FDA Approves Subcutaneous Amivantamab for EGFR+ NSCLC

The FDA has approved amivantamab and hyaluronidase-lpuj (Rybrevant Faspro; subcutaneous amivantamab) for the treatment of patients with non–small cell lung cancer (NSCLC) harboring EGFR mutations, across all approved indications for amivantamab-vmjw (Rybrevant).¹

This regulatory decision was supported by findings from the phase 3 PALOMA-3 trial (NCT05388669), in which the subcutaneous formulation was shown to be noninferior compared with the intravenous (IV) formulation, with both formulations given in combination with lazertinib (Lazcluze).² The geometric mean ratios of trough concentrations (C_trough) for subcutaneous (n = 206) vs IV (n = 212) amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle 2 day 1 and 1.42 (90% CI, 1.27-1.61) at cycle 4 day 1. Additionally, the area under the curve from cycle 2 day 1 to cycle 2 day 15 (AUC_D1-D15) between these arm was 1.03 (90% CI, 0.98-1.09).

Furthermore, the overall response rate (ORR) was 30% (95% CI, 24%-37%) in the subcutaneous arm vs 33% (95% CI, 26%-39%) in the IV arm. The median progression-free survival (PFS) in these respective arms was 6.1 months (95% CI, 4.3-8.1) vs 4.3 months (95% CI, 4.1-5.7). The median overall survival (OS) was significantly longer with the subcutaneous vs IV formulation, at 12.9 months (95% CI, 12.9-not evaluable [NE]) vs NE (10.2-NE), respectively (HR, 0.62; 95% CI, 0.42-0.92; nominal P = .02).

"The FDA approval of the subcutaneous formulation [will] lead to easier use of this therapy," Joshua K. Sabari, MD, said in an interview with OncLive^®. "I think it's going to be better for patients [regarding] ease of utilization in the clinic, lower chair time, and less time in the clinic. This will be a game changer for patients with EGFR-mutant NSCLC."

Sabari is an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, as well as the director of High Reliability Organization Initiatives at the Perlmutter Cancer Center in New York, New York.

This approval follows the December 2024 issuance of a complete response letter (CRL) by the FDA to the biologics license application (BLA) seeking the approval of the fixed subcutaneous combination of amivantamab and recombinant human hyaluronidase for the treatment of patients with NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.³ The BLA was supported by data from PALOMA-3. The CRL cited observations as part of a standard pre-approval inspection at a manufacturing facility. Notably, the CRL did not cite issues with the drug formulation, efficacy data, or safety data.

Previously, in August 2024, the FDA approved the IV formulation of amivantamab plus lazertinib in the first-line setting for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.⁴

What Was the Design of the PALOMA-3 Trial?

PALOMA-3 enrolled patients at least 18 years of age with confirmed advanced or metastatic NSCLC harboring classical EGFR exon 19 deletions or exon 21 L858R mutations who had disease progression during or following treatment with osimertinib (or another approved third-generation EGFR TKI) and platinum-based chemotherapy, regardless of sequence.² Patients were randomly assigned 1:1 to be treated with subcutaneous or IV amivantamab plus lazertinib in 28-day cycles. Patients in the subcutaneous arm received subcutaneous amivantamab at a concentration of 160 mg/mL coformulated with hyaluronidase via manual injection at 1600 mg once a week for the first 4 weeks and every 2 weeks thereafter. Patients in the IV arm received IV amivantamab at a concentration of 50 mg/mL at the approved dose of 1050 mg following the same dosing schedule, with the first infusion split between 2 days. All patients also received lazertinib orally at 240 mg once a day.

The coprimary pharmacokinetic end points for noninferiority were C_trough either before dosing, on cycle 2 day 1, or at steady state (cycle 4 day 1); and per regional health authority guidance) and AUC_D1-D15. Key secondary end points included ORR and PFS. OS served as a predefined exploratory end point.

What Were the Key Safety Findings From the PALOMA-3 Trial?

The rates of infusion-related reactions and venous thromboembolism were lower in the subcutaneous arm (13% and 9%, respectively) vs the IV arm (66% and 14%, respectively). Additionally, the median administration time for the first infusion was 4.8 minutes (range, 0-18) in the subcutaneous arm vs 5 hours (range, 0.2-9.9) in the IV arm. Notably, during cycle 1 day 1, 85% of patients in the subcutaneous arm reported their treatment as convenient vs 52% of those in the IV arm.

References

1. U.S. FDA approval of Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) enables the simplest, shortest administration time for a first-line combination regimen when combined with Lazcluze (lazertinib). News release. Johnson & Johnson. December 17, 2025. Accessed December 17, 2025. https://www.jnj.com/media-center/press-releases/u-s-fda-approval-of-rybrevant-faspro-amivantamab-and-hyaluronidase-lpuj-enables-the-simplest-shortest-administration-time-for-a-first-line-combination-regimen-when-combined-with-lazcluze-lazertinib
2. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial. J Clin Oncol. 2024;42(suppl 17):LBA8505. doi:10.1200/JCO.2024.42.17_suppl.LBA8505
3. Update on U.S. regulatory review of subcutaneous amivantamab. News release. Johnson & Johnson. December 16, 2024. Accessed September 5, 2025. https://www.jnj.com/media-center/press-releases/update-on-u-s-regulatory-review-of-subcutaneous-amivantamab
4. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed September 5, 2025. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx