On December 17, 2025, the U.S. Food and Drug Administration (FDA) approved RYBREVANT FASPRO™ (amivantamab and hyaluronidase-lpuj), establishing the first and only subcutaneous (SC) formulation of amivantamab for patients with epidermal growth factor receptor (EGFR)–mutated non-small cell lung cancer (NSCLC). The approval applies across all FDA-approved indications of RYBREVANT® (amivantamab-vmjw) and enables a shift from prolonged intravenous (IV) infusion to rapid SC administration.
This regulatory milestone introduces a clinically meaningful evolution in the delivery of EGFR- and MET-targeted antibody therapy, with implications for patient experience, infusion-center resource utilization, and long-term disease management strategies in EGFR-mutated NSCLC.
Read About Amivantamab on OncoDaily
Mechanistic Background: Amivantamab and the Rationale for Subcutaneous Delivery
Amivantamab is a fully human bispecific IgG1 antibody targeting EGFR and MET, with immune cell–directing activity. By simultaneously inhibiting EGFR signaling, blocking MET-driven bypass pathways, and engaging immune effector mechanisms, amivantamab addresses multiple drivers of tumor growth and resistance in EGFR-mutated NSCLC (Oxnard et al., 2013; Hayashi et al., 2025).
RYBREVANT FASPRO combines amivantamab with recombinant human hyaluronidase PH20 (rHuPH20) using Halozyme’s ENHANZE® drug-delivery technology, allowing dispersion of large-volume biologics in the subcutaneous space. This formulation enables systemic exposure comparable to IV administration while markedly shortening administration time and reducing infusion-related burden (Bittner et al., 2018; George et al., 2025).
Clinical Evidence Supporting FDA Approval: PALOMA-3
The FDA approval of RYBREVANT FASPRO is supported by results from the Phase 3 PALOMA-3 trial (NCT05388669), a randomized, open-label study enrolling 418 patients with EGFR-mutated advanced or metastatic NSCLC following progression on osimertinib and platinum-based chemotherapy (ClinicalTrials.gov PALOMA-3).
PALOMA-3 evaluated RYBREVANT FASPRO plus lazertinib (LAZCLUZE®) administered subcutaneously versus IV amivantamab-based regimens plus lazertinib. The trial met both co-primary pharmacokinetic endpoints, demonstrating comparable amivantamab exposure between SC and IV formulations, as assessed by Ctrough and AUC parameters (Leighl et al., 2024).
Beyond pharmacokinetic comparability, secondary and exploratory analyses presented at ASCO 2024 and published in the Journal of Clinical Oncology demonstrated favorable clinical outcomes with the SC formulation. Patients treated with SC amivantamab plus lazertinib showed longer duration of response, improved progression-free survival, and a numerically and statistically improved overall survival compared with IV administration in this setting. Median OS favored the SC arm (HR 0.62; 95% CI, 0.42–0.92; nominal P = 0.02), with 12-month survival rates of 65% versus 51% for SC versus IV, respectively (Leighl et al., 2024).
First-Line Disease Control: Context From the MARIPOSA Trial
The approval of RYBREVANT FASPRO builds on the broader clinical foundation established by the Phase 3 MARIPOSA trial (NCT04487080), which evaluated amivantamab plus lazertinib versus osimertinib in the first-line treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R substitution mutations (ClinicalTrials.gov MARIPOSA).
At a median follow-up of 37.8 months, the combination demonstrated a statistically significant overall survival benefit compared with osimertinib (HR 0.75; 95% CI, 0.61–0.92; P = 0.0048). Median OS was not reached in the amivantamab-lazertinib arm (95% CI, 42.9–not estimable), while median OS with osimertinib was 36.7 months (95% CI, 33.4–41.0) (Yang et al., 2025).
Importantly, resistance analyses from MARIPOSA presented at IASLC WCLC 2025 demonstrated significantly lower rates of MET amplification and secondary EGFR resistance mutations, including C797S, in patients receiving the combination compared with osimertinib, supporting the biological rationale for dual EGFR-MET blockade in delaying resistance emergence (Hayashi et al., 2025).
Read About MARIPOSA Trial on OncoDaily
Safety Profile and Key Warnings
The safety profile of RYBREVANT FASPRO is described as largely consistent with IV amivantamab, with notable differences related to administration route. In PALOMA-3, administration-related reactions (ARRs) occurred in 13% of patients receiving SC amivantamab, compared with historically higher rates reported with IV infusion. Most ARRs occurred with the initial dose, and Grade ≥ 3 events were uncommon.
Serious and potentially fatal toxicities remain clinically relevant and are prominently highlighted in the prescribing information. These include interstitial lung disease (ILD)/pneumonitis, venous thromboembolic events (VTE) when combined with lazertinib, severe dermatologic reactions, ocular toxicity, and embryo-fetal toxicity based on animal models. Prophylactic anticoagulation is recommended during the initial months of combination therapy to mitigate VTE risk.
Regulatory and Clinical Implications
The FDA approval of RYBREVANT FASPRO represents a delivery-focused innovation rather than a change in therapeutic target, but its implications are substantial. By enabling five-minute subcutaneous administration, this formulation reduces infusion-center burden, minimizes chair time, and may improve treatment tolerability and adherence without compromising systemic exposure or clinical efficacy (George et al., 2025; Aguiar-Ibáñez et al., 2024).
Within the evolving treatment landscape of EGFR-mutated NSCLC—where long-term survival remains limited despite third-generation TKIs—the availability of a subcutaneous bispecific antibody regimen with demonstrated survival benefit reinforces the role of antibody-based combination strategies aimed at delaying resistance and extending disease control.