6MO Subcutaneous amivantamab administered every 4 weeks (Q4W) in patients with advanced solid malignancies: The phase Ib PALOMA study

Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity approved as intravenous (IV) formulation. Subcutaneous (SC) ami substantially reduces severity/incidence of infusion-related reactions (IRRs; 16% SC vs 67% IV) and administration time (≤7 minutes SC vs 2–4 hours IV; Minchom ASCO 2023). We identified a Q4W dose for ami SC with comparable activity/safety to the IV dose thus further improving patient (pt)/provider experience. PALOMA (NCT0406381) evaluated administration feasibility, safety, and pharmacokinetics of ami SC in pts with advanced solid tumors who may benefit from EGFR/MET-directed therapy. Ami SC was dosed weekly for the first 4 weeks (1600 mg ≥80 kg: 2240 mg), Q4W thereafter (3200 mg ≥80 kg: 4320 mg), and was administered by manual push injection in the abdomen. There are 127 pts enrolled, with 19 pts (median age: 62 years) having received ami SC Q4W as of 16 Nov 2023. Most pts were Asian (68%) and female (53%); 17 (89%) pts had non-small cell lung cancer. Four pts (21%) experienced IRRs, all grade 1–2 after first dose only. IRR-associated symptoms were pyrexia (2 pts), chills, pruritus, urticaria, and myalgia (1 pt each). Most common adverse events (AEs) were rash (79%; primarily grade 1-2, 2 cases grade 3), paronychia (58%), myalgia (47%), fatigue, nausea, stomatitis (32% each), peripheral edema and pyrexia (26% each). Eight pts (42%) experienced grade ≥3 AEs, with 3 (16%) treatment-related (rash 2 pts, hypokalemia 1 pt). Two pts discontinued ami SC due to AEs unrelated to treatment. The geometric mean values for Cycle 2 Ctrough and AUC0-672h for the tested Q4W SC dose were 325 μg/mL and 286612 μg•h/mL, respectively. The SC Q4W dose was refined to 3520 mg (≥80 kg: 4640 mg) to better match the steady state Ctrough of the approved IV Q2W dose. Simulated geometric mean ratios for the refined Q4W dose vs reference IV dose at steady state were 0.92 (90% CI, 0.76–1.11) for Ctrough and 1.27 (90% CI, 1.18–1.36) for AUC0-672h. Ami SC Q4W had lower rates of IRRs and was better tolerated vs ami IV. The ami SC Q4W dose of 3520 mg (≥80 kg: 4640 mg) achieved comparable exposure to the approved IV dose and is being further evaluated in the phase II, PALOMA-2 (NCT05498428) study.