FDA Grants Breakthrough Therapy Designation to Subcutaneous Amivantamab for HNSCC

The FDA has granted breakthrough therapy designation to amivantamab and hyaluronidase-lpuj (Rybrevant Faspro; subcutaneous amivantamab) as monotherapy for the treatment of adult patients with recurrent or metastatic, human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC) following disease progression on or after platinum-based chemotherapy and a PD-L1 or PD-1 inhibitor. The regulatory decision was supported by findings from cohort 1 of the phase 1b/2 OrigAMI-4 study (NCT06385080), which were presented at the 2025 ESMO Congress.

In the efficacy-evaluable population (n = 38) at a median follow-up of 8.3 months (range, 1.1-13.4), the overall response rate (ORR) was 45% (95% CI, 29%-62%). Best responses included complete response (3%), partial response (42%), stable disease (45%), and progressive disease (5%); 2 patients were not evaluable for response. The median time to first response was 6.4 weeks, and the clinical benefit rate (CBR) was 76% (95% CI, 60%-89%). Additionally, 82% of patients experienced target lesion shrinkage. The antitumor responses proved durable, with a median duration of response of 7.2 months (95% CI, 5.3-not evaluable) and a median progression-free survival of 6.8 months (95% CI, 4.2-9.0).

The safety population included 86 patients with a median age of 63.5 years (range, 30-81), all of whom had previously received both immunotherapy and platinum-based chemotherapy. The rate of administration-related reactions was 7%, all of which were grade 1 or 2. The most common grade 3 or higher treatment-emergent adverse effects (TEAEs) deemed related to EGFR inhibition were stomatitis (1%), dermatitis acneiform (7%), rash (2%), paronychia (1%), and pruritus (2%). The most common grade 3 or higher TEAEs related to MET inhibition were hypoalbuminemia (2%) and peripheral edema (1%). Other common grade 3 or higher TEAEs included fatigue (5%), anemia (6%), increased alanine aminotransferase levels (3%), decreased weight (1%), dyspnea (2%), increased aspartate aminotransferase levels (2%), and lymphopenia (5%).

Amivantamab is an EGFR-MET bispecific antibody with a unique triple mechanism of action. Beyond inhibiting the EGFR and MET pathways—the latter of which functions as a key escape pathway for tumors—the drug engages in immune cell-directing activity. In OrigAMI-4, amivantamab was administered via a subcutaneous formulation coformulated with recombinant human hyaluronidase PH20.

The rationale for excluding patients with HPV-positive oropharyngeal cancer and prior anti-EGFR exposure from cohort 1 of the study reflects what was known 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, the goal was to maintain that EGFR inhibition and then add to it in patients expected not to be responding to cetuximab on the basis of MET expression. The cleanest case was in HPV-independent cancer. No biomarker was used to look for MET expression or EGFR expression. For HPV-independent head and neck cancer, EGFR expression is known to be very high across over 90% of cases, and even very low expression is not a predictor of resistance to cetuximab. MET expression can increase in a dynamic fashion after EGFR is inhibited, so amplification or overexpression of MET may not be present at baseline but may go up after EGFR inhibition. There is another cohort in OrigAMI-4 attempting to define whether amivantamab also has activity in HPV-associated cancer.

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. 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. Cetuximab also has a role in combination with radiation; substituting amivantamab for cetuximab during chemoradiotherapy is not recommended, as there is much to learn about tolerability and patient support.

OrigAMI-4 is enrolling patients with recurrent or metastatic HNSCC who had not received prior EGFR-directed therapy and had an ECOG performance score of 0 or 1. Patients are being enrolled across 5 cohorts. In cohort 1, patients with HPV-unrelated disease who had previously received a PD-(L)1 inhibitor and platinum-based chemotherapy received subcutaneous amivantamab monotherapy. All patients in the trial are planned to receive subcutaneous amivantamab at 2400 mg every 3 weeks or 3360 mg every 3 weeks for patients who weigh at least 80 kg. The primary end point of the study is ORR. Secondary end points include duration of response (DOR), CBR, progression-free survival (PFS), overall survival (OS), and safety.

Based on data from OrigAMI-4, the phase 3 OrigAMI-5 study (NCT07276399) is ongoing to evaluate subcutaneous amivantamab plus pembrolizumab (Keytruda) and carboplatin compared with 5-fluorouracil plus pembrolizumab and platinum-based chemotherapy (either carboplatin or cisplatin) in the first-line setting in patients with recurrent or metastatic, HPV-unrelated HNSCC regardless of PD-L1 expression.

Currently, there are limited standard treatment options for patients with recurrent or metastatic HNSCC who have progressed after receiving platinum-based chemotherapy and checkpoint inhibitors. The data showed that the ORR was 45% with amivantamab in that setting, which is a substantial improvement over current standards of care and was the basis of the FDA breakthrough designation. There are also trials now ongoing in the first-line recurrent metastatic setting.