Dr Sabari on the FDA Approval of Subcutaneous Amivantamab for EGFR-Mutant NSCLC

“The IV formulation [of amivantamab] is quite clunky. It’s administered over 2 days—cycle 1 day 1 and day 2—and there is a high risk of IRRs. The subcutaneous formulation is much more user friendly.”

Joshua K. Sabari, MD, an assistant professor in the Department of Medicine at the New York University (NYU) Grossman School of Medicine, as well as the director of High Reliability Organization Initiatives at NYU Langone’s Perlmutter Cancer Center, discussed the clinical and practical implications of the FDA approval of amivantamab and hyaluronidase-lpuj(Rybrevant Faspro; subcutaneous amivantamab) for the treatment of patients with EGFR-mutant non–small cell lung cancer (NSCLC).

Sabari contextualized the approval within the evolving frontline treatment paradigm for EGFR-mutant NSCLC. The phase 3 MARIPOSA trial (NCT04487080) established amivantamab plus lazertinib (Lazcluze) as a standard-of-care combination after demonstrating an overall survival (OS) advantage compared with osimertinib (Tagrisso) monotherapy in this population. Although the intravenous (IV) formulation—amivantamab-vmjw (Rybrevant)—is effective, its clinical use has been limited by logistical challenges, including prolonged infusion times across multiple days during the first cycle and a high incidence of infusion-related reactions (IRRs), which occur in approximately two-thirds of patients receiving IV therapy, according to Sabari.

The development of a subcutaneous formulation was therefore driven by the need to improve treatment tolerability and operational feasibility without compromising efficacy, Sabari explained. He highlighted findings from the phase 1 PALOMA trial (NCT04606381), which evaluated the dose escalation and safety of subcutaneous amivantamab and demonstrated that this route of administration was both feasible and clinically active. These findings supported the subsequent phase 3 PALOMA-3 trial (NCT05388669), which directly compared subcutaneous amivantamab plus lazertinib vs the IV formulation used in the same combination.

In PALOMA-3, the subcutaneous formulation met the trial’s primary objective of pharmacokinetic noninferiority. Geometric mean ratios of trough concentrations and area under the curve were comparable between the subcutaneous and IV administration methods, confirming equivalent systemic exposure. Importantly, an exploratory analysis suggested a potential improvement in OS with the subcutaneous formulation, although Sabari emphasized that these findings should be interpreted cautiously and warrant further follow-up.

From a safety and tolerability perspective, the subcutaneous formulation was associated with a marked reduction in IRRs compared with IV administration. This reduction has meaningful implications for patient experience and clinic workflow, including shorter chair time, fewer premedication requirements, and less need for prolonged monitoring during early treatment cycles, Sabari said. He noted that these advantages may facilitate broader adoption of amivantamab-based therapy in routine practice.

The FDA approval of subcutaneous amivantamab across all approved indications for the IV formulation reflects a shift toward more patient-centered delivery of biologic therapies, according to Sabari. He concluded that subcutaneous amivantamab is likely to enhance treatment accessibility, reduce treatment burden, and potentially improve outcomes for patients with EGFR-mutant NSCLC, reinforcing its role as a preferred formulation in clinical practice.