Abstract 4340: DM1 pharmacokinetics in combination with tucatinib in patients with HER2+ LA/M breast cancer

Abstract Background: HER2CLIMB-02 (NCT03975647) is a randomized, double-blinded, placebo-controlled, global phase 3 study designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 (ado-trastuzumab emtansine) in patients with HER2+ locally advanced/metastatic breast cancer (LA/mBC) who received prior treatment with trastuzumab and a taxane in any setting. Tucatinib is a strong cytochrome P450 3A4 (CYP3A4) inhibitor. The T-DM1 unconjugated payload DM1 is primarily metabolized by CYP3A4. Though T-DM1 is contraindicated for concomitant use with strong CYP3A4 inhibitors, no clinical drug-drug interaction studies have been conducted in patients to assess the impact of strong CYP3A4 inhibitors on DM1 PK. Thus, DM1 PK with and without tucatinib was characterized in HER2CLIMB-02. Methods: Patients in HER2CLIMB-02 were randomized to either tucatinib+T-DM1 or placebo+T-DM1 arms. PK samples were collected on Days 1, 2, 3, and 5 in Cycle 2 (intensive PK substudy) and Day 1 of Cycles 3-6 (all patients). DM1 plasma concentrations were analyzed using validated mass spectrometry methods. DM1 PK parameters following T-DM1 administration, including plasma area under the concentration-time curve up to the last time point (AUClast, Cycle 2 only) and maximal concentrations (Cmax, end of T-DM1 infusion), were calculated using Phoenix (WinNonlin v8.2). Statistical summaries were produced using SAS version 9.4 or later. Results: PK data were available for 196 (substudy: n=27) and 206 (substudy: n=20) patients in the tucatinib and placebo arms, respectively. Geometric mean (GM, CV%) Cycle 2 DM1 AUClast values were 4.93 (34%) and 4.37 (23%) day*ng/mL in the tucatinib (n=11) and placebo (n=11) arms, respectively. Cycle 2 GM (CV%) DM1 Cmax values were 2.38 (26%) and 2.75 (24%) ng/mL in the tucatinib (n=23) and placebo (n=20) arms. Geometric mean ratios for Cycle 2 DM1 AUClast and Cmax were 1.13 (CI90% 0.92-1.4) and 0.86 (CI90% 0.76-0.98), respectively, in the tucatinib versus placebo arms. Likewise, DM1 Cmax GM values for Cycles 3-6 in all study patients were similar between tucatinib and placebo arms. Conclusions: DM1 plasma PK was not impacted by tucatinib in patients with HER2+ LA/mBC. Citation Format: Ariel R. Topletz-Erickson, Diqiong Xie, Flavia Storelli, Julie Meyer, Shawna Hengel, Wentao Feng, Lauren Farr, Amit Garg. DM1 pharmacokinetics in combination with tucatinib in patients with HER2+ LA/M breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4340.