FDA Approves Monthly Dosing for Rybrevant Faspro in EGFR-Mutated NSCLC, Grants Breakthrough Status

The Food and Drug Administration has approved a monthly dosing schedule for Rybrevant Faspro for the treatment of epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Separately, the FDA has granted breakthrough therapy designation for the drug as a monotherapy for adults with head and neck squamous cell carcinoma that is recurrent or metastatic and human papillomavirus (HPV)-unrelated after disease progression on or after platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

Rybrevant Faspro is a subcutaneous co-formulation of amivantamab, a bispecific EGFR-directed and MET receptor-directed antibody, and hyaluronidase, an endoglycosidase. The approval of the monthly dosing regimen was based on data from cohort 5 of the open-label phase 2 PALOMA-2 trial (ClinicalTrials.gov Identifier: NCT05498428).

Treatment-naïve study participants with EGFR Ex19del or L858R mutations (N=77) were administered Rybrevant Faspro 1600mg weekly for the first 4 weeks, followed by a maintenance dose of 3520mg every 4 weeks, alongside lazertinib 240mg daily. The primary endpoint was overall response rate (ORR) based on investigator assessment.

Findings showed at a medium follow-up of 6.5 months, the ORR was 82% (95% CI, 71-90) based on investigator assessment and 87% (95% CI, 77-94) based on independent central review (secondary endpoint). These results were comparable to that of the MARIPOSA study, which demonstrated an ORR of 86% (95% CI, 83-89) with a biweekly dosing regimen of intravenous (IV) amivantamab plus lazertinib.

The safety profile of the monthly dosing regimen of SC amivantamab was similar to that of the biweekly SC dosing schedule. Administration related reactions were consistent across both SC dosing schedules and significantly lower vs IV administration (12% with monthly dosing vs 13% with biweekly dosing vs 66% with IV dosing).

Additionally, the incidence of venous thromboembolic events with the monthly SC dosing schedule was comparable with biweekly SC dosing (both given alongside anticoagulation) and lower than IV administration without anticoagulation (13% with monthly dosing vs 11% with biweekly dosing vs 38% with IV dosing). No new safety signals were identified. Only 8% of patients discontinued amivantamab due to treatment-related adverse events.

Notably, the mean plasma concentration levels were similar when compared with IV and biweekly SC dosing administration.

Under the updated labeling, adult patients on biweekly IV amivantamab or SC Rybrevant Faspro may now transition to a monthly subcutaneous schedule starting on or after week 5. This modification is expected to simplify care delivery and improve patient convenience. The duration of administration for the SC formulation is 5 to 7 minutes, a sharp contrast to the multi-hour infusion required for the IV version.

Rybrevant Faspro is supplied as a solution in a single-dose vial in 4 dosage strengths: amivantamab 1600mg and hyaluronidase 20,000 units per 10mL; amivantamab 2240mg and hyaluronidase 28,000 units per 14mL; amivantamab 2400mg and hyaluronidase 30,000 units per 15mL; and amivantamab 3520mg and hyaluronidase 44000 units per 22mL.

The breakthrough therapy designation for head and neck cancer is supported by data from the open-label Phase 1b/2 OrigAMI-4 study. Results were presented in a mini-oral session at the 2025 European Society for Medical Oncology (ESMO) Congress and demonstrate promising clinical activity, with rapid and durable responses, in a heavily pretreated patient population.

OrigAMI-4 (NCT06385080) is an open-label Phase 1b/2 study evaluating Rybrevant Faspro in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The study includes five cohorts, including Cohort 1, which studied Rybrevant Faspro as monotherapy in patients with human papillomavirus (HPV)-unrelated R/M HNSCC who had received prior platinum-based chemotherapy and PD-1/PD-L1 immunotherapy. Patients with prior anti-EGFR therapy were excluded. Rybrevant Faspro was administered every three weeks (Q3W) at 2400 mg, or 3360 mg for patients weighing 80 kg or more. The primary endpoint is overall response rate (ORR) assessed by blinded independent central review (BICR) using RECIST v1.1.

HPV-unrelated recurrent or metastatic head and neck squamous cell carcinoma is characterized by high rates of epidermal growth factor receptor (EGFR) expression and mesenchymal-epithelial transition (MET) pathway overexpression. Subcutaneous amivantamab is designed to target both pathways, while activating the immune system. The clinical activity observed to date supports further evaluation in this setting, where treatment options remain limited after prior lines of therapy.

Based on these findings, subcutaneous amivantamab is being further evaluated in the ongoing Phase 3 OrigAMI-5 study (NCT07276399), which is assessing the subcutaneous formulation of amivantamab in combination with pembrolizumab and carboplatin versus 5-fluorouracil (5FU) plus pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) as a first-line treatment in patients with HPV-unrelated recurrent or metastatic head and neck squamous cell carcinoma, regardless of PD-L1 expression.

The FDA grants breakthrough therapy designation to expedite the development and regulatory review of investigational medicines intended to treat serious or life-threatening conditions, where preliminary clinical evidence indicates the therapy may demonstrate substantial improvement over available treatment options on at least one clinically meaningful endpoint.

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer, accounting for more than 90 percent of cases and approximately 4.5 percent of all cancers worldwide. It develops in the mucosal linings of the oral cavity, oropharynx, hypopharynx, and larynx. Major risk factors include tobacco and alcohol use, as well as infection with high-risk human papillomavirus (HPV). Around 75 percent of cases are HPV-negative, which is typically associated with a poorer prognosis and reduced response to treatment. Despite advances in surgery, radiation, chemotherapy, and immunotherapy, many patients ultimately progress to advanced, recurrent or metastatic disease.

In December 2025, the U.S. FDA approved Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) across all indications of intravenous Rybrevant (amivantamab-vmjw). This subcutaneously administered therapy is also approved in Europe, Japan, China, and other markets.

Rybrevant Faspro is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme's ENHANZE drug delivery technology.