TAR-200 / Cetrelimab under investigation in muscle-invasive bladder cancer
“Patients with MIBC often have a poor prognosis and are at high risk of death. The standard treatment is platinum-based neoadjuvant chemotherapy for patients eligible for cisplatin, followed by radical cystectomy, which is associated with a high treatment load, ”said Williams, professor and head of the urology division of the medical branch of the University of Texas. “Trimodal therapy is another bladder-sparing treatment, however, we have shown that over 50% of MIBC patients do not receive any definitive treatment. The combination of TAR-200 and cetrelimab is being studied to see if it can improve patient outcomes. “
Williams went on to say that TAR-200 is a new intravesical drug delivery system for sustained release of gemcitabine into the bladder, which increases dwell time and local drug dose. “Treatment with TAR-200 has demonstrated early clinical benefit with favorable toxicity in patients with MIBC. Cetrelimab is an investigational immunoglobulin g4 antibody that targets the PD-1 receptor, blocking PD-L1 and PD-L2 signaling.
SunRISe-2 is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab compared to chemoradiation in participants with MIBC. To be eligible, adults must have an ECOG Performance Index of 0 to 2, and a histologically proven diagnosis, cT2 to T4a, N0, M0 MIBC, and they must be ineligible or refuse radical cystectomy.
Researchers opened recruitment at 272 sites around the world in December 2020 and hope to recruit 550 patients. Participants will be stratified based on results of transurethral resection of bladder tumors screening (visibly complete vs incomplete) and tumor screening stage (T0 vs Ta / T1 / Tis vs T2-T4a).
Participants in arm 1 will receive TAR-200 intravesically every 3 weeks for the first 18 weeks. From week 24, the dosage will drop to every 12 weeks up to 144 weeks. Cetrelimab will be administered every 3 weeks until month 18. Patients in arm 2 will receive standard chemoradiotherapy with cisplatin or gemcitabine for up to 6 weeks, plus the investigator’s choice of conventional hypofractionated chemotherapy.
Primary endpoint is intact bladder event-free survival (BI-EFS) defined as the time from randomization to the first BI-EFS event, including histologically proven MIBC, clinical evidence of lymph node or metastatic disease according to RECIST 1.1, radical cystectomy or death.
Investigators will perform a primary assessment of disease in both arms at week 18. They will perform axial imaging and cystoscopy at week 24, then every 12 weeks until the second year of the study, then every year. the 24 weeks until the fifth year of the study.
The main secondary endpoints include metastasis-free survival, overall survival, overall response rate at 18 weeks, and safety and tolerability. Exploratory endpoints include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, resource utilization health and biomarkers.
MIBC is a potentially fatal disease, but many patients do not receive the aggressive curative treatment recommended. The standard of care is radical cystectomy with pelvic lymphadenectomy or chemoradiation, and the addition of platinum-based neoadjuvant chemotherapy improves survival outcomes.2 However, previous data shows that neoadjuvant chemotherapy is underused, especially in the elderly and in groups with low socioeconomic status.3
In April 2018, the FDA granted Fast Track designation to TAR-200 for the treatment of patients with organ-confined or locally advanced MIBC who are not eligible for curative treatment.4
In 2019, researchers initiated a phase 1b clinical trial (NCT03518320) evaluating TAR-200 in combination with nivolumab (Opdivo) for safety, tolerability and preliminary efficacy in patients with MIBC. The open, multi-center, single-arm study will enroll up to 25 patients who are scheduled to undergo radical cystectomy. Prior to radical cystectomy, patients will receive both TAR-200 and nivolumab on day 1 of 4 consecutive 21-day dosing cycles.5
- Williams SB, Curtie C, Keegan KA et al. SunRISe-2: A phase 3, multicenter, randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus concomitant chemoradiotherapy in participants with muscle invasive urothelial bladder carcinoma. Presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP13-17.
- Huo J, Ray-Zack MD, Shan Y, et al. Patterns of discernment and quality of neoadjuvant chemotherapy use in patients with muscle invasive bladder cancer. Eur Urol Oncol. 2019; 2 (5): 497-504. doi: 10.1016 / j.euo.2018.07.009
- Gray PJ, Fedewa SA, Shipley WU, et al. Eur Urol. 2013; 63 (5): 823-829. doi: 10.1016 / j.eururo.2012.11.015
- TARIS Bio. The US FDA grants TARIS Fast Track designation for TAR-200 (GemRIS) in muscle invasive bladder cancer. Press release. April 3, 2018. Accessed September 11, 2021. https://bwnews.pr/2XaB3ci
- TARIS Bio. TARIS is initiating a clinical trial of TAR-200 in combination with Opdivo (nivolumab) for patients with muscle invasive bladder cancer. Press release. July 10, 2019. Accessed September 11, 2021. https://prn.to/3k4afn2