Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer.

Abstract

1044 Background: Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine for patients with metastatic HER2+ breast cancer (MBC) who have received ≥1 prior HER2-based regimen in the metastatic setting, including patients with brain metastases (BM). TBCRC049 (NCT03501979) is an investigator-initiated phase 2 single-arm study currently enrolling to evaluate the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly diagnosed LM. Here, we report the pre-specified pharmacokinetic (PK) analysis for the first 15 patients to determine bioavailability of tucatinib and its predominant metabolite, ONT-993, in the CSF. Methods: Eligible patients included adults with HER2+ MBC, KPS > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM were allowed. The primary endpoint is overall survival with an accrual goal of 30 pts. Parallel PK samples were collected in plasma and CSF via Ommaya reservoir on day 1 of cycles 1 and 2 at 0h (baseline), 2-3h, 5-7h and 24h (optional) following initiation of tucatinib 300 mg BID. Tucatinib and ONT-993 were quantified in plasma (n=15) and CSF (n=13) using validated liquid chromatography-mass spectrometry methods. Results: Tucatinib and ONT-993 plasma concentrations were consistent with previous studies and exhibited high interindividual variability. Tucatinib and ONT-993 were detectable in the CSF within 2 hours post tucatinib administration; concentrations ranged from 0.57 to 25 ng/mL for tucatinib (IC50 for tucatinib against HER2 is 3.3 ng/mL) and 0.28 to 4.7 ng/mL for ONT-993. Tucatinib concentrations in the CSF per timepoint were in a similar range to unbound plasma (plasmaub) tucatinib. CSF to plasmaub ratios were generally consistent over time; the steady-state (cycle 2) median tucatinib CSF to plasmaub ratio was 0.83 (0.19 to 2.1). ONT-993 CSF to plasmaub ratios were similar to tucatinib CSF to plasmaub ratios. Conclusions: In patients with LM from HER2+MBC who were treated with tucatinib, trastuzumab, and capecitabine, tucatinib and ONT-993 were detectable in the CSF of all patients at median levels similar to plasmaub tucatinib. This is the first documented evidence of tucatinib distributing into the CSF in patients with HER2+MBC. Efficacy and safety of tucatinib, trastuzumab, and capecitabine in patients with HER2+ LM will be reported upon completion of TBCRC 049 accrual. Clinical trial information: NCT03501979 .

Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases

“…The whole-body-4Brain PBPK model for prediction of tucatinib plasma and CNS pharmacokinetics was verified by comparing model-simulated plasma and CSF data with observed clinical data from two clinical studies (ONT-380–004 and TBCRC049), in which patients with metastatic HER2-positive breast cancer were treated with tucatinib (300 mg twice daily), trastuzumab, and capecitabine ( 24, 25 ). The model well predicted tucatinib mean plasma concentration time profiles and inter-individual variabilities, as demonstrated by > 98% of observed plasma concentration data falling within the 5 th and 95 th percentiles of the simulated population mean plasma time profile ( Fig.…”

Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program

“…Patients received a median number of only one prior treatment before the start of treatment, which may partly explain the longer i-PFS and OS in comparison with our cohort. Notably, tucatinib and the metabolite ONT-993 were detected in both plasma and CSF [ 40 ].…”

Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report

“…Both tucatinib and the parent compound ONT-993 were detectable in cerebrospinal fluid (CSF) within 2 hours after drug administration, with concentrations ranging from 0.57 to 25 ng/mL for tucatinib and 0.28 to 4.7 ng/mL for ONT-993. 44 Steady state CSF-to-plasma ratios were 0.83 for tucatinib and were similar for ONT-993.…”