Phase 3 trial to evaluate TAR-200/cetrelimab for muscle-invasive bladder cancer

A randomized phase 3 trial will evaluate TAR-200 plus cetrelimab for patients with muscle-invasive bladder cancer (MIBC).¹

Stephen B. Williams, MD, MS

“Patients with MIBC often have poor prognosis and are at high risk for death. Standard treatment is neoadjuvant platinum-based chemotherapy for cisplatin-eligible patients followed by radical cystectomy, which is associated with high treatment burden,” said study coauthor Stephen B. Williams, MD, MS, professor and chief of the Division of Urology at the University of Texas Medical Branch. “Trimodal therapy is another bladder-sparing treatment; however, we have shown over 50% of MIBC patients receive no definitive therapy. The combination of TAR-200 and cetrelimab is being studied to determine whether it can improve patient outcomes.”

Williams, discussing the trial during the 2021 American Urological Association Annual Meeting, went on to say that TAR-200 is a novel, intravesical drug delivery system enabling 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 signaling from both PD-L1 and PD-L2,” Williams said.

SunRISe-2 (NCT04658862) is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus chemoradiotherapy in participants with MIBC. To be eligible, adults must have an ECOG performance status of 0 to 2, and histologically proven, newly diagnosed cT2 to T4a, N0, M0 MIBC, and they must be ineligible for or refuse radical cystectomy.

Investigators opened enrollment at 272 locations worldwide in December 2020 and hope to recruit 550 patients. Participants will be stratified based on transurethral resection of bladder tumor screening results (visibly complete vs incomplete) and screening tumor stage (T0 vs Ta/T1/Tis vs T2-T4a).

Participants in arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks. Beginning at week 24, dosing will shift to every 12 weeks until 144 weeks. Cetrelimab will be dosed every 3 weeks until month 18. Patients in arm 2 will receive standard-of-care chemoradiotherapy with cisplatin or gemcitabine for up to 6 weeks, plus investigator’s choice of conventional hypofractionated chemotherapy.

The primary end point is bladder intact event-free survival (BI-EFS) defined as time from randomization to first BI-EFS event, including histologically proven MIBC, clinical evidence of nodal or metastatic disease per RECIST 1.1, radical cystectomy, or death.

Investigators will conduct primary disease assessment in both arms at week 18. They will conduct axial imaging and cystoscopy at week 24 and every 12 weeks thereafter through year 2 of the study, and then every 24 weeks through study year 5.

Key secondary end points include metastasis-free survival, overall survival, overall response rate at 18 weeks, and safety and tolerability. Exploratory end points include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, healthcare resource utilization, and biomarkers.

MIBC is a potentially lethal disease, but many patients do not receive the recommended aggressive, curative therapy. The standard of care is radical cystectomy with pelvic lymphadenectomy or chemoradiotherapy, and the addition of platinum-based neoadjuvant chemotherapy improves survival outcomes.² However, previous data show that neoadjuvant chemotherapy is underused, especially in the elderly and in groups with poor 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 ineligible for curative therapy.⁴ 

In 2019, investigators 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-label, multi-center, single-arm study will enroll up to 25 patients who are scheduled for 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

References

1. 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 concurrent chemoradiotherapy in participants with muscle-invasive urothelial carcinoma of the bladder. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP13-17

2. Huo J, Ray-Zack MD, Shan Y, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer. Eur Urol Oncol. 2019;2(5):497-504. doi:10.1016/j.euo.2018.07.009

3. Gray PJ, Fedewa SA, Shipley WU, et al. Eur Urol. 2013;63(5):823-829. doi:10.1016/j.eururo.2012.11.015

4. U.S. FDA grants Fast Track designation to TARIS for TAR-200 (GemRIS) in muscle invasive bladder cancer. News release. TARIS Bio. April 3, 2018. Accessed September 11, 2021. https://bwnews.pr/2XaB3ci

5. TARIS initiates clinical trial of TAR-200 in combination with Opdivo (nivolumab) for patients with muscle-invasive bladder cancer. News release. TARIS Bio. July 10, 2019. Accessed September 11, 2021. https://prn.to/3k4afn2