What Does Priority Review Mean for Subcutaneous Amivantamab in HNSCC?

Contextualized by the recent FDA decision to grant priority review to subcutaneous amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for adults with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose disease has progressed after platinum-based chemotherapy and a PD-1/PD-L1 inhibitor, CancerNetwork^® spoke with Barbara Burtness, MD, about the impact of this regulatory decision.¹ Specifically, she outlined the biological rationale for dual EGFR/MET targeting; the eligibility criteria behind the phase 1b/2 OrigAMI-4 study (NCT06385080); and how the confirmed 42% overall response rate (ORR) of Cohort 1, which supported the regulatory action, compares with other options after checkpoint inhibitor and chemotherapy failure.^2,3 She also touched upon toxicity management strategies and how the subcutaneous formulation may reshape treatment workflows.

Burtness began by explaining why dual EGFR and MET inhibition addresses resistance mechanisms seen with single-agent EGFR-directed therapy in HPV-independent HNSCC. She then discussed the rationale behind OrigAMI-4’s exclusion of HPV-associated oropharyngeal cancer and patients who received prior anti-EGFR therapy, and how tumor boards should identify appropriate candidates for treatment. Burtness went on to contextualize the durability of amivantamab responses against other agents used after checkpoint inhibitor and chemotherapy failure, outline toxicity management strategies for the multidisciplinary care team, and consider how the subcutaneous formulation may influence infusion workflows and the treatment algorithm going forward.

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.

CancerNetwork: Subcutaneous amivantamab is described as the first head and neck cancer therapy engineered to target both EGFR and MET. For colleagues across disciplines, can you explain why this dual targeting matters biologically in HNSCC, and how it may address resistance mechanisms that limit existing EGFR-directed options?

Burtness: For a long time, targeting of EGFR, predominantly with cetuximab (Erbitux), has been standard of care for HPV-independent head and neck cancer. It has been recognized that a proportion of these cases also express another tyrosine kinase growth factor receptor located in the cell membrane, MET, and some overexpress the ligand for MET, hepatocyte growth factor [HGF]. The target has been identified for a long time. It has also been clear that when you effectively downregulate signaling through EGFR, which is an epithelial marker, you shift signaling in the cell from epithelial to a more mesenchymal signaling in a process known as epithelial-to-mesenchymal transition [EMT]. MET is an important growth factor receptor in that EMT transition, and it is recognized that MET can be upregulated after EGFR inhibition. For HPV-independent cancers, there is a very strong case that MET is driving or contributing to one of the main resistance mechanisms. In HPV-associated cancer, it is a little less clear what the role of MET is, although there are some data from Emory suggesting that viral oncoproteins can drive expression of MET, which is also under investigation.

The priority review was supported by cohort 1 of the OrigAMI-4 study, which excluded patients with HPV-positive oropharyngeal cancer and those previously treated with anti-EGFR therapy. What was the rationale for these exclusion criteria, and how should tumor boards think about identifying appropriate candidates if this regimen is approved?

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.

With a reported 42% confirmed ORR compared with a historical 5-year survival rate of about 15% with standard of care, how do these results compare with other agents currently used after checkpoint inhibitor and chemotherapy failure, and what should surgeons and radiation oncologists know about the durability of these responses when counseling patients on next steps?

This will predominantly be used, at present, in patients with recurrent/metastatic disease who presumably received immunotherapy and chemotherapy because they were already deemed not to have a potentially curative option with a salvage operation or reirradiation. Some of those patients may have had a good enough response to chemotherapy, or chemotherapy plus immunotherapy, that radiation was given just to an escape lesion or something similar. In general, this will be prescribed at present in a population that does not have local treatment options. The interesting thing, though, is that there is an ongoing cohort in OrigAMI-4, Cohort 6, that is looking at pembrolizumab [Keytruda] plus amivantamab in the neoadjuvant setting. There, it may well become a valuable part of multidisciplinary management right at the beginning for HPV-negative cancer.

What toxicity management strategies should the broader care team, including those managing residual effects of prior surgery or radiation, anticipate and coordinate around?

All toxicities seen with subcutaneous amivantamab were previously known from other studies with subcutaneous amivantamab, and they are predominantly class effects of EGFR inhibition and MET inhibition, with the addition of hypersensitivity reactions to the drug itself. Whereas those had been potentially severe with the intravenous formulation, they are not with the subcutaneous formulation; in this trial, there was a 15% rate of drug administration-related reactions, and all of those were grade 1 and 2. There were no grade 3 reactions. In terms of the skin reaction, it is not too dissimilar from a cetuximab reaction, so an approach with topical steroids, sunscreen, and oral minocycline or doxycycline, if it becomes more severe, will feel very familiar to most care teams.

In terms of MET toxicity, you are looking at hypoalbuminemia and some soft tissue edema. There are 2 components to that. One is to do everything you can to maintain albumin, protein intake, and nutritional status, which can sometimes be a little fraught in patients with head and neck cancer anyway. The second is soft tissue edema. To your point about aftereffects of prior chemotherapy or radiation, there is a greater risk for facial edema here, maybe more so than in patients with lung cancer. Working closely with your lymphedema team and helping the patient understand how nutrition and facial edema can be linked through the mechanism of protein loss are the mainstays.

How might the delivery advantage of the subcutaneous formulation change infusion center workflows and multidisciplinary coordination in HNSCC compared with intravenous administration, and where do you see this regimen fitting in the broader treatment algorithm if it receives full approval?

The immediate indication for subcutaneous amivantamab is going to be recurrent/metastatic disease in [patients] who do not have surgical and radiation options, so I imagine that will happen in medical oncology departments. However, there is going to be a workflow advantage to giving it subcutaneously, and it is appealing to patients; they like that nobody has to go digging for their vein and like that they are in and out more quickly. If Cohort 6 looks promising, and we have a randomized trial to add it into the neoadjuvant setting, the question will be whether that means surgeons will be routinely giving this subcutaneously, along with subcutaneous pembrolizumab, before the patient goes to the operating room with no medical oncology involvement. Every health system is going to have to decide that for itself.

Both pembrolizumab and amivantamab in that setting could have toxicities that would probably be best managed on a medical service, and surgeons are in the operating room a lot and do not necessarily like to get a lot of [toxicity-related calls]. At our own institution, I am not sure that is the direction we are headed, but every health system has to figure that out on its own.

References

1. Johnson & Johnson’s Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) receives U.S. FDA priority review as potential first-in-class EGFR- and MET- targeted subcutaneous treatment for advanced head and neck cancer. News release. Johnson & Johnson. July 30, 2026. Accessed August 13, 2026. https://tinyurl.com/4ercx9js
2. 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
3. Burtness B, Rosenberg AJ, Calderon B, et al. Amivantamab in recurrent/metastatic head and neck squamous cell carcinoma 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