Subcutaneous Amivantamab Shows Promise in Previously Treated HPV-Negative Head and Neck Cancer

Clinical Summary:

• Design/Population: Cohort 1 of the phase 1b/2 OrigAMI-4 trial evaluated subcutaneous amivantamab monotherapy in patients with recurrent or metastatic HPV-negative head and neck squamous cell carcinoma whose disease had progressed after platinum-based chemotherapy and immune checkpoint inhibitor therapy.
• Key Outcomes: Amivantamab demonstrated a 42% objective response rate, including complete responses, with durable responses and encouraging progression-free and overall survival. The safety profile was consistent with EGFR and MET inhibition, with low rates of infusion-related reactions using the subcutaneous formulation.
• Clinical Relevance: These findings suggest that dual EGFR/MET inhibition with amivantamab may provide a more effective treatment option than EGFR inhibition alone for previously treated HPV-negative head and neck squamous cell carcinoma.

Barbara Burtness, MD, Yale Cancer Center, New Haven, Connecticut, discusses results from cohort 1 of the phase 1b/2 OrigAMI-4 trial evaluating subcutaneous amivantamab monotherapy in patients with recurrent or metastatic HPV-unrelated head and neck squamous cell carcinoma following progression on platinum-based chemotherapy and immune checkpoint inhibitors. 

Dr Burtness reviews the biologic rationale for dual EGFR/MET inhibition and discusses the encouraging clinical activity observed with amivantamab in this heavily pretreated population. She highlights how these findings compare with historical outcomes achieved using cetuximab and discusses the favorable tolerability of the subcutaneous formulation and the potential impact of this regimen as it undergoes FDA priority review. 

Transcript:

Hello, I'm Barbara Burtness, I'm a professor of medical oncology at Yale School of Medicine and a member of the Yale Cancer Center– my area of focus is head and neck cancer. 

At ASCO 2026, I presented the results of an expanded cohort, cohort 1 from the OrigAMI-4 trial. OrigAMI-4 is a trial of the EGFR-MET bispecific antibody amivantamab given in a number of different lines of therapy or in different combinations, but cohort 1 as for patients who had previously progressed after an immune checkpoint inhibitor and after platinum-based chemotherapy. They were then treated with amivantamab subcutaneously as monotherapy. The patients had all either received 1 or 2 prior lines of therapy with nearly half having this as their third line of therapy.

Why look at amivantamab in recurrent metastatic head and neck cancer? In HPV-unrelated head and neck cancer, which is the type of cancer that the patients in cohort 1 had, we know that EGFR is an important target and the EGFR inhibitor cetuximab has been on the market for a long time for this disease. 

But we also know that EGFR inhibition has only modest effects in terms of response rate and overall survival. Although the benefits of EGFR inhibition may be a little bit greater after prior immune checkpoint inhibitor. If we look at the INTERLINK trial for patients who received cetuximab monotherapy on the control arm, in that study who were HPV negative, the response rate was 24%. 

There's been a lot of interest in what are the mechanisms of resistance to cetuximab– one of the things that's become clear is that even in cases where there's not de novo resistance, the cells adapt.

One of the things that's become clear is that even when there is not de novo resistance to cetuximab, the ability of a cancer cell to adapt to EGFR inhibition by upregulating other pathways, and particularly by undergoing a process called epithelial to mesenchymal transition, allows cell survival despite good inhibition of the EGFR pathway. 

And for this reason, bispecific antibodies that prevent this adaptive response may have advantages over EGFR inhibition alone. The second target of amivantamab after EGFR is MET, and we know that MET is over-expressed in HPV-unrelated head and neck cancer. We know that its expression goes up after EGFR inhibition. This seems like a mechanism that could be highly relevant.

In this trial, 102 patients were treated with amivantamab subcutaneously. The infusion reaction rate was 15%. None of those reactions was grade ≥3, so it was all grade 1 or 2 infusion reactions, and that's consistent with the experience with subcutaneous amivantamab and very distinct from the experience with IV amivantamab. Then the other toxicities were predominantly those that are related to EGFR or MET inhibition: skin rash, low magnesium, low albumin, peripheral edema. 

The hypoalbuminemia is something that I think calls for particular attention in head and neck cancer patients because our patients sometimes have difficulty with swallowing and may come to the study or to the use of amivantamab with some malnutrition. You need to pay attention to protein intake and try to encourage an exercise regimen that's appropriate for the patient.

Primary end point of this study was objective response rate, and it was assessed both by the investigator and by blinded independent central review. The response rate by blinded independent central review was 42%, this included complete responses. For the whole cohort, the complete response rate was 15%, and the number of patients who had early progression was quite low at 16%. The median time to response was 6.6 weeks, which is quite rapid.

Looking across pre-specified subgroups like age, sex, race, ECOG performance score, history of smoking, primary tumor location, the response rate was relatively consistent across all these subgroups. It was highest for those patients with oral cavity cancer at 56%, and it was a little bit lower at 11% in those patients with high body weight who were actually dosed a little bit differently than slightly higher dose than patients whose weight is under 80 kilograms. However, there were only 9 patients in that cohort, so that's a little bit difficult to interpret. 

Although this wasn't a pre-specified subset analysis for patients who had had 2 prior lines of therapy as opposed to 1 prior line of therapy, there was no difference. Median duration of response had not been reached with 56% of responders having a response duration more than 6 months and 87% of complete responses being ongoing.

The median progression-free survival was 6.8 months, and the median overall survival was 12.5 months. I referred earlier to the experience using cetuximab in the post-immunotherapy setting where the response rate had been 24% there, the median overall survival was just over 8 months. Here to see a median overall survival of over a year in patients in second and third line I think is quite impressive. 

The data here have been submitted to the FDA and priority review has been granted. We are hopeful that this is something that will be in hand for our patients because it appears truly to be significantly more active than what we've been using previously, which was cetuximab. Thank you very much.

Source:

Burtness B, Rosenberg AJ, Calderon B, et al. Amivantamab in recurrent/metastatic HNSCC after checkpoint inhibitor and chemotherapy: Pivotal results from the phase 1b/2 OrigAMI-4 study. J Clin Oncol. Published online: May 31, 2026. doi: 10.1200/jco-26-01042

PR Newswire. Johnson & Johnson’s RYBREVANT FASPROTM (amivantamab and hyaluronidase-lpuj) receives US FDA Priority Review as potential first-in-class EGFR- and MET-targeted subcutaneous treatment for advanced head and neck cancer. Accessed on July 30, 2026. https://www.prnewswire.com/news-releases/johnson--johnsons-rybrevant-faspro-amivantamab-and-hyaluronidase-lpuj-receives-us-fda-priority-review-as-potential-first-in-class-egfr--and-met-targeted-subcutaneous-treatment-for-advanced-head-and-neck-cancer-302838985.html