FDA Issues Complete Response Letter to Subcutaneous Amivantamab BLA in EGFR+ NSCLC

The FDA has issued a complete response letter to the biologics license application (BLA) seeking the approval of fixed combination amivantamab-vmjw (Rybrevant) and recombinant human hyaluronidase for subcutaneous administration in patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.1

According to Johnson & Johnson, the drug’s developer, the CRL was related to observations as part of a standard pre-approval inspection at a manufacturing facility, and is not associated with the product formulation or efficacy and safety data submitted in the regulatory application. The regulatory agency has not requested any additional clinical studies. Notably, this CRL does not impact the current FDA approval of intravenous (IV) amivantamab in combination with lazertinib (Lazcluze) for patients with locally advanced or metastatic disease harboring these mutations.

“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,” Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head of Oncology, Innovative Medicine, Johnson & Johnson, stated in a news 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.”

The FDA granted priority review to the BLA for subcutaneous amivantamab in August 2024 based on data from the phase 3 PALOMA-3 study (NCT05388669).These results were shared at the 2024 ASCO Annual Meeting, and simultaneously published in the Journal of Clinical Oncology.

PALOMA-3 Overview

PALOMA-3 is a randomized, open-label investigation of the pharmacokinetics (PK), efficacy, and safety of subcutaneous 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. Both 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 served as the coprimary PK noninferiority end points of this trial; overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) served as descriptive efficacy outcome measures.

According to data shared at the 2024 ASCO Annual Meeting, patients given the subcutaneous formulation of amivantamab achieved an ORR of 30% (95% CI, 24%-37%) compared with 33% (95% CI, 26%-39%) for patients given IV amivantamab (n = 212; relative risk, 0.92; 95% CI, 0.70-1.23; P = .001).2 Among confirmed responders, this number was 27% (95% CI, 21%-33%) in the subcutaneous arm and IV arm, respectively, (relative risk, 0.99; 95% CI, 0.72-1.36; P < .001).

Additionally, the study met both coprimary PK noninferiority end points after a median follow-up of 7.0 months (range, 0.1-14.4).

Additional Indications for Amivantamab

Notably, the phase 3 MARIPOSA (NCT04487080), which led to the FDA approval for the IV formulation of amivantamab, evaluated amivantamab in combination with lazertinib (Lazcluze) vs osimertinib or lazertinib alone in the first line for patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R substitutions.1

The primary end point of the study was PFS as assessed by blinded independent central review. Secondary end points included OS, ORR, duration of response, second PFS, and intracranial PFS. Findings showed that the combination regimen was associated with a significant PFS improvement and a favorable OS trend vs amivantamab or lazertinib alone.

Notably, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended the approval of amivantamab plus lazertinib in Europe for this indication in November 2024.

Amivantamab in its IV formulation is also approved in the United States, in Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy; and in combination with chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test.

Subcutaneous amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s Enhanze® drug delivery technology.

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