FDA Approves Subcutaneous Amivantamab for EGFR-Mutated NSCLC Indications

The FDA has approved amivantamab and hyaluronidase-lpuj (Rybrevant Faspro.) for subcutaneous (SC) injection.¹ This new formulation is indicated for all adult patient populations previously approved for the intravenous (IV) formulation of amivantamab, primarily those with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR mutations.

The approval represents a significant shift in the administration of this bispecific antibody. While intravenous (IV) amivantamab often requires multihour infusion protocols, the SC formulation—co-formulated with hyaluronidase-lpuj to facilitate rapid absorption—significantly reduces administration time and the incidence of systemic reactions.

Clinical Trial Data: The PALOMA-3 Study

The FDA based its decision on results from the PALOMA-3 trial (NCT05315154),² a randomized, open-label, multicenter study. The trial compared SC amivantamab plus lazertinib (Lazcluze) against IV amivantamab plus lazertinib in 418 patients with advanced NSCLC carrying EGFR exon 19 deletions or L858R substitution mutations.¹

The study met its primary pharmacokinetic endpoints, demonstrating noninferiority in trough concentrations (C_trough) at steady state and the area under the curve (AUC) during the second cycle of treatment. For the recommended every-2-week dosing schedule, the geometric mean ratio (GMR) for AUC was 1.03 (90% CI, 0.98–1.09), while the steady-state C_trough GMR was 1.43 (90% CI, 1.27–1.61). These values surpassed the prespecified 0.8 threshold required to establish comparability.

Descriptive secondary analyses indicated no notable differences in the overall response rate (ORR) or progression-free survival (PFS) between the 2 delivery methods. Furthermore, investigators observed no detrimental effect on overall survival (OS) in patients receiving the SC formulation.

Safety and Tolerability Profiles

The safety profile of SC amivantamab was largely consistent with the established IV profile, with 1 marked improvement: a reduction in administration-related reactions (ARRs). In the PALOMA-3 trial, the incidence of systemic ARRs in the SC arm was 13%, compared with a 66% incidence of infusion-related reactions (IRRs) in the IV arm.

Despite the improved tolerability during administration, the prescribing information retains warnings for serious adverse events. These include interstitial lung disease/pneumonitis, venous thromboembolic events (particularly when used with lazertinib), dermatologic toxicities, ocular toxicity, and embryo-fetal toxicity. Healthcare providers are advised to monitor for hypersensitivity reactions, especially during initial doses.

"The use of subcutaneous amivantamab has a markedly shorter time of administration, minutes compared with hours with intravenous. [Regarding] pharmacokinetics, efficacy [was] the same to better outcomes for subcutaneous, so there are no disadvantages here. Also, a marked reduction in infusion-related reactions from two-thirds of patients having it cycle 1 day 1 in the first hour to just over 10%, so really a great improvement, both from the patient perspective and from the provider perspective," said Natasha Leighl, MD, MMSc, BSc, clinician investigator and member of the Cancer Clinical Research Unit at Princess Margaret Cancer Centre, in an interview with Targeted Oncology.

Dosing and Administration

The recommended dosage of SC amivantamab and hyaluronidase-lpuj is determined by baseline body weight and varies by indication. Clinicians should refer to the full prescribing information for specific weight-based tiers.

The review was conducted under Project Orbis, an international collaboration between the FDA, the Australian Therapeutic Goods Administration, and Health Canada. This initiative allows for concurrent submission and review of oncology products to expedite global access to new therapies.

REFERENCES

1. FDA approves amivantamab and hyaluronidase-lpuj for subcutaneous injection. News release. US FDA. December 17, 2025. Accessed December 18, 2025. https://tinyurl.com/3fr3nh9y

2. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). ClinicalTrials.gov. Updated December 8, 2025. Accessed December 18, 2025. https://clinicaltrials.gov/study/NCT05388669