EGFR/MET BsAb Amivantamab Inflames Tumor, 9-mo PFS in AREG-High Refractory mCRC

Amivantamab, an EGFR–MET bispecific antibody with effector-cell engagement, was given as IV monotherapy in the Phase 1b/2 OrigAMI-1 trial (NCT05379595) to 76 heavily pre-treated, RAS/BRAF/EGFR wild-type metastatic colorectal cancers (mCRC). High baseline AREG/EREG ligand expression doubled median PFS in left-sided, anti-EGFR-naïve disease to 9.1 months versus 4.5 months for low AREG (P<0.01), eclipsing the ~1.9-month PFS seen with regorafenib salvage therapy. Paired baseline and Cycle 3 Day 1 biopsies (n = 17) showed >800 differentially expressed genes: EGFR and cell-cycle signatures dropped (P<0.01) while dendritic-cell, T-inflamed, cytolytic and NK-cytotoxicity scores rose (all P≤0.05), indicating target blockade plus immune activation. However, no new safety signals emerged in this trial; prior OrigAMI-1 read-outs report grade ≥3 rash or hypoalbuminaemia ≤14% with no treatment-related discontinuations.