Phase 1/2 study of REGN4336 alone or in combination with cemiplimab or nezastomig in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

• DOI: 10.1200/jco.2025.43.5_suppl.tps295
• Publication Date: 2025-02-18T14:40:47Z
• Authors: William Kevin Kelly; Sandy Srinivas; Joseph Maly; Deepak Kilari; Arif Hussain; Biren Saraiya; Bilal Ahmed Siddiqui; Paul Monk; Gurkamal S. Chatta; Vivek Narayan; Divya Rana; Pradeep Thanigaimani; Fang Fang; Dimitris Skokos; Jessica Kirshner; Frank A. Seebach; Israel Lowy; Matthew Ingham; Sabina Sandigursky; Elizabeth Miller

TPS295 Background: mCRPC is characterized by an immunosuppressive tumor microenvironment with few intratumoral effector T cells, leading to low response rates immune checkpoint inhibitors; therefore, novel immunotherapy approaches are needed. Prostate-specific membrane antigen (PSMA) highly expressed in malignant prostate cancer cells. REGN4336 a PSMA×CD3 bispecific antibody (bsAb) that facilitates T-cell–mediated killing bridging PSMA-expressing cells CD3+T providing “signal 1” for T-cell activation. Nezastomig (REGN5678 [PSMA×CD28 bsAb]) enhances activation/proliferation engaging the costimulatory receptor CD28 on T-cells located proximity PSMA, 2.” In preclinical models, demonstrated dose-dependent activity against was enhanced combination cemiplimab (anti–PD-1) or nezastomig. Preclinically, nezastomig + subtherapeutic doses of showed similar efficacy and reduced cytokines compared higher monotherapy, suggesting this strategy may mitigate cytokine release syndrome (CRS). separate clinical trial (NCT03972657), promising mCRPC, but some responders had high-grade immune-mediated AEs. partner Methods: This open-label, Phase 1/2, first-in-human, multicenter study evaluating ± pts (NCT05125016). Pts must have received ≥2 lines systemic therapy metastatic/castration-resistant disease, including second-generation anti-androgen. Prior PSMA-targeted radioligands permitted. Module 1 evaluates monotherapy step-up dosing CRS; 2 will evaluate cemiplimab; 3 Modules 3, receive until tolerated Grade ≤1 CRS, followed therapy. began administered SC; addition, 1–3 IV (+ sarilumab [anti–IL-6] CRS prophylaxis) compare tolerability, PK, immunogenicity across routes. Treatment continues disease progression, intolerable AEs, other withdrawal criteria met. Dose escalation primary objectives: assess safety, determine RP2D regimens expansion antitumor (ORR per modified PCWG3 criteria). Exploratory objectives include PSMA-PET imaging tissue-based biomarker analysis. first combined ×CD3 ×CD28 bsAb mCRPC. As Sept 12, 2024, 35 been enrolled, 4 3. Clinical information: NCT05125016 .