Gemcitabine intravesical system plus cetrelimab misses primary end point in SunRISe-2

Treatment of muscle-invasive bladder cancer (MIBC) in patients who declined or were ineligible for cystectomy using the gemcitabine intravesical system plus cetrelimab was not found to be superior to chemoradiotherapy for bladder-intact event-free survival (BI-EFS), despite achieving complete response (CR) rates described by a study investigator as “compelling.”¹

The data from the phase 3 SunRISe-2 trial were presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California.

In his presentation, Andrea Necchi, MD, an associate professor of oncology at Vita-Salute San Raffaele University in Milan, Italy, and Director of GU Medical Oncology at San Raffaele Hospital, explained that with the emergence of new treatments for MIBC, “The role of these newer therapies…with regard to the established standard of care or chemo radiation is still unknown.”

In the phase 2 SunRISe-4 trial (NCT04919512), investigators reported that neodjuvant gemcitabine intravesical system plus cetrelimab demonstrated activity in patients with MIBC who were cisplatin ineligible.^2,3

The study population for SunRISe-2 comprised adults with histologically confirmed cT2-T4a, N0, M0 MIBC who had an ECOG Performance Status of 0-2, declined or were ineligible for radical cystectomy, and had adequate organ function. Patients were randomly assigned 1:1 to either arm A, comprising gemcitabine intravesical system every 3 weeks (21-day indwelling) followed by every 12 weeks from 24 until week 144 plus intravenous cetrelimab every 3 weeks until week 78, or arm B, comprising concurrent chemotherapy (investigator’s choice of cisplatin, every week) or gemcitabine (twice weekly for 4-6 weeks) plus radiation therapy. The primary end point was BI-EFS; secondary end points included overall response rate (ORR) at week 18, metastasis-free survival (MFS) overall survival (OS), and safety. Median follow-up was 11.3 months (range, 0.03-43.2 months).

Enrollment began in December 2020. On June 28, 2024, “There was a clinical cut-off for futility analysis after 300 patients completed the week 18 overall response rate assessment. And based on the futility analysis, the IMDC recommendation was to terminate the study,” Necchi said. The recommendation occurred on September 9, 2024. Two days later, the sponsor discontinued enrollment, and, “The protocol was amended, allowing those with complete response in arm A to continue the study until completeness and all patients randomized in chemo radiotherapy arm to continue the treatment until the end,” Necchi said.

At ASCO GU, Necchi presented findings from the clinical data cut-off that took place on July 7, 2025, at which time all patients had either completed study treatment, discontinued study treatment, or transitioned to long-term extension.

“For this reason, all the efficacy end points should be regarded as exploratory, and we are presenting the final safety data,” Necchi said.

Discussing the baseline characteristics, Necchi noted that 29.8% of patients in arm A and 29.7% of patients in arm B had an ECOG Performance Status of 1-2. Additionally, 44.4% of patients in arm A and 38.6% of patients in arm B had tumor stage T0 at baseline.

Looking at ORR at week 18, Necchi reported an ORR of 56.7% (95% CI, 49.8-63.5) in arm B vs 65.3% (95% CI, 58.4-71.9) in arm B. The CR rate was 50.7% in arm A compared with 59.4% in arm B. Treatment with the gemcitabine intravesical system plus cetrelimab was not associated with superior BI-EFS; the median BI-EFS was not reached (NR) (95% CI, 22.93-NE) in arm A and NR (95% CI, 26.58-NE) in arm B. Six-month BI-EFS was 73.5% (95% CI, 66.6-79.3) in arm B vs 86.9% (95% CI, 80.9-91.2) in arm B. Twelve-month BI-EFS was 65.5% (95% CI, 57.9-72.1) in arm A vs 79.9% (95% CI, 72.3-85.6) in arm B. Similarly, better MFS and OS were not observed with the gemcitabine intravesical system plus cetrelimab vs CRT.

Necchi described safety as “pretty good” in both arms. In arm A, 79.9% of patients had at least 1 treatment-related adverse event (TRAE) of any grade, and 26.8% had at least 1 grade 3 or higher TRAE. In arm B, 88.0% of patients had at least 1 TRAE of any grade, and 32.0% had at least 1 grade 3 or higher TRAE. The incidence of TRAEs resulting in treatment discontinuation was 15.0% in arm A and 9.5% in arm B. No treatment-related deaths occurred in arm A, 1 occurred in arm B.

“In conclusion, the SunRISe-2 trial was stopped in advance for futility based on overall response rate assessment and the totality of the efficacy data. However, the CR rates in both arms are compelling, being higher than 50% with both strategies…BI-EFS rates in participants at week 18 CR assessment were comparable between arms and were higher than 80% in both arms. There were no unexpected safety findings,” Necchi concluded.

REFERENCES

1. Necchi A, Williams SB, Tran P, et al. Gemcitabine intravesical system (Gem-iDRS) in combination with cetrelimab (CET) versus chemotherapy (CRT) in muscle-invasive bladder (MIBC): SunRISe-2 final results. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract 635. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16933?presentation=256842

2. Necchi A, Guerrero-Ramos F, Crispen PL, et al. Gemcitabine intravesical system plus cetrelimab or cetrelimab alone as neoadjuvant therapy in muscle-invasive bladder cancer: SunRISe-4 primary analysis and biomarker results. J Clin Oncol. 2026;44(7):586-597. doi:10.1200/JCO-25-02382

3. Necchi A, Guerrero-Ramos F, Crispen PL, et al. TAR-200 plus cetrelimab versus cetrelimab monotherapy as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or decline neoadjuvant cisplatin-based chemotherapy (SunRISe-4): interim analysis of a randomised, open-label phase 2 trial. Lancet Oncol. 2025;26(10):1312-1322. doi:10.1016/S1470-2045(25)00358-4