Pegenzileukin (SAR444245) non‑α IL‑2 (IL‑2Rβγ agonist) + PD‑1 cemiplimab hits 40% ORR in metastatic melanoma; 56% ORR in advanced cSCC

Pegenzileukin is a pegylated recombinant IL‑2 variant engineered to avoid IL‑2Rα binding (aiming to reduce classic IL‑2 toxicities/Treg expansion) while engaging IL‑2Rβγ to expand NK and CD8 T cells; here it was combined with cemiplimab (anti‑PD‑1) in an open-label Phase 1/2 study in metastatic/unresectable melanoma (MM) and cutaneous squamous cell carcinoma (cSCC) (NCT04913220). At the RP2D (pegenzileukin 16µg/kg Q3W + cemiplimab 350mg Q3W), ORR was 40% in MM (n=20; 1 CR, 7 PR) and 56.3% in cSCC (n=16; 9 PR), with ≥12‑mo DOR in 75.0% and 85.7% of responders, and 6‑mo PFS rates of 55.0% (MM) and 70.7% (cSCC); in context, cemiplimab monotherapy in advanced cSCC has typically delivered ~35–47% ORR (durable responses common), so the 56% here is directionally above—but still within the broader real‑world/pivotal range and based on small n. DLTs occurred in 4 patients (5 total) including ≥G3 thrombocytopenia, ≥G3 ALT/AST elevation, an infusion reaction, and a G2 cytokine release syndrome; most AEs were G1–2 infusion-related reactions, and pharmacodynamics showed NK/CD8 expansion without increased Tregs.