FDA Issues CRL for SC Amivantamab BLA in EGFR+ NSCLC

• A complete response letter (CRL) from the FDA has been issued to the biologics license application (BLA) submission for amivantamab-vmjw (Rybrevant) and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab).
• The submission was for all currently approved or submitted indications of intravenous (IV) amivantamab in select patients with non–small cell lung cancer (NSCLC).
• Johnson & Johnson, the drug’s developer, stated the CRL concerns manufacturing inspection issues, not product formulation, efficacy, safety, or additional clinical studies.

The FDA has issued a CRL to the BLA for the potential approval of SC amivantamab for the treatment of patients with NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.¹

The CRL issued by the FDA was related to observations made during a standard pre-approval inspection at a manufacturing facility, according to the drug’s developer. These observations are not connected to the product's formulation or the efficacy and safety data submitted as part of the regulatory application.

Importantly, the FDA has not requested any additional clinical trials to evaluate SC amivantamab, and the CRL does not affect the current FDA approval of IV amivantamab in combination with lazertinib (Lazcluze) for the treatment of patients with locally advanced or metastatic disease who harbor the relevant mutations.

Microscopic, photorealistic image of lung cancer cells - Generated with Adobe Firefly

“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,” said Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head of Oncology, Innovative Medicine, Johnson & Johnson, in a press release. “Backed by interim overall survival data showing a strong favorable trend compared [with] osimertinib [Tagrisso], we believe strongly in the robust efficacy and safety of amivantamab—both as a standalone treatment and in combination with lazertinib—for EGFR-mutated advanced lung cancer. We’re proud to have helped so many patients in the front-line setting already with amivantamab and look forward to further expanding treatment options with our subcutaneous formulation pending regulatory review and approval.”

In August 2024, the FDA granted priority review to the BLA for SC amivantamab, as supported by findings from the phase 3 PALOMA-3 study (NCT05388669) presented at the 2024 ASCO Annual Meeting, and simultaneously published in the Journal of Clinical Oncology.²

About the PALOMA-3 Study

The PALOMA-3 trial is a randomized, open-label, phase 3 study which enrolled 418 patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy. Experts sought to evaluate the pharmacokinetics (PK), efficacy, and safety of SC amivantamab in combination with lazertinib compared with IV amivantamab plus lazertinib in patients with EGFR-mutated advanced or metastatic NSCLC following progression on osimertinib and chemotherapy.

The primary PK noninferiority end points of the trial were area under the curve at cycle 2 between days 1 and 15 and trough concentration on cycle 2 day 1, or cycle 4 day 1. Additional end points were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

A total of 206 patients received SC amivantamab and 212 received the IV form. The median age of those enrolled was 61 years, female patients made up 67%, 61% were Asian, and patients received a median of 2 prior lines of therapy.

At ASCO 2024, SC amivantamab demonstrated comparable ORR to IV administration in patients with NSCLC with EGFR exon 19 deletion or L858R mutations. SC amivantamab also led to a significantly shorter administration time and a 5-fold reduction in infusion-related reactions.

Further, SC amivantamab led to longer rates of OS, PFS, and duration of response. Overall, the study met both coprimary PK noninferiority end points after a median follow-up of 7.0 months (range, 0.1-14.4).

Amivantamab currently has several FDA approved indications, including as a single agent for patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy; combined with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations; combined with carboplatin and pemetrexed for 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 treatment with an EGFR TKI; and in combination with carboplatin and pemetrexed for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.³

REFERENCES

1. Update on U.S. regulatory review of subcutaneous amivantamab. News release. Johnson & Johnson. December 16, 2024. Accessed December 17, 2024. https://www.jnj.com/media-center/press-releases/update-on-u-s-regulatory-review-of-subcutaneous-amivantamab

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. RYBREVANT® (amivantamab-vmjw) injection, for intravenous use Initial U.S. Approval: 2021. Highlights of prescribing information. Accessed December 18, 2024. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf