Subcutaneous Amivantamab Nabs Breakthrough Therapy Designation in HNSCC

The FDA has granted a breakthrough therapy designation to subcutaneous amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for the treatment of adults with a specific subset of this disease. The designation applies to patients with recurrent or metastatic HNSCC that is unrelated to human papillomavirus (HPV) and whose disease has progressed following prior treatment with both platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

This regulatory nod is intended to expedite the development and review of an agent. The therapy is currently approved across multiple settings for non–small cell lung cancer and is under active investigation in other solid tumors, including colorectal cancer. The breakthrough designation is reserved for investigational therapies that, based on preliminary clinical evidence, may offer a substantial improvement over existing options on one or more clinically significant endpoints.

The decision was primarily driven by encouraging data from the open-label phase 1b/2 OrigAMI-4 study (NCT06385080), which were presented in a mini-oral session at the 2025 European Society for Medical Oncology Congress. The findings highlighted the agent’s promising clinical activity, demonstrating rapid and durable responses in a patient population that is often heavily pretreated and has few remaining standards of care. This early success has already paved the way for further investigation, with the agent now being evaluated in the phase 3 OrigAMI-5 study (NCT07276399). That trial is assessing the subcutaneous formulation in combination with pembrolizumab and carboplatin against a regimen of 5-fluorouracil plus pembrolizumab and platinum-based chemotherapy as a first-line treatment for patients with HPV-unrelated recurrent or metastatic HNSCC, irrespective of their PD-L1 expression levels.

A Targeted Approach

The OrigAMI-4 study provides the foundational evidence for this new designation. Cohort 1 of the trial specifically enrolled adult participants with HPV-unrelated recurrent or metastatic HNSCC who had experienced disease progression following prior lines of therapy with a checkpoint inhibitor and platinum-based chemotherapy. The study employs a weight-based dosing strategy for subcutaneous amivantamab. Patients receive a dose of 1600 mg on cycle 1 day 1 (or 2240 mg for those weighing 80 kg or more), followed by a maintenance dose of 2400 mg (or 3360 mg for patients ≥80 kg) in subsequent cycles.

As of the July 1, 2025 data cutoff, with a median follow-up of 3.5 months, 86 participants had received at least 1 dose of the study drug. The clinical benefit rate, defined as confirmed response or durable stable disease, was 76%. In the efficacy population of 38 patients, who had a longer median follow-up of 8.3 months, the confirmed objective response rate was 45%. Responses were not only frequent but also rapid and durable; the median time to first response was just 6.4 weeks, and the median duration of response had not yet been reached, clocking in at 7.2 months.

Subcutaneous amivantamab is a fully human bispecific antibody designed to target both EGFR and MET simultaneously.

Safety and Future Directions

From a safety perspective, subcutaneous amivantamab was reported to be well tolerated within the study. Administration-related reactions were observed in only 7% of participants, and investigators noted that no new safety signals emerged beyond the established profile of the intravenous formulation. This favorable tolerability is particularly important for community oncologists managing patients who may have already endured significant toxicity from prior lines of platinum-based therapy and immunotherapy.

The significance of this designation was underscored by Kiran Patel, vice president of Global Head, Solid Tumor Clinical Development and Diagnostics at Johnson & Johnson. “Patients with HPV-unrelated recurrent or metastatic head and neck cancer often face rapid disease progression and have limited treatment options,” Patel stated in the press release announcing the designation. “Receiving Breakthrough Therapy Designation underscores the FDA’s recognition of these early clinical data and the urgent need for new therapies. Dual targeting EGFR and MET has shown meaningful clinical benefit in lung cancer, helping patients live longer by changing disease biology and preventing treatment resistance. We are now applying this same multi-targeted approach in head and neck cancer with the goal of improving outcomes for patients.”

The ongoing phase 3 OrigAMI-5 study will help determine whether this subcutaneous therapy can move from the later-line setting to become a frontline standard.

REFERENCES

1. Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) receives US FDA Breakthrough Therapy Designation for patients with advanced head and neck cancer. News release. February 18, 2026. Accesed February 18, 2026. https://tinyurl.com/5crjz5s6

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