AUA 2025: NeoSTOP-IT: 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

(UroToday.com) The 2025 AUA annual meeting featured a bladder cancer clinical trials in progress session and a presentation by Dr. Alexander Wei discussing NeoSTOP-IT, 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 (MIBC).

Neoadjuvant chemotherapy followed by radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. However, the median age of diagnosis is 73 years of age, and radical cystectomy is associated with significant morbidity (60%) and mortality (5%). Trimodality therapy with chemoradiation is typically reserved for patients who are not eligible for neoadjuvant chemotherapy or radical cystectomy, thus, novel bladder-sparing methods should be explored.

The rationale for this study is that modern neoadjuvant therapies for muscle-invasive bladder cancer with concurrent cisplatin-based chemotherapy and PD-1 blockade have shown pathologic complete response rates of ~35% prior to radical cystectomy. This approach has shown organ-sparing potential, with most patients electing to defer radical cystectomy after achieving a clinical complete response. However, 25% of patients who achieve complete response recur locally and require a radical cystectomy. So, is a deeper response required to remain cystectomy-free?

Lymphocyte activation gene-3 (LAG-3) is a promising target that carries significant potential to overcome mechanisms of immune intolerance. Increased LAG-3 expression results in decreased T-cell activation and has been observed in urothelial cancer patients refractory to PD-1 inhibition, which suggests that LAG-3 blockade may help overcome T-cell intolerance. Fianlimab is an anti-LAG-3 monoclonal antibody with previously demonstrated tolerability and efficacy both as a single agent and when combined with cemiplimab, an anti-PD-1 antibody.

The hypothesis for the phase 2 NeoSTOP-IT trial is that a combination of cisplatin-based chemotherapy + combined PD-1 (cemiplimab) and LAG-3 (fianlimab) blockade will allow bladder preservation for a significant number of patients with muscle-invasive bladder cancer. The primary objective is to measure the rate of clinical complete response following treatment with neoadjuvant chemotherapy combined with cemiplimab +/- fianlimab. The secondary objectives are (i) bladder-intact survival, (ii) recurrence-free survival, (iii) overall survival, and (iv) safety and tolerability. Clinical complete response will be defined as:

• No evidence of high-grade malignancy on biopsy
• No malignant cells on urine cytology, and
• No definitive evidence of local or metastatic disease on cross-sectional imaging

Patients will be randomized 2:1 to receive neoadjuvant gemcitabine + cisplatin (split dose allowed) + cemiplimab (350 mg every 3 weeks) +/- fianlimab (1600 mg every 3 weeks) with the option of cystectomy deferral and 1 year of maintenance cemiplimab + fianlimab or cemiplimab monotherapy for patients who achieve a clinical complete response: 

Key inclusion criteria include:

• Histologically confirmed bladder urothelial carcinoma (mixed histology allowed if there is a urothelial carcinoma component)
• T2-T3, N0, M0
• Cisplatin eligible
• ECOG performance status 0-1

Key exclusion criteria include:

• Previous systemic chemotherapy or bladder-directed radiation for urothelial carcinoma
• Prior systemic immune checkpoint inhibitors targeting T-cell pathways
• Concurrent upper urinary tract (ie, ureter, renal pelvis) invasive urothelial carcinoma
• No history of autoimmune conditions or solid organ transplant

From a statistical standpoint, the null hypothesis will be rejected if 70% of patients achieve a clinical complete response of 43%. A minimum of 21 patients will give the trial at least 80% power for a one-sided, one-proportion Z-test at a significance of 0.05 in the combination cemiplimab + fianlimab arm. Toxicity will be monitored using the Bayesian method, and the study will stop if there is a 70% probability that the serious treatment-related adverse event rate is 30% or more.

There will also be exploratory translational research objectives to identify molecular alterations in pre-treatment biopsies that may predict response (whole-exome sequencing). Dr. Wei and colleagues will also evaluate whether longitudinal changes in ctDNA correlate with outcomes after therapy, and they will also identify immune cell populations at the single-cell level that predict response or resistance (single-cell RNA sequencing). Finally, they will establish patient tumor-derived organoid lines to further study tumor evolution and drug response. Dr. Wei concluded his presentation discussing NeoSTOP-IT by highlighting that the study is fully funded, IRB approved, and expected to begin accrual in May 2025.

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Urological Association's 2025 Annual Meeting, between April 26 – 29, 2025 in Las Vegas, NV.