OrigAMI-5: A randomized, phase 3 study of amivantamab plus pembrolizumab and carboplatin vs standard of care pembrolizumab plus platinum and 5-fluorouracil as first-line treatment in recurrent/metastatic head and neck cancer.

TPS6127 Background: Recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC) is associated with significant morbidity and mortality. Current first-line standard of care regimens, including combinations of pembrolizumab with platinum-based chemotherapy with/without 5-fluorouracil (5-FU), yield low response rates and poor long-term outcomes, with a median survival of approximately 1 year. Many patients with R/M HNSCC exhibit EGFR and MET overexpression. Amivantamab is an EGFR-MET bispecific antibody with immune cell–directing activity that is FDA-approved in EGFR -mutated advanced non-small cell lung cancer. In a prior report of the phase 1b/2 OrigAMI-4 study (NCT06385080), subcutaneous (SC) amivantamab monotherapy demonstrated a confirmed objective response rate of 45% among participants with HPV-unrelated R/M HNSCC whose disease had previously progressed on immune checkpoint inhibitor and platinum-based chemotherapy (Harrington Oral Oncology 2025). The objective of this phase 3 randomized study is to assess the efficacy of SC amivantamab in addition to pembrolizumab and carboplatin, as compared to the standard of care (pembrolizumab plus carboplatin or cisplatin and 5-FU) as first-line therapy for participants with R/M HNSCC. Methods: The ongoing multicenter, global OrigAMI-5 study (ClinicalTrials.gov identifier: NCT07276399) is planned to open in approximately 205 sites in 22 countries. Eligible participants will have HPV-unrelated R/M HNSCC (primary tumor locations: oral cavity, oropharynx, hypopharynx, or larynx); all primary oropharyngeal tumors must be human papillomavirus (HPV)-negative. All participants, regardless of combined positive score (CPS), are eligible but must have local testing results to determine CPS for stratification and be treatment-naïve in the R/M setting; systemic therapy in the locally advanced setting is allowed if completed >6 months prior. Prior exposure to EGFR or MET targeting agents is exclusionary. Approximately 500 participants will be randomly assigned 1:1 to receive SC amivantamab (co-formulated with recombinant human hyaluronidase rHuPH20) with pembrolizumab and carboplatin, or 5-FU plus pembrolizumab and investigator’s choice of carboplatin or cisplatin. Randomization will be stratified by programmed cell death ligand 1 (PD-L1) CPS (<1, 1–19, ≥20) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1). The primary endpoints will be objective response rate and overall survival. Secondary endpoints include progression-free survival, duration of response, and patient-reported outcomes. Safety assessments will include adverse event monitoring and laboratory abnormalities. Clinical trial information: NCT07276399 .