A phase 2, randomized, open-label study of gemcitabine/cisplatin plus cemiplimab (REGN2810, anti-PD-1) with or without fianlimab (REGN3767, anti-LAG-3) for organ preservation in patients with localized muscle-invasive bladder cancer (NeoSTOP-IT).
Authors: Alexander Z Wei, Basil Bakir, Andrew T Lenis, Christopher B. Anderson, Karie Runcie, Guarionex Joel DeCastro, Samuel S Pan, Michael M Shen, James M. McKiernan, Mark N. Stein
Journal: Journal of Clinical Oncology (2025)

TPS882 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) remains the standard of care for muscle-invasive bladder cancer (MIBC) – a disease with a median diagnosis age of 73 years old. While curative, RC negatively impacts quality of life and conveys significant rates of morbidity (60%) and mortality (5%), highlighting the need for bladder preservation. Several trials have shown the curative potential of NAC (Grossman, NEJM 2003), immunotherapy (Necchi, JCO 2018), and chemoimmunotherapy (Galsky, Nat Med 2023) (Powles, NEJM 2024) in patients with MIBC. LAG-3 is an immune checkpoint receptor that is highly expressed in exhausted tumor-infiltrating lymphocytes within bladder cancer contributing to increased tumor tolerance and a poor overall prognosis. Fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) has been previously shown to be both tolerable and effective in patients with solid tumors. Methods: Neo-STOPIT is a phase 2, open-label, randomized trial with continuous Bayesian toxicity monitoring. Eligible patients must have histologically confirmed MIBC (T2-T3 N0 M0). Mixed histology is permitted if there is a urothelial component. Upper tract disease, prior immunotherapy, and/or bladder chemoradiation is not permitted. Patients will undergo maximal transurethral resection of bladder tumor (TURBT) followed by gemcitabine and cisplatin (21 day cycles). Patients will be randomized 2:1 to receive concomitant cemiplimab (350 mg IV q3w) + fianlimab (1600 mg IV q3w) or cemiplimab. Patients will then repeat TURBT and imaging. Patients with clinical complete response (cCR) may defer RC and continue maintenance immunotherapy for 13 more cycles with surveillance urinary cytology/cystoscopy, imaging, and circulating tumor DNA. Patients without a cCR will undergo RC. The primary endpoint of cCR is defined as the absence of: residual tumor on cystoscopy, metastatic disease on cross-sectional imaging, and positive urine cytology. Secondary endpoints include bladder-intact survival, recurrence free survival, overall survival, and safety/tolerability. Translational exploratory endpoints, including organoid establishment, are planned. We will enroll 36 patients (24 patients in C+F arm). We hypothesize that 70% patients in the C+F arm will achieve cCR compared to 43% (historical control). At least 21 patients will give us 80% power for a one-sided Z-test at a significance of 0.05. To ensure patient safety, toxicity will be monitored using the Bayesian method of Thall et. al. The study will be stopped, at any time during the study, if we observe 70% or more probability that the serious treatment-related adverse event rate is &gt;30%. Recruitment will begin January 2025. Clinical trial information: NCT06571708 .