Hypervigilance: A phase Ib clinical trial to optimize risk-benefit of nezastomig (PSMAxCD28 costimulatory bispecific antibody) plus cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer (mCRPC).

TPS295 Background: Prostate cancer harbors an immunosuppressive tumor microenvironment (TME), with few effector T cells and absent costimulatory signaling required for optimal T cell activation. Nezastomig is a first-in-class bispecific antibody targeting prostate-specific membrane antigen (PSMA) and CD28, the canonical co-stimulatory receptor on T cells. In an ongoing first-in-human phase 1/2 trial in patients with mCRPC (NCT03972657), nezastomig plus cemiplimab (anti-PD-1) induced durable clinical responses closely associated with immune-mediated toxicities. These toxicities were typically observed to be early-onset (within the first six weeks of dosing unpublished). We therefore hypothesized that with intensive toxicity monitoring and mitigation strategies and a less frequent dosing interval, the combination of nezastomig plus cemiplimab will have an acceptable risk-benefit profile and lead to durable clinical responses. Methods: This is an open-label, single-center phase Ib clinical trial in patients with mCRPC refractory to standard treatment options or refusing or intolerant to the current standard of care. Prior immunotherapies (including T cell engagers) and prior PSMA-targeted radioligand therapy are permitted. Patients receive three weekly doses of nezastomig as part of a monotherapy lead-in phase and then transition to every three-week dosing with the combination of nezastomig plus cemiplimab. A back-fill Bayesian optimal interval (BF-BOIN design has been implemented to find the recommended phase II doses, with dosing decisions based on safety, efficacy, and favorable immune TME changes (increase in CD8+ T cells and decrease in CD4+FoxP3+ regulatory T cells) identified in paired pre- and on-treatment tumor biopsies obtained after the first dose of combination therapy. Four dose levels of nezastomig will be investigated, ranging from 30 mg to 600 mg; the dose of cemiplimab is fixed at 350 mg IV every three weeks. Strict stopping rules have been implemented for patient safety. A total of up to 60 patients will be enrolled on study. The study is currently open and enrolling and to date, n=6 patients have been enrolled in the initial cohort (NCT06826768). Clinical trial information: NCT06826768 .