,, , , ^, Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval (CI). The diamonds represent the estimated overall effect of the meta-analysis based on random effects.

Figure 4

(A) Objective response rate (ORR) and (B) intracranial (IC)-ORR according to brain metastases status.^,,,, , , , , , , ^, Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval (CI). The diamonds represent the estimated overall effect of the meta-analysis based on random effects. BM, brain metastasis.