FDA Approval of Subcutaneous Amivantamab Offers Faster, Safer Option for EGFR-Mutated NSCLC

The FDA has approved the subcutaneous administration of a fixed combination of amivantamab (Rybrevant; Johnson & Johnson) and a recombinant human hyaluronidase for patients with non–small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations.1

This injectable formulation offers a more convenient option for patients, as it can be administered under the skin rather than via the lengthy intravenous (IV) infusions approved last year.2,3

"The subcutaneous approval for amivantamab is a significant step forward in our therapeutic armamentarium," Martin Dietrich, MD, PhD, of the Cancer Care Centers of Brevard and University of Central Florida, said in an interview with The American Journal of Managed Care® (AJMC).4 "...By having a slower onset of the antibody via subcutaneous application, we actually bypass the vast majority of infusion-related reactions, making the treatment a lot easier for patients and for the infusion area, safer, and also more quickly done."

The approval comes after the FDA issued a Complete Response Letter (CRL) last year in response to the treatment’s Biologics License Application.2 The CRL was unrelated to the product’s formulation or its efficacy and safety data. Instead, it was issued due to observations at a manufacturing facility during a standard pre-approval inspection. As a result, no additional clinical studies were required.

The FDA approved subcutaneous amivantamab with recombinant human hyaluronidase for epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) based on the phase 3 PALOMA-3 trial, which showed noninferior efficacy to intravenous (IV) administration with added safety and convenience benefits. | Image Credit: Tada Images - stock.adobe.com

Subcutaneous Amivantamab Demonstrates Noninferiority to IV Administration

Subcutaneous amivantamab received FDA approval based on results from the phase 3 PALOMA-3 study (NCT0538869), which were presented at the 2024 American Society of Clinical Oncology Annual Meeting.5 Because prior phase 3 studies of IV amivantamab demonstrated efficacy in EGFR-mutated advanced NSCLC, researchers hypothesized that a subcutaneous formulation could maintain efficacy while improving tolerability and reducing administration time.6

The PALOMA-3 trial helped determine this, with patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy randomized 1:1 to receive subcutaneous or IV amivantamab, both combined with lazertinib.

The coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points included objective response rate (ORR) and progression-free survival (PFS), whereas overall survival (OS) was a predefined exploratory end point.

Of the 418 patients enrolled, 206 received subcutaneous treatment and 212 received IV treatment. The trial met its primary noninferiority criteria, with geometric mean ratios of Ctrough for subcutaneous to IV amivantamab of 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. Also, the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09).

As for clinical outcomes, ORR was 30% in the subcutaneous arm and 33% in the IV arm. Additionally, median PFS was 6.1 and 4.3 months for patients in the subcutaneous and IV groups, respectively. Notably, OS was significantly longer in the subcutaneous group (HR for death, 0.62; 95% CI, 0.42-0.92; nominal P = .02).

The safety profile also supported subcutaneous administration, which was associated with fewer adverse events, namely infusion-related reactions (IRRs; 13% vs 66%) and venous thromboembolism (9% vs 14%).

Convenience was another major advantage. The median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) with subcutaneous amivantamab compared with 5 hours (range, 0.2-9.9) for IV amivantamab. Consequently, 85% of patients in the subcutaneous group and 52% in the IV group considered treatment convenient during cycle-1-day-1, with convenience rates of 85% and 35%, respectively, at the end of treatment.

Based on these findings, the researchers concluded that subcutaneous amivantamab combined with lazertinib demonstrated noninferiority to IV administration, while offering a consistent safety profile, greater convenience, and prolonged survival

“Compared with the IV formulation, subcutaneous amivantamab maintains efficacy, improves patient and health care provider experience, and substantially reduces the rate of IRRs,” the authors concluded.

References

1. U.S. FDA approval of rybrevrent 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 18, 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. Klein H. FDA rejects subcutaneous amivantamab for NSCLC over manufacturing concerns. AJMC. December 17, 2024. Accessed December 18, 2025. https://www.ajmc.com/view/fda-rejects-subcutaneous-amivantamab-for-nsclc-over-manufacturing-concerns
3. Jeremias S. FDA approves amivantamab for EGFR-positive NSCLC with exon 19 deletion, exon 21 L858R substitution. AJMC. September 20, 2024. Accessed December 18, 2025. https://www.ajmc.com/view/fda-approves-amivantamab-for-egfr-positive-nsclc-with-exon-19-deletion-exon-21-l858r-substitution
4. Bonavitacola J. FDA Approval of Subcutaneous Amivantamab is Significant Step Forward in NSCLC: Martin Dietrich, MD, PhD. AJMC. December 18, 2025. Accessed December 18, 2025. https://www.ajmc.com/view/fda-approval-of-subcutaneous-amivantamab-is-significant-step-forward-in-nsclc-martin-dietrich-md-phd
5. 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 August 19, 2025. Accessed December 18, 2025. https://clinicaltrials.gov/study/NCT05388669
6. Leighl NB, Akamatsu H, Sun Min Lim, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated NSCLC: primary results from the phase 3 PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605. doi:10.1200/jco.24.01001