Abstract CT064: Updated safety and efficacy results from a phase 1/2 study of nezastomig, a first-in-class co-stimulatory PSMA×CD28 bispecific antibody (bsAb), plus cemiplimab (anti-PD-1) in patients (pts) with metastatic castration-resistant prostat

Abstract Background: Initial results from a Phase 1/2 trial (NCT03972657) of the co-stimulatory PSMA×CD28 bsAb nezastomig (REGN5678) plus anti-PD-1 antibody cemiplimab in mCRPC suggested a correlation between clinical activity and high-grade immune-mediated adverse reactions (imARs). Here, we present updated safety and efficacy results, and new survival and biomarker analyses. Methods: Pts with mCRPC who had received ≥2 prior lines of systemic therapy, including ≥1 prior second-generation anti-androgen, were enrolled. Dose levels (DLs) of intravenous (IV) nezastomig ranged from 0.1 to 300 mg weekly (QW). Most pts received nezastomig monotherapy for 3 weeks, followed by combination with cemiplimab 350 mg IV every 3 weeks (Q3W) until disease progression or unacceptable toxicity. Primary and secondary endpoints included safety, tolerability, pharmacokinetics, and PSA50 and PSA90 responses. Exploratory endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Biomarker analyses included immune cell phenotyping and cytokine profiling from peripheral blood. Results: At data cutoff (Feb 16, 2024), 78 pts had been treated in combination with cemiplimab. Treatment-related adverse events of any grade occurred in 60 pts (77%); most commonly fatigue (27%), cytokine release syndrome (13%; all G1 except one G2), and nausea (13%). imARs ≥G3 occurred in 11 pts (14%), primarily in pts with PSA50 responses (8/11). All imARs ≥G3 occurred after cemiplimab addition. Two pts (3%) experienced G5 imARs (HLH, hepatitis). Clinical responses were observed exclusively at nezastomig DLs ≥30 mg (n=61), where 15 pts (25%) achieved PSA50 and 10 pts (16%) achieved PSA90. Kaplan-Meier (KM)-estimated median rPFS (95% CI) was 5.0 months (2.1-12.0) at DLs ≥30 mg and 2.1 months (1.9-3.5) at DLs <30 mg. As of an additional data cutoff performed for longer term survival (Jul 19, 2024, median follow-up of 22.7 months [IQR 16.3-36.7]), the KM-estimated median OS (95% CI) was 17.3 months (11.0-not estimable) at DLs ≥30 mg and 10.3 months (3.7-12.6) at DLs <30 mg. Peripheral blood analyses suggest increased T-cell activation and inflammatory signaling following nezastomig plus cemiplimab treatment. Conclusions: Updated results provide further evidence of durable clinical anti-tumor activity in mCRPC at nezastomig DLs 30-300 mg QW combined with cemiplimab 350 mg Q3W. In preliminary analyses, encouraging survival outcomes were observed with the higher nezastomig DLs plus cemiplimab. Anti-tumor responses were tightly associated with high-grade imARs. Exploration of nezastomig dose ranging is ongoing along with additional combination strategies. The mechanism linking clinical anti-tumor activity and toxicity is being investigated. Citation Format: Bilal A. Siddiqui, Jingsong Zhang, Benedito A. Carneiro, Kevin K. Zarrabi, Mark N. Stein, David R. Wise, Edward P. Gelmann, Che-Kai Tsao, Gerald Falchook, Joseph W. Kim, Xin Gao, Przemyslaw W. Twardowski, Divya Rana, Fang Fang, Shilpa Govindraj, Jennifer S. Sims, Dimitris Skokos, Frank A. Seebach, Israel Lowy, Pradeep Thanigaimani, Matthew Ingham, Sabina Sandigursky, Elizabeth Miller. Updated safety and efficacy results from a phase 1/2 study of nezastomig, a first-in-class co-stimulatory PSMA×CD28 bispecific antibody (bsAb), plus cemiplimab (anti-PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT064.