Phase 1/2 study of REGN4336 alone or in combination with cemiplimab or nezastomig in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
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
Journal: Journal of Clinical Oncology (2025)

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