Clinical Pharmacologist Pfizer Bothell, Washington, United States
Background: Tucatinib (TUC) is a potent HER2-directed tyrosine kinase inhibitor approved for adults with HER2+ metastatic breast cancer (mBC) who have received prior anti-HER2 therapies in the metastatic setting, and has FDA accelerated approval for adults with RAS WT HER2+ metastatic colorectal cancer (mCRC) that has progressed following fluoropyrimidine- oxaliplatin- and irinotecan-based chemotherapy. TUC is a strong cytochrome P450 (CYP) 3A inhibitor and weak CYP2C8 inhibitor. Paclitaxel (PTX) is used to treat several cancers, including mBC, mCRC and gastric or gastroesophageal junction adenocarcinoma (GEC), and is extensively metabolized to mostly inactive metabolites by CYP2C8 (6-α-hydroxy-PTX and 6-α-3’-p-dihydroxy-PTX) and to a lesser extent by CYP3A (to 3’-p-hydroxy-PTX and 6-α-3’-p-hydroxy-PTX). In MOUNTAINEER-02, a phase 2 trial evaluating the safety and efficacy of TUC in combination with PTX, trastuzumab (TRAS), and ramucirumab (RAM) in previously treated HER2+ GEC patients, we investigated the impact of TUC on PTX pharmacokinetics. Methods: Seventeen subjects with HER2+ GEC were enrolled in the MOUNTAINEER-02 trial. Two PTX doses were evaluated: 60 mg/m2 (n=8) and 80 mg/m2 (n=9) IV (on Days 1, 8 & 15 every 28 days). TUC 300 mg PO BID started 12h post PTX administration on C1D1. The PK of PTX and its main metabolites (6-α-hydroxy-PTX, 3’-p-hydroxy-PTX and 6-α-3’-p-dihydroxy-PTX) in plasma up to 8 hours after the start of PTX infusion was assessed in absence (C1D1) and presence of steady-state tucatinib (C1D8). Results: PTX AUClast did not change in presence of TUC for both 60 mg/m2 (geometric mean ratio [GMR] at C1D8 vs. C1D1 = 1.01, CI90% 0.81-1.26, n=6) and 80 mg/m2 (GMR=0.95, CI90% 0.68-1.33, n=6) PTX dose levels. As expected, the metabolite-to-parent AUClast ratio (MR) of metabolites formed by CYP3A (3’-p-hydroxy-PTX and 6-α-3’-p-dihydroxy-PTX) were reduced in presence of TUC. The MR of 6-α-hydroxy-PTX (formed by CYP2C8) was not reduced in presence of TUC. Adverse events reported for the combination of TUC, PTX, TRAS and RAM were consistent with their known safety profiles. Conclusion: Results from the MOUNTAINEER-02 trial suggest that although TUC inhibits the CYP3A pathway, it does not increase PTX plasma concentrations. Preliminary data indicate that the combination of TUC with PTX, TRAS and RAM is tolerable.
