A phase 1/2 study of nezastomig (anti-PSMA×CD28) with or without cemiplimab (anti–PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and clear cell renal cell carcinoma (ccRCC).

TPS293 Background: Advanced mCRPC and metastatic ccRCC are urologic malignancies with poor prognoses, and novel therapies that can improve long-term outcomes remain an unmet medical need. Prostate-specific membrane antigen (PSMA) is a validated therapeutic target for prostate cancer. It is a transmembrane protein with enzymatic activity highly expressed by prostate cancer cells and ccRCC neovasculature. Nezastomig (REGN5678) is a first-in-class, PSMA×CD28 co-stimulatory bispecific antibody (bsAb) that facilitates T-cell mediated tumor killing by bridging PSMA-expressing cells with the costimulatory receptor, CD28, on T cells. Preliminary results have been reported from an open-label, Phase 1/2, first-in-human, multicenter study of nezastomig + cemiplimab in heavily pretreated pts with mCRPC (NCT03972657). In the dose escalation phase, nezastomig (30–300 mg) intravenously (IV) once weekly (QW) + cemiplimab (350 mg) IV once every 3 weeks (Q3W) reduced prostate-specific antigen levels and induced radiographic responses, providing the first evidence of clinical activity with a ×CD28 bsAb in solid tumors. The study has been amended to continue evaluation of nezastomig monotherapy in mCRPC based on the observed clinical activity and possible toxicity from the combination. Nezastomig is also being evaluated in pts with metastatic ccRCC. Methods: Pts with mCRPC must have received ≥2 prior lines of systemic therapy approved for metastatic and/or castration-resistant disease, including a second-generation androgen receptor signaling inhibitor. Pts with metastatic ccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including an anti-programmed cell death-(ligand) 1 therapy and either ipilimumab and/or a tyrosine kinase inhibitor. Nezastomig IV QW monotherapy starting dose for the mCRPC and ccRCC cohorts was informed by tolerability and clinical activity. Dose escalation of nezastomig monotherapy will occur in separate cohorts for mCRPC and ccRCC. When a maximum tolerated dose/presumptive recommended Phase 2 dose is identified, additional expansion cohorts may be evaluated. In pts with progressive disease after ≥6 weeks of nezastomig monotherapy, low-dose cemiplimab IV Q3W may be added. Dose escalation primary objectives are to determine safety, tolerability, and pharmacokinetics of nezastomig. Dose expansion primary objective is to assess efficacy of nezastomig (measured by objective response rate per modified Prostate Cancer Working Group 3 criteria [mCRPC cohorts] and per Response Evaluation Criteria in Solid Tumors version 1.1 [ccRCC cohorts]). The study is open and enrolling; 101 pts (97 with mCRPC; 4 with ccRCC) have been enrolled as of September 12, 2024. Clinical trial information: NCT03972657 .