FDA Grants Approval for Subcutaneous Amibantamab (Rybrevant Faspro) in EGFR-Mutated NSCLC

The FDA has granted full approval to amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for subcutaneous (SC) administration in adult patients with advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). This decision was supported by results from the Phase 3 PALOMA-3 trial, which demonstrated that SC amivantamab achieved pharmacokinetic noninferiority to the intravenous (IV) formulation, with comparable objective response rates (ORR ~30%), duration of response (DOR), and progression-free survival (PFS ~6.1 months), while reducing administration-related reactions.

Rybrevant Faspro Profile & Mechanism

• Profile: Fixed-dose subcutaneous formulation with recombinant human hyaluronidase (rHuPH20).
• Mechanism: Dual receptor targeting
  • Amivantamab simultaneously binds the extracellular domains of:
    • EGFR, including activating mutations (exon 19 deletion, L858R) and exon 20 insertions
    • MET, a key bypass and resistance pathway in EGFR-mutant NSCLC
• Target Population: Adult patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations, including:
  • EGFR exon 19 deletion or exon 21 L858R substitution
  • EGFR exon 20 insertion mutations following progression on platinum-based chemotherapy
  • Patients with disease progression after osimertinib and chemotherapy, where dual EGFR/MET targeting is clinically relevant
• Delivery System: Subcutaneous (SC) injection, typically delivered over ~5 minutes
• Treatment Schedule: Fixed-dose SC administration
  • Administered on a weekly schedule during the initial cycle, followed by dosing every 2 weeks thereafter (aligned with prior IV amivantamab schedules)

PALOMA-3 Study Design (NCT05388669)

• Study Design: Phase 3, randomized, multicenter, open-label trial.
• Study Objective: Demonstrate noninferiority of pharmacokinetic exposure for subcutaneous amivantamab compared with the intravenous formulation when both are combined with lazertinib.
• Participants: Adults with advanced or metastatic NSCLC
• Primary Endpoint: Trough plasma concentration (Cₜᵣₒᵤgₕ) & area under the concentration-time curve (AUC).
• Secondary Endpoints: Objective response rate (ORR), duration of response (DOR), & progression-free survival (PFS).

Study Outcomes

• Primary Endpoint
  • Cₜᵣₒᵤgₕ: Genomic mean ratios for SC versus IV trough concentrations at prespecified time points (Cycle 2 day 1 and Cycle 4 day 1) met the predefined noninferiority margins.
  • AUC: Over cycle 2 (AUC_D1-D15) for SC amivantamab was comparable to IV, with genomic mean ratios within prespecified noninferiority bounds.
• Key Secondary Enpoints:
  • ORR:
    • SC arm: ~30%
    • IV arm: ~33%
  • DOR:
    • Median DOR was comparable for SC and IV amivantamab; no clinically meaningful differences were observed.
  • PFS:
    • SC arm: Median PFS ~6.1 months
    • IV arm: Median PFS ~4.3 months

Regulatory Milestones

• Approval Date: December 17, 2025.
• Regulatory Pathway: Approval was based on a Biologics License Application submitted under Section 351(a) of the Public Health Service Act for amivantamab co-formulated with hyaluronidase.
• Approval Review: The FDA conducted its review under Project Orbis, an initiative that facilitates concurrent regulatory review with international partners.

Safety

• Most Common Adverse Reactions (≥20%):
  • Dermatologic:
    • Rash (acneiform, maculopapular)
    • Paronychia
    • Pruritus
  • Edema:
    • Peripheral edema (classically associated with MET inhibition)
  • Gastrointestinal:
    • Nausea
    • Diarrhea
  • Musculoskeletal:
    • Musculoskeletal pain
  • General:
    • Fatigue
• Administration-related reactions occoured less frequently with SC administration than IV (chills, flushing, hypotension, dyspnea, fever).
• Severity of Toxicity:
  • Grade 1-2 (most common)
    • The majority of dermatologic, gastrointestinal, and edema-related events
    • Typically manageable with supportive care
    • Rarely require permanent discontinuation
  • Grade ≥3 (less frequent but clinically significant)
    • Severe rash or skin infection, interstitial lung disease/pneumonitis, serious venous thromboembolism, severe administration-related reactions.
    • Grade ≥3 events may necessitate dose interruption, treatment discontinuation, or systemic therapy (e.g., corticosteroids, anticoagulation).
• Treatment Modifications:
  • Grade 1-2: Continue treatment, intake topical corticosteroids and/or oral antibiotics as needed
  • Grade 3: Withhold amivantamab until improvement to ≤ Grade 2, then resume at the same or reduced dose per labeling
  • Recurrent Grade 3 or 4: Permanent discontinuation

SC amivantamab maintains a predictable and manageable safety profile consistent with IV amivantamab, with reduced administration-related reactions and no new safety signals.

Development Status

• Current Status: Approved by the FDA on December 17th, 2025 for SC administration across all indications previously approved for the IV formulation of amivantamab.
• Prescribing information: Available at Drugs@FDA
• Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA

Sources:

Leighl, Natasha B, 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.” Journal of Clinical Oncology, vol. 42, no. 17_suppl, 5 June 2024, pp. LBA8505–LBA8505, https://doi.org/10.1200/jco.2024.42.17_suppl.lba8505. Accessed 2 Jan. 2026.

“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, 19 Dec. 2025, clinicaltrials.gov/study/NCT05388669. Accessed 2 Jan. 2026.