Zongertinib (selective irreversible HER2 TKI) drives 45% ORR with mostly grade 1 diarrhea in HER2+ CRC

Zongertinib is an irreversible, HER2-selective tyrosine kinase inhibitor designed to spare wild-type EGFR (aiming to reduce classic EGFR-TKI rash/diarrhea) and was evaluated as monotherapy in a pooled subgroup of HER2-positive colorectal cancer across a Phase Ia dose-escalation/expansion study (NCT04886804) and the ongoing Phase II Beamion PANTUMOR-1 trial (NCT06581432). In 20 heavily pretreated HER2-positive CRC patients (n=20; median 2.5 prior systemic lines; 40% had prior HER2-directed therapy including trastuzumab/pertuzumab/T-DXd), confirmed investigator-assessed ORR was 45% (9/20; all PRs) with stable disease in 45% (DCR 90%) and median treatment duration 5.1 months (range 0–18); 35% remained on treatment at cutoff. TRAEs occurred in 70% with only 5% grade ≥3 (one grade 3 lipase increase); most common TRAEs were diarrhea 45% (all grade 1) and rash 15% (all grade 1)—notably milder than HER2-targeted standards in this setting like tucatinib+trastuzumab (FDA-approved for RAS WT HER2+ mCRC) with ORR ~39% and median PFS ~8 months, or T-DXd in HER2+ mCRC with ORR ~38% and grade ≥3 drug-related AEs ~41% (cross-trial comparisons). HER2 amplification/overexpression is a relatively small slice of mCRC (≈3% overall; ~5% in RAS WT), so this is a niche but clinically important biomarker-defined population.