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

TPS296 Background: Advanced mCRPC and mccRCC are urologic malignancies associated with poor prognoses, presenting an unmet need for novel therapies that can improve long-term outcomes for patients. Prostate-specific membrane antigen (PSMA) is a transmembrane protein with enzymatic activity and is highly expressed by prostate cancer cells and mccRCC neovasculature. PSMA has been validated as a therapeutic target for prostate cancer. 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 expressed on T cells. Cemiplimab is an anti–programmed cell death-1 (PD-1) monoclonal antibody that targets inhibitory T-cell immune checkpoints. Preliminary results from the dose escalation phase of this study (NCT03972657) showed that nezastomig + cemiplimab reduced prostate-specific antigen (PSA) levels and induced radiographic responses; this provided the first evidence of clinical activity with a PSMA×CD28 co-stimulatory bsAb in solid tumors. Additionally, there was suggested correlation between clinical activity and high-grade immune-mediated adverse reactions in patients with mCRPC. The study has now been amended to reintroduce patient cohorts that will receive nezastomig + cemiplimab combination therapy following a benefit–risk evaluation. Methods: During the dose escalation phase of this open-label, Phase 1/2, first-in-human, multicenter study, nezastomig will be administered at increasing dose levels in combination with cemiplimab in separate cohorts for patients with mCRPC or mccRCC. When a maximum tolerated dose/presumptive recommended Phase 2 dose is identified, additional expansion cohorts may be evaluated. Patients with mCRPC must have received ≥2 prior lines of systemic therapy approved for metastatic or castration-resistant disease, including a second-generation androgen-receptor signaling inhibitor and a lutetium-based PSMA-targeted radioligand. Patients with mccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including anti–PD-1/anti–PD-ligand 1 therapy and either ipilimumab or a tyrosine kinase inhibitor. Dose escalation primary endpoints are safety, tolerability, and nezastomig pharmacokinetics. The dose expansion primary endpoint is a composite response rate of PSA and radiographic responses per modified Prostate Cancer Working Group 3 criteria (mCRPC cohorts) and objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1 (mccRCC cohorts). This study is open and currently enrolling patients. Clinical trial information: NCT03972657 .