The FDA has issued a Complete Response Letter (CRL) to Johnson & Johnson for its Biologics License Application (BLA) seeking approval of a subcutaneous formulation of amivantamab (Rybrevant) in combination with recombinant human hyaluronidase. This formulation was intended for patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. The CRL, received on December 16, 2024, stems from observations made during a standard pre-approval inspection at a manufacturing facility.
Johnson & Johnson stated that the CRL is unrelated to the product's formulation, efficacy, or safety data, and the FDA has not requested any additional clinical studies. The existing FDA approval for intravenous (IV) amivantamab, particularly its use in combination with lazertinib for locally advanced or metastatic disease with the specified EGFR mutations, remains unaffected.
Yusri Elsayed, MD, MHSc, PhD, Global Therapeutic Area Head of Oncology, Innovative Medicine, Johnson & Johnson, stated, “We’re working closely with the FDA to bring subcutaneous amivantamab to patients as quickly as possible, and are confident in our path to resolution.” He emphasized the robust efficacy and safety profile of amivantamab, both as a standalone treatment and with lazertinib, citing interim overall survival data showing a favorable trend compared to osimertinib.
The BLA for subcutaneous amivantamab was granted priority review in August 2024, based on data from the Phase 3 PALOMA-3 study (NCT05388669). The PALOMA-3 trial was a randomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of subcutaneous amivantamab plus lazertinib compared to IV amivantamab plus lazertinib in patients with EGFR-mutated advanced or metastatic NSCLC who had progressed on osimertinib and chemotherapy.
PALOMA-3 Trial Details
The PALOMA-3 trial enrolled 418 patients and aimed to demonstrate non-inferiority in pharmacokinetics, measured by area under the curve (AUC) and trough concentration (Cmin). Efficacy endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Data presented at the 2024 ASCO Annual Meeting showed that the subcutaneous amivantamab arm achieved an ORR of 30% (95% CI, 24%-37%) compared to 33% (95% CI, 26%-39%) in the IV amivantamab arm (relative risk, 0.92; 95% CI, 0.70-1.23; P = .001). The study met its co-primary PK noninferiority endpoints after a median follow-up of 7.0 months (range, 0.1-14.4).
Amivantamab's Existing Approvals
Amivantamab is currently approved as monotherapy for adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after platinum-based chemotherapy. It is also approved in combination with chemotherapy for first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations. The combination of amivantamab and lazertinib has shown promising efficacy in improving progression-free survival for patients with EGFR exon 19 deletions and L858R mutations.
The subcutaneous formulation of amivantamab is co-formulated with recombinant human hyaluronidase PH20, utilizing Halozyme’s Enhanze® drug delivery technology.
