FDA Approves Amivantamab and Hyaluronidase for Metastatic HNSCC

The FDA has granted accelerated approval to amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for the treatment of adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed on or following platinum based-chemotherapy and an anti-PD1/PD-L1 antibody.^1,2

The approval was based on the phase 1b/2 OrigAMI-4 trial (NCT06385080) which demonstrated an overall response rate (ORR) of 42% (95% CI, 32%-52%) with the agent (n = 102), including a 15% complete response (CR) rate.² Moreover, partial responses occurred in 28% of patients and 56% of patients achieved a response that was longer than 6 months.

“Today’s approval represents a meaningful step forward for patients with head and neck squamous cell carcinoma, a disease where treatment options have historically been limited and outcomes remain poor,” said Angelo De Claro, M.D., director of the FDA’s Oncology Center of Excellence in a news release.¹ “This therapy offers patients and their physicians a new option with the potential to make a real difference in people’s lives.”

Notably, the approval follows the February 2026 breakthrough therapy designation for amivantamab and hyaluronidase as well as the July 2026 priority review designation.^3,4

How was OrigAMI-4 designed?

The multi-cohort, open-label study enrolled 6 cohorts of patients, the approval was based off cohort 1 of the trial which required patients to have histologically or cytologically confirmed recurrent or metastatic HNSCC that was considered incurable by local therapies.^2,5 Patients in cohort 1 were also required to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 1 or less, and adequate bone marrow and organ function.⁵

If patients had uncontrolled illness including interstitial lung disease (ILD), pneumonitis, pulmonary fibrosis, they were not included in the trial. Patients were also not allowed to have untreated brain metastases or a history of clinically significant cardiovascular disease.

Patients in cohort 1 of the trial received a subcutaneous injection of amivantamab and hyaluronidase on a bodyweight-based scale that ranged from 1600 mg to 2240 mg on day 1 of cycle one, followed by an injection that ranged from 2400 mg to 3360 mg on days 8 and 15 of cycle 1 and then every 3 weeks from cycle 2 onwards.

ORR by blinded independent central review (BICR) was the primary end point of the trial, whereas secondary end point was duration of response by BICR.²

What was the safety profile of amivantamab and hyaluronidase in metastatic HNSCC?

No new safety signals were identified with the agent and the safety profile was consistent with the established profile of amivantamab. Common adverse effects (AEs) that occurred in at least 20% of patients were rash (79%), fatigue (39%), nail toxicity (35%), stomatitis (32%), and edema (28%). Additonally, serious AEs that occurred in at least 2% of patients were (8%), hemorrhage (4.9%), dysphagia (2.9%), pneumothorax (2.9%), anemia (2%), dyspnea (2%), fatigue (2%), hepatic enzyme increased (2%), and ILD/pneumonitis (2%).

Importantly, AEs led to deaths in 6 patients, 2% of which were sudden deaths and myocardial ischemia, tumor hemorrhage, aspiration pneumonia, and ILD/pneumonitis each accounted for 1%.

What are the next steps for amivantamab and hyaluronidase in metastatic HNSCC?

Johnson & Johnson noted that continued approval for the agent is potentially contingent on its clinical benefit being confirmed by the phase 3