(UroToday.com) The 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 13th and 15th 2025, was host to the Trials in Progress Poster Session A: Prostate Cancer. Dr. Bilal Siddiqui presented the trial in progress poster 293: 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).
Dr. Siddiqui highlighted that advanced metastatic castration-resistant prostate cancer (mCRPC) and metastatic clear cell renal cell carcinoma (ccRCC) are both urologic malignancies with poor prognoses, and novel therapies that improve long-term outcomes remain under investigation in both malignancies and are desperately needed. Prostate-specific membrane antigen (PSMA) is a validated therapeutic target for prostate cancer. It is a transmembrane protein with enzymatic activity that is highly expressed by prostate cancer cells and the neovasculature of ccRCC.
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 plus cemiplimab in heavily pretreated patients with mCRPC (NCT03972657). In the dose-escalation phase, nezastomig (30–300 mg intravenously [IV] once weekly [QW]) plus cemiplimab (350 mg IV once every three weeks [Q3W]) reduced PSA levels and induced radiographic responses, providing the first evidence of clinical activity with a CD28 bsAb in solid tumors.
The aforementioned study has been amended to continue the evaluation of nezastomig monotherapy in mCRPC based on the observed clinical activity and potential toxicity from the combination therapy. Dr. Siddiqui mentioned that Nezastomig is also being evaluated in patients with metastatic clear cell renal cell carcinoma.
- Patients 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.
- Patients with metastatic clear cell renal cell carcinoma must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including an anti-programmed cell death-(ligand) 1 (PD-(L)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 patients 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 in the mCRPC cohort and per Response Evaluation Criteria in Solid Tumors version 1.1 in the metastatic ccRCC cohort.
Currently, the study is open and enrolling, 101 pts (97 with mCRPC; 4 with ccRCC) have been enrolled as of September 12, 2024.
Presented by: Bilal Siddiqui, MD, Assistant Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.