Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases

Abstract

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, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM.

Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint.

Results: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine.

Conclusions: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Keywords: Breast cancer; Deruxtecan; Intrathecal; Leptomeningeal; Trastuzumab.

Graphical abstract

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram demonstrating search and inclusion of studies for meta-analysis.

Fig. 2

Comparison of routes of administration of anti-HER2 therapy. (A) OS and (B) CNS-specific PFS of patients who received intrathecal versus no intrathecal administration of a HER2-targeted regimen. P-values calculated with Log-Rank test.

Fig. 3

Comparison of trastuzumab deruxtecan (TDXd) to other HER2-targeted therapies for breast cancer leptomeningeal metastases. (A) OS and (B) CNS-specific PFS of patients who received treatment with T-DXd compared to those who did not. (C) OS and (D) CNS-specific PFS of patients who received treatment with T-DXd versus T-DM1. (E) T1 post-contrast MRIs obtained from a patient before and while on treatment with T-DXd. Left and right images represent unique views that demonstrate reduction in size of leptomeningeal lesions while on treatment. (F) T1 post-contrast (left) and T2 (right) MRIs obtained from a second patient before and while on treatment with T-DXd. Left (T1 post-contrast) images demonstrate reduction in size of leptomeningeal lesions while on treatment. Right (T2 MRI) images demonstrate improvement in mass effect on the fourth ventricle. The patients presented in (E) and (F) both demonstrated profound clinical improvements, one of which remains on treatment, with response ongoing. Red arrows point to areas of interest to compare in pre- and on-treatment MRIs. P-values calculated with Log-Rank test. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)