Subcutaneous Delivery of Amivantamab in Patients With Advanced Solid Malignancies: The Phase Ib PALOMA Study

Abstract

Intravenous amivantamab is associated with frequent infusion-related reactions that are mitigated by slow infusion rates and a split-dosing approach over 2 days at first administration. The phase Ib PALOMA study evaluated subcutaneous amivantamab in participants with advanced solid malignancies. Subcutaneous amivantamab exhibited good tolerability and meaningfully shortened administration time; demonstrated safety, pharmacokinetic, and pharmacodynamic profiles consistent with intravenous amivantamab; and reduced the frequency and severity of infusion-related reactions versus intravenous amivantamab. Purpose: Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. Patients and Methods: PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. Results: The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (<= 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, >= 80 kg), 2400 mg (3360 mg, >= 80 kg), and 3520 mg (4640 mg, >= 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. Conclusion: Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcu-taneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.