Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastr

TPS509 Background: Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd. Methods: Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and in situ hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing. Clinical trial information: NCT06324357 .