Background: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous (IV), or intrathecally (IT) administered HER2-targeted therapy regimens for patients with HER2+ BCLM. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BCLM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (IT or IV), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (TDXd). The primary endpoint was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 44 publications with 200 patients, corresponding to 257 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable (OS: HR=0.9, 95% CI: 0.64-1.4, P=0.76; PFS: HR=0.8, 95% CI: 0.57-1.2, P=0.35) and multivariable (OS: HR=1.4, 95% CI: 0.68-3.1, P=0.4; PFS: HR=0.8, 95% CI: 0.41-1.7, P=0.6) analyses, we observed no significant difference between IT, oral or IV administration of HER2-targeted therapy. Meanwhile, ECOG performance status remained independently associated with prolonged OS (HR=2.2, 95% CI: 1.5-3.2, P<0.001) and PFS (HR=2.2, 95% CI: 1.5-3.2, P<0.001 and HR=1.9, 95% CI: 1.4-2.8, P<0.001) in the final multivariable model. ECOG status was not associated with route of trastuzumab delivery (P>0.40). Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors (OS: P=0.647; PFS: P=0.983). In a cohort of 7 patients, TDXd demonstrated improved OS compared to other HER2-targeted therapies and compared to T-DM1 (P<0.05). Conclusions: The results of this meta-analysis suggest that IT administration of HER2-targeted therapy for patients with HER2+ BCLM confers no additional benefit over oral and/or IV treatment regimens. We also present the first evidence supporting the efficacy of TDXd compared to alternative strategies for this patient population. Although the number of patients receiving TDXd in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.