Subcutaneous Amivantamab Wins EU Approval in Multiple EGFR+ Advanced NSCLC Indications

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The European Commission has approved a subcutaneous formulation of amivantamab (Rybrevant) for use in combination with lazertinib (Lazcluze) for the first-line treatment of adult patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, and as monotherapy for the treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after progression on or following platinum-based therapy.1

The approval of the subcutaneous formulation was supported by data from the phase 3 PALOMA-3 trial (NCT05388669). During the study, patients with EGFR-mutated advanced NSCLC who experienced disease progression following treatment with osimertinib (Tagrisso) and platinum-based chemotherapy were randomly assigned to receive subcutaneous amivantamab plus lazertinib (n = 206) or intravenous (IV) amivantamab plus lazertinib (n = 212).2

Findings showed the trough concentration (Ctrough) geometric mean ratio for subcutaneous vs IV amivantamab was 1.15 (90% CI, 1.04-1.26) at cycle 2, day 1, and 1.42 (90% CI, 1.27-1.61) at cycle 4, day 1. The cycle 2 area under the curve (AUCD1-D15)was 1.03 (90% CI, 0.98-1.09).

Regarding efficacy, patients treated in the subcutaneous arm experienced an overall response rate (ORR) of 30% vs 33% for those in the IV arm. The median progression-free survival (PFS) was 6.1 months compared with 4.3 months for the subcutaneous and IV formulations, respectively. The subcutaneous formulation was also associated with improved overall survival (OS; HR, 0.62; 95% CI, 0.42-0.92; nominal P = .02).

“While great strides have been made in the treatment of EGFR-mutated NSCLC, a critical need still exists for treatment approaches that are not only effective but also more convenient for patients, while optimizing experience in the clinic,” Silvia Novello, MD, PhD, professor of medical oncology in the Oncology Department at San Luigi Hospital in Orbassano at the University of Turin in Italy, stated in a news release.1 “The approval of subcutaneous amivantamab will have a meaningful impact on clinical practice, offering patients greater convenience and an improved treatment experience, without compromising on the well-established efficacy of intravenous amivantamab.”

PALOMA-3 enrolled patients at least 18 years of age with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression on or after osimertinib or another approved third-generation EGFR TKI and platinum-based chemotherapy.2

Patients were randomly assigned 1:1 to receive subcutaneous amivantamab co-formulated with hyaluronidase at 1600 mg (2240 mg for those at least 80 kg in weight) once per week for the first 4 weeks and every 2 weeks thereafter; or IV amivantamab at 1050 (1400 mg for those at least 80 kg in weight) once per week for 4 weeks, then once every 2 weeks. All patients received oral lazertinib at 240 mg once per day.

Key stratification factors included history of brain metastases (yes vs no), EGFR mutation type (exon 19 deletion vs exon 21 L858R mutation), race (Asian vs non-Asian), and last line of therapy (osimertinib vs chemotherapy).

The inferiority of Ctrough and AUCD1-D15 served as the trial’s primary end point. Secondary end points included ORR, PFS, and OS.

Regarding safety, any-grade adverse effects (AEs) occurred in 99% of patients in both arms. The rates of grade 3 or higher AEs were 52% for the subcutaneous arm vs 56% for the IV arm. Serious AEs occurred in 29% and 30% of patients, respectively. In the subcutaneous arm, AEs led to interruption of any treatment in 62% of patients, dose reduction of any agent in 31% of patients, and discontinuation of any study treatment in 13% of patients. In the IV arm, these respective rates were 60%, 25%, and 14%.

The most common any-grade AEs reported in at least 15% of patients in either group were paronychia (subcutaneous arm, 54%; IV arm, 51%), hypoalbuminemia (47%; 37%), rash (46%; 43%), acneiform dermatitis (31%; 33%), nausea (29%; 25%), stomatitis (28%; 33%), peripheral edema (25%; 28%), increased alanine aminotransferase levels (22%; 27%), decreased appetite (22%; 25%), fatigue (21%; 20%), vomiting (21%; 20%), diarrhea (21%; 19%), constipation (20%; 20%), headache (20%; 17%), increased aspartate aminotransferase levels (20%; 21%), anemia (19%; 19%), pruritus (16%; 12%), hypocalcemia (16%; 13%), myalgia (16%; 6%), asthenia (15%; 11%), thrombocytopenia (14%; 16%), and infusion-related reactions (13%; 66%).

References

1. European Commission approves subcutaneous Rybrevant (amivantamab) for the treatment of patients with advanced EGFR-mutated non-small cell lung cancer. News release. Janssen-Cilag International NV. April 7, 2025. Accessed April 7, 2025. https://www.globenewswire.com/news-release/2025/04/07/3056770/0/en/European-Commission-approves-subcutaneous-RYBREVANT-amivantamab-for-the-treatment-of-patients-with-advanced-EGFR-mutated-non-small-cell-lung-cancer.html
2. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605. doi:10.1200/JCO.24.01001