Subcutaneous Amivantamab Nears EU Approval in Advanced EGFR+ NSCLC

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended an extension of the marketing authorization for subcutaneous (SC) amivantamab (Rybrevant) in combination with lazertinib (Lazcluze) in the first line for patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations; and as monotherapy for patients with advanced NSCLC with activating EGFR exon 20 insertion mutations following progression on platinum-based therapy.1

For both indications, the recommended dosing schedule is weekly administration of SC amivantamab from weeks 1 to 4, then every 2 weeks thereafter.

The positive opinion was supported by findings from the phase 3 PALOMA-3 study (NCT05388669), in which SC amivantamab demonstrated noninferiority compared with intravenous (IV) administration of the agent in patients with refractory EGFR-mutated advanced NSCLC.

Results presented during the 2024 ASCO Annual Meeting showed that the study met both of its coprimary pharmacokinetic end points of the 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).1,2

Regarding efficacy, the overall response rate (ORR) was 30% (95% CI, 24%-37%) with SC amivantamab (n = 206) vs 33% (95% CI, 26%-39%) with IV amivantamab (n = 212; relative risk [RR], 0.92; 95% CI, 0.70-1.23; P = .001), which met noninferiority criteria. Among confirmed responders, the ORRs in the SC and IV arms were 27% (95% CI, 21%-33%) vs 27%, respectively, (RR, 0.99; 95% CI, 0.72-1.36; P < .001).2

Notably, treatment administration time was reduced to approximately 5 minutes with SC amivantamab compared with approximately 5 hours for the first infusion of IV amivantamab across 2 days.1

“The SC formulation of amivantamab offers an improved treatment experience for patients, reducing administration time from hours to minutes and substantially lowering rates of infusion-related reactions compared [with] the currently approved IV therapy,” Silvia Novello, MD, PhD, a professor of medical oncology in the Oncology Department at San Luigi Hospital in Orbassano, University of Turin, Italy, stated in a news release. “This positive CHMP opinion is a welcome milestone in the treatment of EGFR-mutated NSCLC, with the ability to make a meaningful difference in clinical practice and provide patients with more time to spend with their loved ones and to focus on what matters most to them.”

Data from PALOMA also supported the FDA’s decision to grant priority review to the biologics license application (BLA) for SC amivantamab for patients with NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations in August 2024.3 However, in December 2024, the FDA issued a complete response letter to this BLA, citing observations as part of a standard pre-approval inspection at a manufacturing facility.

The IV formulation of amivantamab was previously granted marketing authorization by the European Commission for the following indications1:

In combination with lazertinib in first-line advanced NSCLC displaying EGFR exon 19 deletions or exon 21 L858R substitution mutations.

In combination with carboplatin and pemetrexed in advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations following progression on prior therapy, including an EGFR TKI.

In combination with carboplatin and pemetrexed in first-line advanced NSCLC with activating EGFR exon 20 insertion mutations.

As monotherapy for advanced NSCLC with activating EGFR exon 20 insertion mutations following progression on platinum-based therapy.

PALOMA-3 Trial Design

PALOMA-3 evaluated the efficacy, pharmacokinetics, and safety of SC vs IV amivantamab in combination with lazertinib in patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after osimertinib (Tagrisso) and platinum-based chemotherapy.1,2

Patients were randomly assigned to receive 1600 mg (2240 mg for patients weighing 80 kg or greater) of SC amivantamab (n = 206) or 1050 mg (1400 mg for those weighing 80 kg or greater) of IV amivantamab (n = 212) plus 240 mg of oral lazertinib daily.2 Of these patients, 416 received at least 1 dose of their assigned treatment. Prophylactic anticoagulation was recommended during the first 4 months of treatment.

In addition to the study’s coprimary pharmacokinetic noninferiority end points, key secondary end points included progression-free survival (PFS), ORR, duration of response, patient satisfaction, and safety. Overall survival (OS) served as a predefined exploratory end point.

Additional Efficacy and Safety Data

The median PFS was 6.1 months (95% CI, 4.3-8.1) in the SC arm vs 4.3 months (95% CI, 4.1-5.7) in the IV arm (HR, 0.84; 95% CI, 0.64-1.10; P = .20); however, statistical significance was not reached. The median OS was notably longer in the subcutaneous arm (HR, 0.62; 95% CI, 0.42-0.92; nominal P = .02), with 65% vs 51% of patients alive at 12 months, respectively.

In terms of safety, a five-fold reduction in infusion-related reactions was also observed with SC vs IV amivantamab (13% vs 66%, respectively). No grade 4/5 reactions were observed. Most reactions occurred during cycle 1, and none required hospitalization in the SC arm compared with 2 events in the IV arm. No infusion-related discontinuations occurred in the SC arm vs 4 in the IV arm. Prophylactic anticoagulant use was similar between groups (80% vs 81%). Venous thromboembolism occurred in 9% and 14% of patients in the SC and IV arms, respectively. Notably, for those receiving prophylactic anticoagulation in either arm, grade 3 or higher bleeding events were not common (2% vs 1%).

By the end of treatment, 85% of patients reported that SC amivantamab was convenient or very convenient compared with 35% of those treated with IV amivantamab.

“At Johnson & Johnson, we are committed to optimizing every part of the lung cancer treatment journey for patients and health care professionals,” Henar Hevia, PhD, senior director and EMEA Therapeutic Area Lead of Oncology at Johnson & Johnson Innovative Medicine, concluded. “The positive CHMP recommendation for SC amivantamab takes us one step closer to making this a reality, providing the established efficacy benefits of IV amivantamab with improved safety outcomes and greater convenience for patients.”

References

1. CHMP recommends subcutaneous Rybrevant (amivantamab) for the treatment of patients with advanced EGFR-mutated non-small cell lung cancer. Johnson & Johnson. February 3, 2025. Accessed February 4, 2025. https://www.jnj.com/media-center/press-releases/chmp-recommends-subcutaneous-rybrevant-amivantamab-for-the-treatment-of-patients-with-advanced-egfr-mutated-non-small-cell-lung-cancer
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. Update on U.S. regulatory review of subcutaneous amivantamab. News release. Johnson & Johnson. December 16, 2024. Accessed February 4, 2025. https://www.jnj.com/media-center/press-releases/update-on-u-s-regulatory-review-of-subcutaneous-amivantamab