FDA Approves Monthly Dosing Schedule for Rybrevant Faspro in EGFR-Mutated Lung Cancer

The U.S. Food and Drug Administration approved a new once-monthly dosing schedule for Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) in combination with oral Lazcluze (lazertinib) for first-line treatment of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Patients may transition to monthly dosing as early as week 5, after receiving weekly injections during weeks 1 through 4.

The newly approved schedule delivers consistent outcomes compared with the previously approved bi-weekly subcutaneous dosing regimen. Data supporting the monthly dosing schedule were recently presented at the 2025 World Conference on Lung Cancer. Findings from the PALOMA-2 study showed that once-monthly Rybrevant Faspro combined with Lazcluze produced a high objective response rate in previously untreated patients with EGFR-mutated advanced NSCLC.

Administration-related reactions occurred in 12% of patients receiving monthly dosing compared with 13% with bi-weekly subcutaneous dosing and 66% with historical intravenous administration. Venous thromboembolic events were also comparable between monthly and bi-weekly subcutaneous dosing. These events occurred in 13% of patients receiving monthly dosing compared with 11% in patients who received bi-weekly subcutaneous dosing with anticoagulation and 38% in historical intravenous data without anticoagulation.

No new safety signals were identified with the monthly schedule. Only 8% of patients discontinued amivantamab due to treatment-related side effects. Mean plasma concentration levels were consistent with historical intravenous and bi-weekly subcutaneous dosing, supporting pharmacokinetic comparability.

The approval builds on the earlier FDA approval of Rybrevant Faspro, which changed administration time from hours with intravenous delivery to minutes with subcutaneous injection. Compared to intravenous delivery, Rybrevant Faspro offers significantly higher patient convenience and lower burden on healthcare resources, reducing administration time from several hours to five minutes.

PALOMA-2 is an open-label phase 2 study evaluating the efficacy, safety and pharmacokinetics of first-line subcutaneous amivantamab administered by manual injection in combination with Lazcluze and or chemotherapy in patients with EGFR-mutated advanced or metastatic NSCLC. The primary end point was objective response rate.

The MARIPOSA study is a randomized phase 3 trial that enrolled 1,074 patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. The study compared Rybrevant plus Lazcluze versus Tagrisso (osimertinib) and versus Lazcluze alone in the first-line setting. The primary endpoint is progression-free survival as assessed by blinded independent central review.

An analysis from MARIPOSA presented at the 2025 World Congress on Lung Cancer showed that the combination significantly reduced the development of EGFR- and MET-driven resistance compared with Tagrisso in the first-line setting. MET amplifications occurred in 3% of patients receiving the combination compared with 13% of those receiving Tagrisso. Secondary EGFR mutations such as C797S were reported in 1% of patients on the combination versus 8% with Tagrisso. Acquired MET amplification led to early discontinuation in 23% of patients on Tagrisso within six months compared with 4% on the combination.

At a median follow-up of 37.8 months, Rybrevant plus Lazcluze showed a statistically significant reduction in the risk of death compared to osimertinib (hazard ratio 0.75; 95 percent confidence interval 0.61-0.92, P=0.0048). Median overall survival was not yet reached with the combination (95 percent CI, 42.9-not estimable) and the overall survival benefit is projected to exceed four years, which is at least one year beyond the median of three years observed with osimertinib (36.7 months; 95 percent CI, 33.4-41.0).

Based on the results from the Phase 3 PALOMA-3 study, Rybrevant Faspro delivered consistent results to Rybrevant, meeting both co-primary pharmacokinetic endpoints as measured by amivantamab levels in the blood. Data presented at the 2024 American Society of Clinical Oncology Annual Meeting and published in the Journal of Clinical Oncology found that the subcutaneous arm showed longer duration of response, improved progression-free survival, and longer overall survival compared to the intravenous arm. Median overall survival was notably higher for patients treated with the subcutaneous arm in combination with Lazcluze (HR 0.62; 95 percent CI, 0.42–0.92; nominal P=0.02). At 12 months, 65 percent of patients receiving subcutaneous administration were alive, compared with 51 percent treated with intravenous administration.

In a separate development, the FDA granted Breakthrough Therapy Designation for subcutaneous Rybrevant Faspro as a monotherapy for adults with advanced head and neck squamous cell carcinoma. The designation covers patients with cancer 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.

The Breakthrough Therapy Designation is supported by data from the open-label Phase 1b/2 OrigAMI-4 study. Results were presented at the 2025 European Society for Medical Oncology Congress and demonstrate promising clinical activity, with rapid and durable responses, in a heavily pretreated patient population.

Subcutaneous amivantamab is being further evaluated in the ongoing Phase 3 OrigAMI-5 study, which is assessing the subcutaneous formulation of amivantamab in combination with Keytruda (pembrolizumab) and carboplatin versus 5-fluorouracil (5FU) plus pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) for HPV-unrelated recurrent or metastatic head and neck squamous cell carcinoma, regardless of PD-L1 expression.

Rybrevant Faspro is contraindicated in patients with known hypersensitivity to hyaluronidase or any of its excipients. The therapy can cause hypersensitivity and administration-related reactions, including dyspnea, flushing, fever, chills, chest discomfort, hypotension and vomiting. In PALOMA-3, all grade administration-related reactions occurred in 13% of patients and 0.5% were grade 3 (severe). Most occurred with the initial dose.

Rybrevant Faspro is approved across all indications of Rybrevant (amivantamab-vmjw). Rybrevant Faspro is approved in multiple settings for locally advanced or metastatic non-small cell lung cancer and is also being evaluated in additional solid tumors, including colorectal cancer.