FDA Approves Amivantamab and Hyaluronidase for Recurrent/Metastatic HNSCC

The FDA has granted accelerated approval to subcutaneous amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) as a single agent for adults with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose disease has progressed on or after platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.¹ The indication excludes patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma, as determined by p16 immunohistochemistry.

The approval is based on objective response rate (ORR) and duration of response (DOR) findings from cohort 1 of the phase 1b/2 OrigAMI-4 trial (NCT06385080). Among 102 patients treated with the bispecific epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) antibody, the confirmed ORR by blinded independent central review (BICR) was 42% (95% CI, 32%-52%), with complete responses in 15% of patients and partial responses in 28%.² According to the FDA, currently approved therapies in this setting yield response rates of roughly 20% or lower, and this is the first approval in 10 years for patients with recurrent or metastatic HNSCC previously treated with platinum-based chemotherapy.¹

Among responders, 56% maintained a response for at least 6 months (range, 1.4+ to 19.7+ months).² In the published analysis, the median time to first response was 6.6 weeks (range, 5.6-43.4), the median DOR was not reached (95% CI, 6.9-not reached), and 63% of responses were ongoing at the time of analysis.³ Investigator-assessed ORR was 47% (95% CI, 37%-57%), and 84% of evaluable patients experienced shrinkage of target lesions. At a median follow-up of 11.8 months (range, 1.1-21.9), median progression-free survival was 6.8 months (95% CI, 5.2-8.3) and median overall survival was 12.5 months (95% CI, 10.2-16.8).

"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," Angelo De Claro, MD, director of the FDA's Oncology Center of Excellence, stated 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."

Safety Profile of Subcutaneous Amivantamab in HNSCC

No new safety signals emerged in OrigAMI-4.² Adverse reactions reported in at least 20% of patients were rash (79%), fatigue (39%), nail toxicity (35%), stomatitis (32%), and edema (28%).

Serious adverse reactions occurred in 39% of patients. Those reported in at least 2% of patients included pneumonia (8%), hemorrhage (4.9%), dysphagia (2.9%), pneumothorax (2.9%), anemia (2%), dyspnea (2%), fatigue (2%), increased hepatic enzymes (2%), and interstitial lung disease (ILD)/pneumonitis (2%). Fatal adverse reactions occurred in 6% of patients and included sudden death (2%) as well as 1 case each of myocardial ischemia, tumor hemorrhage, aspiration pneumonia, and ILD/pneumonitis. Administration-related reactions occurred in 13% of patients, all grade 1 or 2, and 8% discontinued because of treatment-related adverse events.³

The prescribing information includes warnings and precautions for hypersensitivity and administration-related reactions, ILD/pneumonitis, dermatologic adverse reactions, ocular toxicity, and embryo-fetal toxicity.¹

OrigAMI-4 Trial Design and Confirmatory OrigAMI-5 Study

OrigAMI-4 is an ongoing, open-label, multicenter phase 1b/2 study with 6 cohorts in recurrent or metastatic HNSCC.² Cohort 1 enrolled patients with HPV-unrelated disease that had progressed on or after platinum-based chemotherapy and a PD-1/PD-L1 inhibitor; patients who had received prior anti-EGFR therapy were excluded.³

Patients received subcutaneous amivantamab at 1600 mg (2240 mg for those weighing at least 80 kg) on cycle 1 day 1, followed by 2400 mg (3360 mg for those weighing at least 80 kg) every 3 weeks until disease progression or unacceptable toxicity. The primary end point was ORR, and the key secondary end point was DOR, both assessed by BICR; additional secondary end points included progression-free survival, overall survival, and safety. The median patient age was 63.5 years, 45% of patients were Asian, and 43% were White.

EGFR and MET are overexpressed in 80% to 90% of recurrent or metastatic HNSCC tumors.² This is the agent's first indication outside of non-small cell lung cancer.

Continued approval may depend on confirmation of benefit in the ongoing phase 3 OrigAMI-5 trial (NCT07276399), which is evaluating subcutaneous amivantamab plus carboplatin and pembrolizumab as first-line treatment for recurrent or metastatic HNSCC. The FDA previously granted breakthrough therapy designation to subcutaneous amivantamab for this indication in February 2026 and priority review in July 2026.

"Outcomes remain poor for patients whose head and neck cancer progresses, and treatment options are limited," Barbara Burtness, MD, medical oncologist and professor of medicine at Yale Cancer Center in New Haven, Connecticut, stated in a news release.² "The OrigAMI-4 findings represent important progress and highlight the potential of dual EGFR- and MET-targeting with amivantamab as a distinct treatment approach in recurrent or metastatic head and neck cancer, excluding HPV-associated oropharyngeal squamous cell carcinoma. The meaningful responses observed in this study are encouraging for patients who have long faced limited treatment options."

References

1. FDA grants accelerated approval to a new treatment for head and neck squamous cell carcinoma. News release. FDA. November 5, 2026. Accessed November 5, 2026. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-new-treatment-head-and-neck-squamous-cell-carcinoma

2. Johnson & Johnson announces U.S. FDA approval of Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) as first and only dual-targeted therapy for advanced head and neck cancer. News release. Johnson & Johnson. November 5, 2026. Accessed November 5, 2026. www.jnj.com/media-center/press-releases/johnson-johnson-announces-u-s-fda-appro…herapy-for-advanced-head-and-neck-cancer

3. Burtness B, Harrington KJ, Ji D, 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