Beamion BCGC-1: Four new phase Ib/II cohorts to evaluate oral zongertinib with other agents in HER2-positive metastatic breast cancer (mBC) and metastatic colorectal cancer (mCRC).

TPS3177 Background: Zongertinib, an oral, irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Phase (Ph) Ib/II trial evaluating zongertinib in HER2-positive tumors. Trial details for Cohorts A–K, evaluating zongertinib as monotherapy or combined with T-DM1, T-DXd, or trastuzumab ± capecitabine in patients (pts) with HER2-positive mBC, and with T-DXd in pts with HER2-positive metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC), have recently been published (Hurvitz et al, Future Oncol 2025). In addition to BC and GEAC, early-phase data indicate zongertinib is also active in mCRC (Yoh et al, Ann Oncol 2025, abstr 491P). Here, we report 4 new cohorts (L–O) to evaluate the efficacy and safety of zongertinib plus zanidatamab in HER2-positive mBC, or plus trastuzumab or mFOLFOX6 ± trastuzumab in HER2-positive mCRC. Methods: For the 4 new cohorts, pts must have histologically/cytologically confirmed, unresectable HER2-positive mBC or mCRC, and documented HER2-positive disease (overexpression/amplification). Pts with mBC must have disease progression following ≥1 prior HER2-targeted treatment; pts with mCRC must have disease progression/recurrence during or following their latest treatment. Pts with brain metastases are allowed. There are 3 new Ph Ib cohorts (M, N, and O; each ~20 pts). Cohorts M and N will assess zongertinib in mCRC: pts will receive once-daily zongertinib across escalating dose levels plus mFOLFOX6 every 14 days (Cohort M), or mFOLFOX6 every 14 days + trastuzumab every 21 days (Cohort N; Table). In Cohort O, pts with mBC will receive once-daily zongertinib across escalating dose levels plus zanidatamab every 21 days. Dose escalation will be guided by a BLRM with overdose control. In Ph II, Cohort L, a new dose justification cohort (~40 pts with mCRC), will receive zongertinib 120 mg once daily plus trastuzumab every 21 days. In Ph Ib, the primary endpoint is DLTs during the MTD evaluation period; secondary endpoints include objective response (OR) by RECIST v1.1, DLTs in the on-treatment period, and pharmacokinetics (PK). In Ph II, the primary endpoint is OR by RECIST v1.1; secondary endpoints include PFS, disease control, AEs leading to dose reduction, PK, and pt-reported outcomes. Pts will remain on treatment until any protocol-defined stopping criterion occurs. Clinical trial information: NCT06324357 . Cohort Indication Zongertinib Regimen Ph Ib dose escalation M mCRC + mFOLFOX6: oxaliplatin (85 mg/m 2 ), leucovorin (400 mg/m 2 ), 5-FU (2400 mg/m 2 ) N mCRC + mFOLFOX6: oxaliplatin (85 mg/m 2 ), leucovorin (400 mg/m 2 ), 5-FU (2400 mg/m 2 ) + trastuzumab (8 mg/kg loading; 6 mg/kg maintenance) O mBC + zanidatamab (1800 mg <70 kg; 2400 mg ≥70 kg) Ph II dose justification L mCRC + trastuzumab (8 mg/kg loading; 6 mg/kg maintenance)