FDA Grants Breakthrough Therapy Designation to Subcutaneous Amivantamab for Advanced 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.¹

This 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. At a median follow-up of 8.3 months (range, 1.1-13.4), the overall response rate (ORR) in the efficacy-evaluable population (n = 38) was 45% (95% CI, 29%-62%).² 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.

“Currently, we have limited standard treatment options for that patient population,” Ranee Mehra, MD, said in an interview with OncLive®. “The data showed that the ORR was 45% with amivantamab in that setting, which is a substantial improvement over our current standards of care. [This was] the basis of [subcutaneous amivantamab receiving] FDA breakthrough designation. Those are exciting data because they give us a potential future treatment option for these patients and allow for the development of this drug in the recurrent setting for patients who have received prior treatment. There are also trials now ongoing in the first-line recurrent metastatic setting.”

Mehra is director of Head and Neck Medical Oncology and a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center in the University of Maryland Medical System in Baltimore.

What is the design of the OrigAMI-4 study?

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.

What was the safety profile of subcutaneous amivantamab monotherapy in recurrent HNSCC?

In the safety-evaluable population (n = 86), 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%).

Notably, the rate of administration-related reactions was 7%, all of which were grade 1 or 2. The study investigators deemed this finding and the overall safety profile in this study to be consistent with prior reports of subcutaneous amivantamab.

What are the future directions for investigating subcutaneous amivantamab in HNSCC?

Based on data from OrigAMI-4, the phase 3 OrigAMI-5 study (NCT07276399) is ongoing to evaluate subcutaneous amivantamab plus pembrolizumab (Keytruda) and carboplatin (paraplatin) compared with 5-fluorouracil (Adrucil) 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.^1,3 This trial is enrolling patients at least 18 years of age who have an ECOG performance status of 0 or 1 and measurable disease per RECIST 1.1 criteria.³ The primary end points are OS and ORR. Secondary end points include PFS, DOR, safety, and quality of life (QOL).

“Patients with recurrent or metastatic head and neck cancer can be symptomatic from their disease, so having treatment options that will result in significant and deep responses is vital to improve their QOL,” Mehra concluded.

References

1. Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) plus immunotherapy shows strong clinical benefit with 56 percent overall response rate in first-line recurrent or metastatic head and neck cancer. News release. Johnson & Johnson. February 19, 2026. Accessed February 20, 2026. https://www.jnj.com/media-center/press-releases/rybrevant-faspro-amivantamab-and-hyaluronidase-lpuj-plus-immunotherapy-shows-strong-clinical-benefit-with-56-percent-overall-response-rate-in-first-line-recurrent-or-metastatic-head-and-neck-cancer
2. Harrington KJ, Rosenberg A, Yang M-H, et al. 1327MO Amivantamab in recurrent/metastatic head & neck squamous cell cancer (HNSCC) after disease progression on checkpoint inhibition and chemotherapy: results from the phase Ib/II OrigAMI-4 study. Ann Oncol. 2025;36(suppl 2):S773. doi:10.1016/j.annonc.2025.08.1959
3. A study of amivantamab in addition to standard of care agents (SOC) compared with SOC alone in participants with recurrent/​metastatic head and neck cancer (OrigAMI-5). ClinicalTrials.gov. Updated February 13, 2026. Accessed February 20, 2026. https://clinicaltrials.gov/study/NCT07276399