FDA Approves First Dual-Targeted Therapy for Advanced HNSCC

The FDA granted accelerated approval on November 5 to amivantamab and hyaluronidase-lpuj (Rybrevant Faspro; Johnson & Johnson) for adults with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose disease has progressed on or after platinum-based chemotherapy and immunotherapy.¹

Newly-Approved Therapy Targets Key Drivers of HNSCC Tumor Progression

The decision marks the treatment’s first approval beyond non-small cell lung cancer (NSCLC). Amivantamab and hyaluronidase are the only subcutaneous combination therapy approved for adults with EGFR-mutated NSCLC, including those with exon 19 deletions, exon 21 L858R substitution mutations, and exon 20 insertion mutations. Depending on the specific mutation and treatment setting, clinicians may use the dual-targeted therapy as monotherapy or in combination with lazertinib (Lazcluze; Johnson & Johnson) or chemotherapy.

The approval also makes amivantamab and hyaluronidase the first and only dual-targeted therapy approved to treat this patient population. Additionally, it marks the first approval in 10 years of a drug for patients with recurrent or metastatic HNSCC who had received prior platinum-based chemotherapy.²

EGFR and MET are key drivers of tumor progression and are overexpressed in 80% to 90% of recurrent and metastatic HNSCC tumors, often contributing to poor prognosis. Administered as a 5-minute subcutaneous injection, amivantamab and hyaluronidase target both the EGFR and MET pathways simultaneously while activating immune cell-directing activity.

“At a time when treatment advances are urgently needed to improve outcomes for patients, this new option offers renewed hope for patients and their families,” Amanda Hollinger, executive director of the Head and Neck Cancer Alliance, said in a news release.

OrigAMI-4 Demonstrates Clinically Meaningful Responses in Previously Treated HNSCC

The approval, which followed the FDA’s Breakthrough Therapy Designation in February 2026 and Priority Review designation in July 2026, was based on clinically meaningful and durable tumor responses demonstrated in the OrigAMI-4 trial (NCT06385080), a multicohort, multicenter, open-label, ongoing phase 1b/2 study.

The trial includes 6 cohorts evaluating the dual-targeted therapy across different treatment settings and regimens. Cohort 1 evaluated subcutaneous amivantamab administered every 3 weeks in 102 eligible participants whose disease progressed following treatment with a PD-L1 inhibitor and platinum-based chemotherapy.³ The primary end point was overall response rate (ORR), and the secondary end point was duration of response (DOR), both assessed by blinded independent central review.

The confirmed ORR was 42% (95% CI, 32%-52%), including complete responses in 15% of patients and partial responses in 27%, according to findings presented at the 2026 American Society of Clinical Oncology Annual Meeting. Regarding DOR, 56% of participants maintained a response for more than 6 months.

At a median follow-up of 11.8 months (range, 1.1-21.9), median progression-free survival and overall survival were 6.8 months (95% CI, 5.2-8.3) and 12.5 months (95% CI, 10.2-16.8), respectively. Treatment-related discontinuations were low (8%), and adverse events were consistent with previous experience, with no new safety signals. The most common adverse reactions included rash, fatigue, nail toxicity, and edema.

“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,” Barbara Burtness, MD, medical oncologist and professor of medicine at Yale Cancer Center, said in a news release. “The meaningful responses observed in this study are encouraging for patients who have long faced limited treatment options.”

Continued approval may be contingent upon clinical benefit demonstrated in the phase 3 OrigAMI-5 study (NCT07276399), the ongoing confirmatory trial in first-line HNSCC.

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 9, 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 US FDA approval of RYBREVENT 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 9, 2026. https://www.jnj.com/media-center/press-releases/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
3. Burtness B, Rosenberg AJ, Calderon B, et al. Amivantamab in recurrent/metastatic head and neck squamous cell cancer after checkpoint inhibitor and chemotherapy: pivotal results from the phase Ib/II OrigAMI-4 Study. J Clin Oncol. 2026;44(24):2271-2277. doi:10.1200/JCO-26-01042