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

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 .