3106 Background: Zongertinib, an irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Phase Ib/II multicohort trial investigating zongertinib, as monotherapy or combined with other agents, in HER2-positive metastatic breast cancer, metastatic colorectal cancer, and mGEAC. Here, we report the first data from Cohort C (Phase Ib), in which patients (pts) with HER2-positive mGEAC received zongertinib combined with T-DXd, as well as supporting preclinical data. Methods: Preclinical activity of zongertinib plus T-DXd was assessed in xenograft mouse models of HER2-positive gastric cancer. In Cohort C, pts with histologically/cytologically confirmed, unresectable, HER2-positive mGEAC were enrolled. Pts had documented HER2-positive disease (overexpression/amplification) and disease progression following HER2-directed treatment. Pts received escalating doses of zongertinib once-daily plus a fixed dose of T-DXd (6.4 mg/kg) every three weeks. Dose escalation was guided by a BLRM with overdose control. Pts remained on treatment until any protocol-defined stopping criterion occurred. The primary endpoint was 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 mouse models, the addition of zongertinib to T-DXd led to increased antitumor activity. In Beamion BCGC-1, as of November 4, 2025, 19 pts had been enrolled to Cohort C and received zongertinib 60 mg (n=4), 120 mg (n=9), 240 mg (n=4), or 300 mg (n=2). Median age was 63 years, 74% male, 74%/26% ECOG PS 0/1. All pts had received prior trastuzumab-based therapy. Treatment-emergent adverse events (TEAEs; any grade G/G≥3) were reported in 17/9 (89%/47%) pts. AEs related to zongertinib (any G/G≥3) were reported in 13/2 (68%/11%) pts. There were no zongertinib-related G4/5 AEs. The most-common TEAEs (any G/G≥3) were nausea (53%/0%), decreased appetite (47%/5%), and diarrhea (47%/0%). One pt each had G1 pneumonitis and interstitial lung disease; both recovered. AEs leading to zongertinib dose reduction/discontinuation were reported in 1/2 pts. AEs leading to T-DXd dose reduction/discontinuation were reported in 8/1 pts. The first confirmed responses to zongertinib combined with T-DXd were observed across the different zongertinib dose levels (60 mg: 1 CR, 2 PR; 120 mg: 2 PR, 5 SD; 240 mg: 1 PR, 1 SD). Conclusions: No new safety signals were observed for zongertinib in combination with T-DXd; further dose escalation is ongoing. Encouraging clinical activity was observed in pretreated pts with HER2-positive mGEAC who had disease progression following prior trastuzumab-based therapy. Clinical trial information: NCT06324357 .
Nakayama et al. (Wed,) studied this question.