FDA Breakthrough Designation Expands Amivantamab Beyond Lung Cancer

The granting of breakthrough therapy designation (BTD) by FDA to Johnson & Johnson’s subcutaneous amivantamab and hyaluronidase-lpuj (brand name Rybrevant Faspro) for treating adults with recurrent or metastatic human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC) expands the oncological applications of amivantamab, a bispecific antibody. The indication is for patients who have progressed on platinum-based chemotherapy and a programmed cell death protein 1 (PD-1) or PD-L1 inhibitor. ¹

The designation expands the development of amivantamab and hyaluronidase-lpuj, a co-formuated product, beyond lung cancer and is supported by early clinical data demonstrating rapid and durable responses in a heavily pretreated population with limited treatment options, according to the company.

“Patients with HPV-unrelated recurrent or metastatic head and neck cancer often face rapid disease progression and have limited treatment options,” said Kiran Patel, vice president, global head, Solid Tumor Clinical Development and Diagnostics, Johnson & Johnson, in a company press release.¹ “Receiving [b]reakthrough [t]herapy [d]esignation underscores [FDA’s] recognition of these early clinical data and the urgent need for new therapies.”

What is driving the breakthrough designation?

The BTD is supported by results from an open-label Phase Ib/II study (OrigAMI-4, NCT06385080), which evaluated amivantamab and hyaluronidase-lpuj as monotherapy in patients with HPV-unrelated recurrent or metastatic HNSCC who had previously received platinum chemotherapy and PD-1/PD-L1 immunotherapy.

Data presented at the 2025 annual meeting of the European Society for Medical Oncology showed promising clinical activity, including rapid and durable responses. The primary endpoint is overall response rate assessed by blinded independent central review using RECIST v1.1 criteria.²

Patients with prior anti- epidermal growth factor (EGFR) therapy were excluded. The subcutaneous formulation was administered every three weeks at 2400 mg or 3360 mg for patients weighing 80 kg or more.

FDA grants BTD to investigational therapies intended to treat serious or life-threatening conditions when preliminary clinical evidence indicates potential substantial improvement over available options on at least one clinically meaningful endpoint. The designation enables expedited development and regulatory review.¹

Why target EGFR and MET in HPV-unrelated HNSCC?

HPV-unrelated recurrent or metastatic HNSCC is associated with high rates of EGFR expression and overexpression of the mesenchymal-epithelial transition (MET) pathway. These tumors are typically more aggressive and less responsive to treatment than HPV-positive disease, and outcomes following immunotherapy progression remain poor.³

Amivantamab, a fully human bispecific antibody, is designed to target both EGFR and MET while engaging immune effector mechanisms. The dual-target approach is intended to address tumor signaling and treatment resistance pathways simultaneously. Dual EGFR and MET inhibition has previously demonstrated clinical benefit in EGFR-mutated non-small cell lung cancer, supporting exploration of this mechanism in additional solid tumors.⁴

“Dual targeting EGFR and MET has shown meaningful clinical benefit in lung cancer, helping patients live longer by changing disease biology and preventing treatment resistance. We are now applying this same multi-targeted approach in head and neck cancer with the goal of improving outcomes for patients,” Patel said.¹

What comes next in clinical development?

Subcutaneous amivantamab is now being evaluated in a Phase III trial (OrigAMI-5, NCT07276399). The study is assessing the subcutaneous formulation in combination with pembrolizumab and carboplatin versus standard 5-fluorouracil plus pembrolizumab and platinum-based chemotherapy as first-line treatment for patients with HPV-unrelated recurrent or metastatic HNSCC, regardless of PD-L1 expression.

Rybrevant Faspro is co-formulated with recombinant human hyaluronidase PH20 using Enhanze drug delivery technology and is approved across multiple indications in non-small cell lung cancer based on prior intravenous Rybrevant data.

HNSCC accounts for more than 90% of head and neck cancers globally. Approximately 75% of cases are HPV-negative, a subgroup associated with poorer prognosis and limited post-immunotherapy options.³ The BTD for amivantamab and hyaluronidase-lpuj signals regulatory recognition of early efficacy in a population with significant unmet need and positions the program for accelerated development in head and neck cancer.

References

1. Johson & Johnson. RYBREVANT FASPRO (amivantamab and hyaluronidase-lpuj) receives U.S. FDA Breakthrough Therapy Designation for patients with advanced head and neck cancer. Press Release. Feb. 18, 2026.
2. Harrington KJ, Rosenberg AJ, Yang M-H, et al. Subcutaneous amivantamab in recurrent/metastatic head and neck squamous cell cancer after disease progression on checkpoint inhibitor and chemotherapy: Preliminary results from the phase 1b/2 OrigAMI-4 study. Oral Oncology 2025;171:107791. doi: 10.1016/j.oraloncology.2025.107791
3. Park R, Chung CH. Advanced Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma: Unmet Need and Emerging Therapies. Mol. Cancer Ther. 2024;23(12):1717–1730. doi: 10.1158/1535-7163.MCT-24-0281
4. Feldt SL, Bestvina CM. The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications. Cancers (Basel). 2023;15(11):2998. doi: 10.3390/cancers15112998