Novel Chemo Delivery System Misses Mark in Muscle-Invasive Bladder Cancer

A novel combination of an investigational intravesical drug delivery system designed to provide sustained release of gemcitabine into the bladder (Gem-iDRS, Inlexzo) and systemic treatment with the investigational immunotherapy cetrelimab failed to outperform standard chemoradiation in patients with muscle-invasive bladder cancer, according to findings from the phase III SunRISe-2 trial presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

In this exclusive MedPage Today video, Andrea Necchi, MD, of IRCCS San Raffaele Hospital and Scientific Institute in Milan, discusses why the study was stopped early and what the findings may still suggest about bladder-preserving strategies.

Following is a transcript of his remarks:

SunRISe-2 was a randomized controlled superiority study with Gem-iDRS — formally referred to as TAR-200 — plus systemic immune therapy cetrelimab versus concurrent chemoradiotherapy in patients with muscle-invasive bladder cancer, cT2-T4a, N0, M0 stage who were ineligible or declined for radical cystectomy. The patients were randomized to receive experimental therapy with intravesical therapy and systemic therapy or chemoradiation in 1:1 fashion.

The primary endpoint of the study was bladder-intact event-free survival [BI-EFS], and there were additional secondary endpoints, including objective response rate, metastasis-free survival, overall survival, and safety.

The trial was stopped in advance for futility, started in December 2020 with accrual with a projected enrollment of 550 patients. In June 2024, the study was stopped based on the IDMC [independent data monitoring committee] recommendation, based on the futility analysis that occurred considering the overall response rate assessed at week 18. And based on this and based on the totality of the data, the sponsor decided to discontinue the enrollment in September 2024.

And then the protocol was amended allowing continuation of therapy in patients who were in complete response [CR] in the experimental arm and all patients who were randomized in the chemoradiation arm to complete the treatment. So the clinical cutoff analysis was July 2025. We have reported that on this analysis, including the exploratory survival outcomes and safety.

Patients were pretty well balanced between arms, classical chemoradiotherapy population, with 30% of the patients presenting with performance status 1 or 2, and 44% in Gem-iDRS and cetrelimab arm and 38% of the patients in chemoradiation arm presented with a clinically-resected, radically-resected disease before starting therapy at the time of randomization.

The overall response rate at week 18, which was the secondary endpoint used for futility analysis, showed that the clinical CR rate was 50.7% with the intravesical and systemic therapy, while there was 59% with chemoradiotherapy. Bladder-intact event-free survival in complete responders was fully overlapping with the estimates of 6 months and 12 months overlapping. In the ITT [intention-to-treat] population, there was a numerically higher estimate for 6 month and 12-month BI-EFS for chemoradiotherapy as compared to TAR-200 and cetrelimab, while metastasis-free survival/overall survival were completely overlapping between the arms.

Treatment was well tolerated in both arms with the reported treatment-related adverse event of grade 3 or higher being in the range of 30% in both arms. There was no huge rate of discontinuation therapy. There was only one treatment-related death in the chemoradiotherapy arm.

So overall, the SunRISe-2 trial was stopped in advanced for futility based on the interim objective response rate assessment. The finalized [data] showed a compelling CR rate in both arms, around 50% in both arms of CR rate. The BI-EFS, bladder-intact event-free survival, in participants with the week 18 CR assessment was pretty high in both arms, being higher than 80% at the projection of 12 months in both arms.

So the study overall suggests that there could be an opportunity for Gem-iDRS and cetrelimab as an alternative approach to chemoradiation in patients who had to save their bladder while getting the most powerful tools for potentially being cured from muscle-invasive bladder cancer.