Dr Arnold on the Evaluation of Chemo With Amivantamab or Cetuximab in RAS/BRAF Wild-Type mCRC

"The OrigAMI-2 trial is now the proof of concept…trying to define a new standard of care."

Dirk Arnold, MD, PhD, a professor of oncology and gastrointestinal cancer expert at the University of Hamburg in Germany, discussed the rationale and potential clinical implications of the ongoing phase 3 OrigAMI-2 trial (NCT06662786), which is evaluating subcutaneous amivantamab-aamt (Rybrevant) vs intravenous (IV) cetuximab (Erbitux), both in combination with investigator’s choice of FOLFOX or FOLFIRI, as first-line treatment for patients with left-sided, RAS/BRAF wild-type metastatic colorectal cancer (mCRC).

OrigAMI-2 is currently enrolling with a target accrual of over 1000 patients across more than 200 international sites. The trial is designed to assess progression-free survival (PFS) by blinded independent central review as the primary end point. Key secondary end points include overall survival, investigator-assessed PFS, objective response rate (ORR), duration of response, time to subsequent therapy, curative resection rate, and patient-reported outcomes. Patients are stratified by chemotherapy backbone, prior adjuvant therapy, and extent of disease.

Subcutaneous amivantamab, a bispecific EGFR/MET-targeted antibody co-formulated with recombinant human hyaluronidase PH20, is also being evaluated for its administration route, which may offer improved convenience and a more favorable safety profile compared with traditional IV therapies. In OrigAMI-2, subcutaneous amivantamab is dosed at 1600 mg weekly during the first cycle (2240 mg for patients ≥80 kg), followed by biweekly dosing. IV cetuximab is administered at 500 mg/m² biweekly or 400 mg/m² followed by 250 mg/m² weekly per investigator discretion.

According to Arnold, current standard of care for this patient population involves chemotherapy plus anti-EGFR therapy, typically cetuximab or panitumumab. However, resistance mutations frequently emerge early with selective EGFR blockade. Arnold noted that amivantamab’s mechanism of action may help delay the onset of acquired resistance, potentially improving response durability and long-term outcomes.

Arnold emphasized that OrigAMI-2 is one of the largest trials in mCRC to date and is designed to inform a potential shift in the frontline treatment paradigm. He also noted that the trial complements OrigAMI-3, a second-line study evaluating amivantamab in the same molecular subgroup. Collectively, these trials may define the future role of amivantamab across multiple lines of therapy in patients with RAS/BRAF wild-type mCRC.