Zanidatamab dose optimization in patients with HER2-positive biliary tract cancer (BTC).

546 Background: Zanidatamab (zani) is a dual HER2-targeted bispecific antibody that binds 2 distinct HER2 domains, resulting in receptor crosslinking, clustering, and internalization as well as leading to reductions in cell-surface levels of HER2, phosphorylation of HER family members (EGFR, HER2, and HER3), downstream signaling, and ligand-dependent and -independent proliferation. Zani also induces complement-dependent cytotoxicity as well as antibody-dependent cellular cytotoxicity and phagocytosis. In the phase 2 HERIZON-BTC-01 study (Study 203), zani 20 mg/kg Q2W demonstrated a 41.3% confirmed objective response rate (cORR) and a manageable safety profile in patients (pts) with previously treated HER2+ BTC (IHC3+/2+ and ISH+). The objective of this analysis is to report optimal dose selection for zanidatamab in patients with HER2+ BTC through pharmacokinetic modeling. Methods: Source data included the phase 1 ZW25-101 study (Study 101; NCT02892123), Study 203 (NCT04466891), and in vitro study for ligand-dependent growth inhibition (LDGI) in HER2-expressing human cancer cell lines. In the LDGI study, cancer cells were cultured in media containing epidermal growth factor and were treated with different zani concentrations. The IC90 value for LDGI was obtained by nonlinear regression using the logistic dose-response model. To assess target saturation, the population pharmacokinetic model was used to simulate clearance at steady state following 5-30 mg/kg Q2W. The clinical utility of zani was evaluated based on the correlation of zani concentrations with both efficacy and safety. Results: Study 101 included 192 patients with HER2-expressing solid tumors (dose ranged from 5-30 mg/kg including QW, Q2W, and Q3W). The Ctrough values following the first zani 5 mg/kg QW dose were below the IC90 (25.0 μg/mL) for LDGI, and no confirmed responses were observed at this dose. The Ctrough values following the first zani dose of 10 mg/kg QW or 20 mg/kg Q2W were above IC90 and the 2 dose levels demonstrated a cORR of 25% and 28.6%, respectively. The simulated clearance suggests that the target-mediated elimination pathway was saturated at the dose level of 20 mg/kg Q2W, since clearance was comparable to that of the higher dose of 30 mg/kg Q2W. The efficacy and safety of 20 mg/kg Q2W was further evaluated in 87 pts with HER2-amplified BTC enrolled in Study 203. The clinical utility analysis based on the data from Study 203 demonstrated that the majority of pts had an exposure range on the plateau part of the efficacy curve. Conclusions: The zani dose of 20 mg/kg Q2W is expected to maximize the clinical benefit for pts with HER2+ BTC based on: reaching the desired target exposure (IC90 for LDGI), saturating target-mediated elimination pathway, and the clinical utility analysis of safety and efficacy. Higher exposures are not expected to result in higher responses. Clinical trial information: NCT02892123 , NCT04466891 .