Zongertinib combination therapy in HER2-positive metastatic breast cancer (mBC): First results from a phase Ib/II trial.

Abstract

1044 Background: Zongertinib, an irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Ph Ib/II multicohort trial investigating zongertinib as monotherapy or in combination with other agents in HER2-positive mBC, metastatic colorectal cancer, and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma. Here, we report the first data from 4 Ph Ib cohorts evaluating zongertinib plus antibody-drug conjugates (ADCs) or trastuzumab-based therapy in patients (pts) with HER2-positive mBC, focusing on ADC combinations, as well as supporting preclinical data. Methods: Preclinical activity of zongertinib combinations was assessed in xenograft mouse models. Beamion BCGC-1 includes pts with confirmed, unresectable HER2-positive mBC who progressed following HER2-directed therapy. Pts received escalating doses of zongertinib plus fixed doses of T-DM1 (Cohort A; 3.6 mg/kg), T-DXd (Cohort B; 5.4 mg/kg), trastuzumab (Cohort K; 8 mg/kg loading dose followed by 6 mg/kg) or capecitabine (1000 mg/m 2 ) plus trastuzumab (Cohort G; 8 mg/kg loading dose followed by 6 mg/kg). The primary endpoint is the occurrence of DLTs during the MTD evaluation period. Secondary endpoints included further safety assessments and objective response (investigator-assessed; RECIST v1.1). Results: In xenograft mouse models, the addition of zongertinib to T-DM1 or T-DXd led to increased antitumor activity. As of November 4, 2025, 12 pts had been enrolled to Cohort A (median age: 58 years), 16 to Cohort B (median age: 58 years), 4 to Cohort G (median age: 48 years) and 7 to Cohort K (median age: 58 years). Most pts were heavily pretreated, with prior exposure to T-DXd, T-DM1 and/or TKIs. In Cohort A, treatment emergent adverse events (TEAEs) and zongertinib-related AEs (any grade [G]/G3) were reported in 12/5 (100%/42%) and 11/5 (92%/42%) pts, respectively. Three (25%) pts had AEs leading to zongertinib dose reduction. No pts had an AE leading to zongertinib discontinuation. The most common TEAEs (any G/G3) were increased AST (7/1 [58%/8%] pts), decreased platelet count (5/2 [42%/17%] pts) and increased ALT (5/1 [42%/8%] pts). In Cohort B, TEAEs and zongertinib-related AEs (any G/G3) were reported in 14/7 (88%/44%) and 14/5 (88%/31%) pts, respectively. Three (19%) pts had AEs leading to zongertinib dose reduction and 3 (19%) had AEs leading to zongertinib discontinuation. The most common TEAEs (any G/G3) were anemia (8/2 [50%/13%] pts), diarrhea (8/2 [50%/13%] pts) and nausea (8/1 [50%/6%] pts). No grade 4 or 5 TEAEs occurred in Cohorts A and B. Efficacy analyses are ongoing and will be presented. Conclusions: No new safety signals were observed with zongertinib plus T-DXd or T-DM1. Dose escalation was ongoing in Cohorts A and B at data cutoff. Clinical trial information: NCT06324357 .