A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics

Abstract

Background Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive LMD. Methods This multicenter study enrolled 34 LMD patients in a combined Phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the Phase I; the Phase II was limited to HER2-positive breast cancer. Results Intrathecal trastuzumab was well tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended Phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for Phase 2 dose treated patients was 8.3 months (95% CI 5.2 to 19.6). The Phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2 to 20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable CSF concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. Conclusion This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023

“…However, it is not clear whether these results can be reproduced with photon radiotherapy (LoE 2b/ B/AGO+/−). Patients with HER2+ disease may benefit from intrathecal administration of trastuzumab based on recent studies demonstrating improved outcome (LoE 3a/C/AGO+/−) [29,30].…”

Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan

“…In particular, neratinib plus capecitabine showed preliminary activity in LM, with median LM-PFS of 4 months and OS of 10 months 13 . In addition, the use of intrathecal trastuzumab has demonstrated ORR of 19.2%, SD in 50%, with a CBR of 70%, and median-OS of 10.5 months 14 . Given the favorable CSF pharmacokinetic profile and proven intra-cranial activity, tucatinib has been identified as a potential therapeutic for patients with LM, and is under investigation in the TBCRC049 trial (NCT03501979) 15 .…”

Advances in the Management of Central Nervous System Metastases from Breast Cancer

“…Partial responses were observed in 19.2% of the patients, and stable disease was seen in 50% of the participants. This study suggests the potential for improved outcomes in HER2-positive LMD [ 58 ]. However, further analysis needs to be conducted for the evaluation of intrathecal trastuzumab.…”