In a pharmacokinetic analysis of the first 15 patients in the phase 2 TBCRC049 study, researchers saw the first evidence for concentrations of tucatinib and ONT-993 in the cerebral spinal fluid of patients with HER2+ metastatic breast cancer with newly diagnosed leptomeningeal metastasis.
Tucatinib (Tukyska) and its predominant metabolite, ONT-993, were detectable in the cerebrospinal fluid (CSF) of patients with leptomeningeal metastasis (LM) HER2+ positive breast cancer marking the first evidence for tucatinib distribution into the CSF of patients with HER2+ metastatic breast cancer, according to findings presented at the 2021 virtual ASCO Annual Meeting.
Patients on the phase 2 single-arm TBCRC049 (NCT03501979) study had consistent ranges of tucatinib and ONT-993 upon analysis and were detectable within 2 hours after administration of tucatinib. Concentrations ranged from 0.57-25 ng/mL for tucatinib and 0.28-4.7 ng/mL for ONT-993, from cycles 1 to 2. These concentrations for tucatinib were above the prespecified IC50 levels of tucatinib against HER2 (3.3 ng/mL).
Concentrations of tucatinib in the patients’ CSF were in a similar range to unbound plasma tucatinib, which was used in previous treatments in this patient population. The median ratios of tucatinib concentrations in the CSF over time were 0.60 (0.17-2.0) in the first cycle and 0.83 (0.19-2.1) at the steady state in cycle 2. Moreover, the CSF to unbound plasma ratio was consistent over time with a ratio of 0.83, and ONT-933 ratios were found to be similar at 0.66 (0.18-4.0) in cycle 1 and 1 (0.27-3.8) at cycle 2.
The study is currently still recruiting patients, so results were determined from a pharmacokinetic analysis of the first 15 patients on the study, which is halfway to the accrual goal of 30 patients. Patients eligible for the study were adults with HER2+ metastatic breast cancer Karnofsky Performance Status score > 50, and newly diagnosed LM, which was defined as positive CSF cytology along with radiographic evidence of LM.
Plasma and CSF via Ommaya reservoir were collected on the first day of treatment cycles 1 and 2 following the imitation of twice a day tucatinib at 300 mg. Patients also received trastuzumab (Herceptin) intravenously every 21 days at 6 mg/kg and capecitabine (Xeloda) on days 1-14 at 1000 mg/m2. Concentrations of tucatinib were measured in plasma of all 15 patients and CSF in 13 patients, using validated liquid chromatography-mass spectrometry methods.
The primary end point of this study is overall survival and the study was initially launched to evaluate the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM. Tucatinib was originally approved by the FDA based off the results of the HER2CLIMB (NCT02614794) trial for tucatinib administered orally twice a day and is indicated to treat both central nervous system metastases and systemic disease. Targeting HER2 led to a lower potential for EGFR toxicities in comparison to the use of dual inhibitors. The study is ongoing and will release safety and efficacy results when patient accrual is completed.
Stringer-Reasor E, O’Brien B, Topletz-Erickson A, et al. S 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. J Clin Oncol. 2021;39(suppl 15; abstr 1044). doi: 10.1200/JCO.2021.39.15_suppl.1044