On December 17, the U.S. Food and Drug Administration (FDA) approved amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for subcutaneous injection for adult patients across all indications approved for the intravenous formulation of amivantamab (Rybrevant).
PALOMA-3
The subcutaneous injection of amivantamab and hyaluronidase-lpuj was evaluated in PALOMA-3 (ClinicalTrials.gov identifier NCT05388669), a randomized, open-label, multicenter, multiregional trial in adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations. A total of 418 patients were randomly assigned 1:1 to receive either subcutaneous amivantamab and hyaluronidase-lpuj plus lazertinib or intravenous amivantamab plus lazertinib.
The primary outcome measures were trough concentrations at steady state (Ctrough), overall response rate, progression-free survival, and overall survival. At the recommended every-2-week dosage, the observed geometric mean ratio (GMR) (90% confidence interval [CI]) for cycle 2 AUC day 1–15 was 1.03 (0.98–1.09) and for steady-state Ctrough on cycle 4 day 1 was 1.43 (1.27–1.61). For the recommended every-3-week dosage, the simulated GMRs (90% CI) for the average concentration of cycle 2 day 1–21 was 1.20 (1.15–1.26) and for steady-state Ctrough was 1.32 (1.23–1.42), with the lower limits of the GMRs (90% CI) also above the prespecified threshold of 0.8 for comparability.
There were no notable differences in descriptive analyses of overall response rate and progression-free survival and no evidence of a potential detrimental effect on overall survival observed in patients who received subcutaneous amivantamab compared to patients who received intravenous amivantamab.
The safety profile of the subcutaneous amivantamab arm was generally similar to the safety profile of the intravenous amivantamab arm in PALOMA-3; one exception is that the incidence of systemic administration reactions for subcutaneous amivantamab was lower than the incidence of infusion-related reactions for intravenous amivantamab. The incidence of systemic administration reactions of any grade was 13% for subcutaneous amivantamab compared to 66% for infusion-related reactions for intravenous amivantamab.
The prescribing information includes warnings and precautions for hypersensitivity and administration-related reactions, interstitial lung disease/pneumonitis, venous thromboembolic events with concomitant use with lazertinib, dermatologic adverse reactions, ocular toxicity, and embryo-fetal toxicity.
The recommended dosage of subcutaneous amivantamab is based on baseline bodyweight and depends on the specific indication.
Expedited Programs
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Australian Therapeutic Goods Administration and Health Canada. The application reviews may be ongoing at the other regulatory agencies.
This review also used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
