Abstract Background: Trastuzumab deruxtecan (T-DXd), a novel antibody-drug conjugate (ADC), has shown promising intracranial efficacy in breast cancer (BC) patients with brain metastases (BM). This meta-analysis evaluates the intracranial activity and systemic efficacy of T-DXd in patients with metastatic BC and BM. Methods: A systematic search was conducted from inception until May 6, 2025, across PubMed, Cochrane Library, and oncology conference abstracts (ASCO, ESMO, SABCS, and EANO). Eligible studies included clinical trials and cohort studies reporting outcomes for BC patients with BM receiving T-DXd. Random-effects meta-analysis models with Freeman-Tukey transformations were used for pooling proportions (intracranial clinical benefit rate IC-CBR, intracranial objective response rate IC-ORR, and 12-month systemic overall survival OS). Systemic progression-free survival (PFS) was pooled using a random-effects inverse-variance model. For PFS, means and standard deviations (SDs) were extracted when available or estimated from medians and IQRs using the Wan et al. (2014) method: mean = (Q1 + median + Q3)/3 and SD = (Q3 − Q1)/1.35, adjusted for sample size. Heterogeneity was assessed using the I2 statistic, with values ≤25% considered low, 26-75% moderate, and 75% high. Registration: osf.io/swghm. Results: Of the 489 screened records, 14 studies were included; 1 was a randomized controlled trial, 6 were prospective single-arm trials, and 7 were retrospective cohort studies, including real-world data from early access programs. Median patient age was 56.3 years; 97.3% had HER2-positive BC, and 2.7% HER2-low. Prior cranial radiotherapy was administered in 61%, with concurrent radiotherapy at T-DXd initiation in 1.4%. Median follow-up duration was 12.9 months (IQR: 11-15). T-DXd was administered uniformly at 5.4 mg/kg IV every three weeks, with protocol-specified dose reductions allowed. Pooled IC-CBR was 81% (95% CI: 69-91%, p0.001), indicating strong intracranial clinical efficacy, with low heterogeneity (I2=18.6%). IC-ORR was 62% (95% CI: 51-74%, p0.001), suggestive of substantial intracranial tumor responses. Moderate heterogeneity was noted (I2=71.8%). The pooled mean systemic PFS was 12.6 months (95% CI: 7.1-18.1, I2=99.8%, p0.001). Pooled 12-month OS was 81% (95% CI: 66-93%, p0.001), highlighting favorable survival outcomes despite high heterogeneity (I2=86.5%). Conclusion: T-DXd demonstrates robust intracranial activity and 12-month survival in breast cancer patients with brain metastases. The pooled IC-CBR of 81% notably exceeds historical benchmarks reported with T-DM1 or chemotherapy, which typically range from 30-50% in this population. Prospective studies are needed to refine patient selection and optimize therapeutic sequencing. Citation Format: Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia. Intracranial Activity and Systemic Efficacy of Trastuzumab Deruxtecan in Breast Cancer Patients with Brain Metastases abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-12.
Sarfraz et al. (Tue,) studied this question.