Who Are The Key Candidates to Receive Subcutaneous Amivantamab for HNSCC?

The rationale for excluding patients with HPV-positive oropharyngeal cancer and prior anti-EGFR exposure from cohort 1 of the phase 1b/2 OrigAMI-4 study (NCT06385080) highlights the strategic development of subcutaneous amivantamab-vmjw (Rybrevant Faspro) in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Speaking with CancerNetwork®, Barbara Burtness, MD, explained that HPV-independent tumors consistently feature high EGFR expression, where MET upregulation often serves as a key mechanism of acquired resistance following EGFR blockade.

Because amivantamab functions as a bispecific antibody targeting both EGFR and MET, cohort 1 specifically selected patients with HPV-negative HNSCC to maximize therapeutic activity without requiring baseline biomarker selection. For multidisciplinary tumor boards, these findings suggest amivantamab may offer an alternative to traditional cetuximab (Erbitux) regimens in the third-line recurrent or metastatic setting following progression on platinum-based chemotherapy and immune checkpoint inhibitors, while its role in combination with definitive radiation therapy remains under investigation.

Burtness is a medical oncologist and Anthony N. Brady Professor of Medicine (Medical Oncology) at Yale Cancer Center in New Haven, Connecticut. She is also the chief translational research officer, chief of Head and Neck Cancers/Sarcoma, co-leader of Developmental Therapeutics, and associate cancer center director for Translational Research at Yale Cancer Center.

Transcript:

Those eligibility criteria specifically reflected what we knew about the role of MET in resistance to EGFR inhibition, with cetuximab having very clear activity in HPV-negative cancer and less clear activity in HPV-positive cancer. To capitalize on the known activity of cetuximab, because amivantamab is an EGFR/MET bispecific antibody, you want to maintain that EGFR inhibition and then add to that in patients who you expect were not responding to cetuximab on the basis of MET expression. The cleanest case was in HPV-independent cancer. We did not use a biomarker to look for MET expression, and we did not use a biomarker to look for EGFR expression.

For HPV-independent head and neck cancer, it is known that EGFR expression is very high across over 90% of cases, and it is also the case that even very low expression is not a predictor of resistance to cetuximab. That is why we do not need to look for EGFR [expression] to use this EGFR/MET bispecific. The reason we do not need to look for—or at least to date have not demonstrated that we need to look for—MET expression is that MET expression can increase in a dynamic fashion after EGFR is inhibited. You might not have amplification or overexpression of MET at baseline, but after you inhibit EGFR, it might go up. For both of those reasons, it was felt that the population classically treated with cetuximab, [those with] HPV-negative head and neck cancer, would be the appropriate patients for this cohort. There is another cohort in OrigAMI-4 that is attempting to define whether amivantamab also has activity in HPV-associated cancer.

In tumor boards, people will be reaching for this in the place where they normally reach for cetuximab at present for recurrent/metastatic disease. Cetuximab also has a role in combination with radiation; that is not something I would recommend substituting amivantamab for during chemoradiotherapy. There is a lot we have to learn about how to do that, whether it is tolerable, and how to support patients through it. But for the [patient with] recurrent/metastatic [disease] who has progressed after chemotherapy and an immune checkpoint inhibitor, amivantamab—now with a response rate of 42% and an overall survival of over a year for those patients, including those who received it in the third line—becomes a more appealing option than cetuximab. For the patient who either received chemotherapy plus [immunotherapy] in the first line or received [immunotherapy] in the first line and chemotherapy in the second line, and you are [considering] cetuximab, that would be the time to substitute amivantamab.

Reference

Harrington KJ, Rosenberg AJ, Yang MH, et al. Subcutaneous amivantamab in recurrent/metastatic head and neck squamous cell cancer after disease progression on checkpoint inhibitor and chemotherapy: preliminary results from the phase 1b/2 OrigAMI-4 study. Oral Oncol. 2025;171:107791. doi:10.1016/j.oraloncology.2025.107791