OrigAMI-3: A randomized, phase 3 study of amivantamab plus FOLFIRI vs cetuximab or bevacizumab plus FOLFIRI in participants with recurrent, unresectable, or metastatic RAS/BRAF wild-type colorectal cancer.
Background: Among patients with metastatic colorectal cancer (mCRC), approximately 50% are wild-type for KRAS, NRAS, and BRAF (RAS/BRAF WT) without actionable genomic alterations. Standard first-line therapy for RAS/BRAF WT mCRC is 5-FU-based doublet chemotherapy (FOLFOX or FOLFIRI) plus anti-EGFR or anti-VEGF therapy. The choice of second-line treatment is dependent on first-line treatment (eg, oxaliplatin-based chemotherapy in the first-line necessitates irinotecan-based in the second-line, and vice versa). Known resistance mechanisms to anti-EGFR therapy are MET alterations, with MET amplification occurring in 5%-23% of EGFR-resistant mCRC and increasing in prevalence over subsequent lines of therapy. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity and is FDA-approved for 4 indications in EGFR-mutated advanced non-small cell lung cancer. In the phase 1b/2 OrigAMI-1 study (NCT05379595), amivantamab plus FOLFIRI demonstrated promising antitumor activity, independent of line of therapy, in participants (pts) with RAS/BRAF WT mCRC without prior anti-EGFR exposure (Pietrantonio ESMO 2024). The objective of this phase 3 randomized study is to assess the efficacy of amivantamab plus FOLFIRI vs cetuximab or bevacizumab plus FOLFIRI, as second-line therapy for pts with recurrent RAS/BRAF WT mCRC. Methods: The global OrigAMI-3 study (NCT06750094) is planned to open in 230 sites in 25 countries. Eligible pts will be WT for KRAS, NRAS, and BRAF, have recurrent unresectable or mCRC, and must have had disease progression on one prior line of systemic therapy for metastatic disease (prior regimen must be fluoropyrimidine-based and oxaliplatin-based therapy). Pts with treated, stable, and asymptomatic brain metastases are allowed. Key exclusion criteria include known dMMR/MSI-H status without prior immunotherapy, HER2-positive or amplified tumor, and prior exposure to irinotecan or agents targeting EGFR or MET. Approximately 700 pts will be randomly assigned 1:1 to receive subcutaneous amivantamab (co-formulated with recombinant human hyaluronidase [rHuPH20]) plus FOLFIRI vs intravenous cetuximab or bevacizumab (investigator’s choice, per local guidelines) plus FOLFIRI. Randomization will be stratified by choice of cetuximab or bevacizumab, primary tumor location (left vs right-sided), duration of first-line therapy (<6 months or ≥6 months), and prior anti-VEGF therapy (yes or no). The dual primary endpoints will be progression-free survival by blinded independent central review and overall survival. Secondary endpoints include objective response rate, duration of response, and patient-reported outcomes. Safety assessments will include monitoring adverse events and laboratory abnormalities.
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