In a First, FDA Approves Monthly Subcutaneous Amivantamab for EGFR+ NSCLC

The FDA has approved amivantamab-vmjw and hyaluronidase-lpuj (Rybrevant Faspro) for a subcutaneous (SC) dosing regimen that allows for once-monthly administration following an initial induction phase. This approval specifically applies to the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, used in combination with lazertinib (Lazcluze) as a first-line therapy. This regulatory milestone establishes the combination as the first and only EGFR-targeted therapy capable of monthly maintenance dosing, significantly reducing the treatment burden for this patient population.¹

Clinical Trial Foundations and Dosing Schedules

The approval is primarily supported by data from the phase 3 PALOMA-3 trial (NCT05388669),² which demonstrated that the SC formulation of amivantamab noninferior pharmacokinetics and efficacy compared to the intravenous (IV) formulation. Data from the study supported the December 2025 approval of SC amivantamab.³

Additionally, the first-line indication is rooted in the MARIPOSA trial (NCT04487080), which showed superior survival for the combination of amivantamab and lazertinib compared with osimertinib (Tagrisso) monotherapy.⁴

Under the newly approved label, patients receive the SC formulation weekly for the first 4 weeks. Beginning at week 5, the dosing frequency transitions to once every 4 weeks. This shift from the previous biweekly IV schedule represents a substantial improvement in healthcare delivery, reducing chair time for patients and lessening the logistical strain on infusion centers.

Efficacy and Safety Profile

In the PALOMA-3 study, the SC administration of amivantamab demonstrated an objective response rate that was comparable to the IV formulation.² Specifically, the SC arm showed a consistent safety profile, with a notable advantage: a significant reduction in infusion-related reactions (IRRs). IRRs occurred in approximately 13% of patients receiving the SC formulation compared with 66% of patients receiving the IV formulation. Furthermore, 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.

The most common adverse events reported in clinical trials include rash, nail toxicity, musculoskeletal pain, and stomatitis. Due to the mechanism of the bispecific antibody, which targets both EGFR and MET, clinicians should remain vigilant for interstitial lung disease and venous thromboembolism (VTE). In the MARIPOSA trial, the use of prophylactic anticoagulation was recommended for the first 4 months of treatment to mitigate VTE risk.^2,4

Mechanism of Action and Clinical Significance

Amivantamab is a fully human bispecific antibody that binds to the extracellular domains of EGFR and MET. Its mechanism of action includes blocking ligand binding, promoting receptor degradation, and inducing antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis via immune effector cells. Lazertinib is a third-generation, central nervous system-penetrant EGFR tyrosine kinase inhibitor (TKI). By combining these agents, the regimen provides dual inhibition of the EGFR and MET pathways, addressing common resistance mechanisms seen with TKI monotherapy.

The transition to a monthly SC maintenance dose is expected to improve patient quality of life and treatment adherence. For oncology providers, the SC formulation offers a more efficient workflow.

“A monthly dosing schedule offers patients convenience without sacrificing efficacy,” said Danny Nguyen, MD, assistant clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope, and principal investigator for the PALOMA-3 and MARIPOSA studies, in a news release.¹ “With a flexible schedule that reduces time in the clinic, patients may be able to stay on therapy longer and free up time to focus on the moments that matter most.”

This FDA action reflects a broader trend in oncology toward SC delivery systems that utilize hyaluronidase to facilitate the absorption of large-volume biologics, ultimately bridging the gap between clinical efficacy and patient-centered care.

REFERENCES

1. FDA approves RYBREVANT FASPRO™ (amivantamab and hyaluronidase-lpuj) as the only EGFR-targeted therapy that can be administered once a month. News release. Johnson & Johnson. February 17, 2026. Accessed February 17, 2026. https://tinyurl.com/yc3jed7a

2. Leighl NB, Akamatsu H, Lim SM, et al. Natasha B. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol 42, 3593-3605(2024). doi:10.1200/JCO.24.01001

3. FDA approves amivantamab and hyaluronidase-lpuj for subcutaneous injection. News release. US FDA. December 17, 2025. Accessed February 17, 2025. https://tinyurl.com/3fr3nh9y

4. Yang JCH, Lu S, Hayashi H, et al. Overall survival with amivantamab–lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393:1681-1693. doi: 10.1056/NEJMoa2503001