Gemcitabine Intravesical System Plus Cetrelimab Misses the Mark in Muscle-Invasive Bladder Cancer

Gemcitabine intravesical system (Gem-iDRS; Inlexzo; previously TAR-200) plus cetrelimab (JNJ-63723283) did not result in a superior bladder-intact event-free survival (BI-EFS) vs concurrent chemoradiotherapy (CRT) in patients with muscle-invasive bladder cancer (MIBC) not receiving radical cystectomy, according to data from the final analysis of the SunRISE-2 study (NCT04658862).¹

The findings, which were shared during the 2026 Genitourinary Cancers Symposium (ASCO GU), showed that the median BI-EFS with Gem-iDRS plus cetrelimab (n = 262) was not reached (NR; 95% CI, 22.93-not evaluable [NE]) vs NR (95% CI, 26.58-NE) with CRT (n = 256). In the Gem-iDRS/cetrelimab arm, the 6- and 12-month BI-EFS rates were 73.5% (95% CI, 66.6%-79.3%) and 65.5% (95% CI, 57.9%-72.1%); these respective rates were 86.9% (95% CI, 80.9%-91.2%) and 79.9% (95% CI, 72.3%-85.6%) in the CRT arm.

The study had been stopped early for futility based on objective response rate (ORR) assessment at week 18. Gem-iDRS plus cetrelimab (n = 215) elicited an ORR of 56.7% (95% CI, 49.8%-63.5%) at week 18 vs 65.3% (95% CI, 58.4%-71.9%) with CRT (n = 202). However, complete response (CR) rates were greater than 50% in both the Gem-iDRS/cetrelimab (50.7%; n = 109) and CRT (59.4%; n = 120) arms. “The CR rate achieved in the Gem-iDRS plus cetrelimab arm is notable given the lack of a systemic cytotoxic agent utilized in that arm,” Andrea Necchi, MD, PhD, an associate professor at Vita-Salute San Raffaele University and head of genitourinary medical oncology at IRCCS San Raffaele, in Milan, Italy, said in a presentation of the data.

He added that BI-EFS rates were comparable in patients with a CR at week 18 between the arms. The median BI-EFS with Gem-iDRS/cetrelimab (n = 109) was NR (95% CI, NE-NE) vs NR (95% CI, NE-NE) with CRT. In the Gem-iDRS plus cetrelimab arm, the 6-month BI-EFS rate was 92.5% (95% CI, 84.8%-96.4%) and the 12-month BI-EFS rate was 86.0% (95% CI, 76.5%-91.9%). In the CRT arm, these respective rates were 95.0% (95% CI, 88.5%-97.9%) and 82.0% (95% CI, 70.4%-89.4%).

Moreover, Gem-iDRS paired with cetrelimab did result in superior metastasis-free survival (MFS) or overall survival (OS) vs CRT. The median MFS with Gem-iDRS/cetrelimab was NR (95% CI, 26.78-NE) vs NR (95% CI, NE-NE) with CRT. The 6-month MFS rate with Gem-iDRS/cetrelimab was 84.3% (95% CI, 78.2%-88.8%) vs 87.5% (95% CI, 81.6%-91.6%) with CRT; the 12-month MFS rates in the respective arms were 75.6% (95% CI, 68.2%-81.5%) and 82.3% (95% CI, 75.1%-87.6%). The median OS with Gem-iDRS plus cetrelimab was NR (95% CI, NE-NE) vs NR (95% CI, NE-NE) with CRT. The 6- and 12-month OS rates with Gem-iDRS/cetrelimab were 96.2% (95% CI, 92.8%-98.0%) and 88.8% (95% CI, 83.2%-92.6%), respectively, vs 98.2% (95% CI, 95.1%-99.3%) and 95.4% (95% CI, 90.8%-97.7%), respectively, with CRT.

What is the unmet need in patients with MIBC who are not eligible to undergo radical cystectomy?

Although the MIBC paradigm has expanded with the emergence of novel drugs that are efficacious irrespective of cisplatin eligibility, the role of new therapies with regard to standard-of-care CRT is not known. Previous data from the phase 2 SunRISe-4 study (NCT04919512) showed that Gem-iDRS plus cetrelimab elicited activity when given as neoadjuvant treatment in cisplatin-ineligible patients with MIBC.^2,3

Moreover, data from cohort 2 of the phase 2b SunRISe-1 trial (NCT04640623) supported the FDA’s decision to approve the gemcitabine intravesical system for use in adult patients with BCG-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ, with or without papillary tumors, in September 2025.⁴ In that study, the gemcitabine intravesical system (n = 83) elicited a confirmed CR rate of 82% (95% CI, 72%-90%) in this population, with 51% of patients remaining in CR for 1 year or longer.⁵

What was the design of SunRISe-2?

The randomized, controlled, phase 3, superiority study included patients with histologically confirmed cT2 to T4a, N0, and M0 MIBC who were at least 18 years of age and had an ECOG performance status ranging from 0 to 2.¹ Patients must have declined or not been eligible to receive radical cystectomy and were required to have acceptable organ function.

Participants were randomized 1:1 to receive Gem-iDRS given every 3 weeks with 21-day indwelling for 18 weeks followed by every 12 weeks from week 24 to week 144 plus cetrelimab given every 3 weeks until week 78 (arm 1) or investigator’s choice of cisplatin weekly for 4 to 6 weeks or gemcitabine twice weekly for 4 to 6 weeks plus radiotherapy (arm 2). Radiotherapy could have been conventional with 64 Gy to the bladder only for up to 6.5 weeks or hypofractionated at 55 Gy to the bladder only for up to 4 weeks.

Patients were stratified by screening repeat transurethral resection of bladder (re-TURBT; visibly complete vs incomplete) and tumor stage at the time of screening re-TURBT (T0 vs Ta/T1/Tis vs T2 to T4a). The primary end point of the study was BI-EFS, and secondary end points included week 18 ORR, MFS, OS, and safety.

The study design assumed a 12% absolute improvement in the 2-year BI-EFS rate, providing a 90% power to detect a HR of 0.65 between the arms leveraging a 2-sided α of 0.05. The median follow-up time for the final analysis, which was shared at the 2026 ASCO GU, was 11.3 months (range, 0.03-43.2).

In December 2020, the study began enrollment, with a goal of recruiting 550 participants. On June 28, 2024, a futility analysis would be conducted; this would occur after 300 patients completed the week 18 response assessment to examine the futility end point of week 18 ORR. Subsequently, on September 9, 2024, the independent data monitoring committee recommended to terminate the study for futility.

“The IDMC recommendation to continue the study was contingent on whether ORR with Gem-iDRS plus cetrelimab was higher vs CRT or lower vs CRT by up to 15% points. If the ORR with Gem-iDRS plus cetrelimab was lower vs CRT by more than 15% points, the IDMC would review the risks and benefits of Gem-iDRS plus cetrelimab to inform the nonbinding recommendation for futility,” Necchi noted in the presentation. “The totality of data was examined to inform the decision on termination for futility, including the primary and key secondary end points. The hazard ratios [HRs], confidence intervals around the HRs, and trends in the Kaplan-Meier curves for the efficacy end points of BI-EFS, MFS, and OS were considered to inform the decision.”

On September 11, 2024, the sponsor stopped enrollment with 518 patients randomized. Those randomized to arm 1 who had a CR at week 18 were permitted to continue to receive treatment; those in arm 2 were also allowed to complete treatment. July 7, 2025, was the clinical data cutoff date. All efficacy analyses regarding ORR, BI-EFS, MFS, and OS were exploratory; safety was also evaluated. The data were presented at the meeting.

What was the patient population enrolled to SunRISe-2?

Across the Gem-iDRS plus cetrelimab (n = 262) and CRT (n = 256) arms, the median patient age was 71.5 years (range, 36-91) and most were male (78.2%; 76.6%) and White (58.4%; 60.2%). Patients were from North and South America (35.1%; 34.8%), Europe (32.1%; 34.8%), and Asia (32.8%; 30.5%). Just under half of patients in the respective arms were former smokers (46.9%; 45.7%) and about one-third of patients in both arms were never smokers (34.4%; 37.5%). Most patients had visibly complete re-TURBT (85.9%; 87.1%).

Moreover, more than half of patients in the Gem-iDRS/cetrelimab and CRT arms had an ECOG performance status of 0 (70.2%; 70.3%), and the remainder had a status of 1 or 2 (29.8%; 29.7%). Most patients did not receive radical cystectomy because they refused it (85.1%; 85.2%); the remaining approximate 15% of patients in each arm were not eligible (14.9%; 14.8%). In the Gem-iDRS/cetrelimab arm, 44.4% of patients had T0 stage at screening re-TURBT, 26.6% had Ta/T1/Tis, and 29.0% had ≥ T2; these respective rates were 38.6%, 31.8%, and 29.7% in the CRT arm. Only 3.1% of those in the Gem-iDRS/cetrelimab arm had variant histology vs 7.1% of those in the CRT arm. In the CRT arm, 64.7% of patients received conventional radiation and 35.3% received a hypofractionated approach.

What was the safety profile of Gem-iDRS plus cetrelimab in this population of MIBC?

The median duration of exposure to Gem-iDRS was 18.2 weeks (range, 1-151); the median duration of exposure for cetrelimab was 22.7 weeks (range, 0-82); and the median duration of exposure to CRT was 6.4 weeks (range, 0-15).

In the Gem-iDRS/cetrelimab arm, 79.9% of patients experienced at least 1 treatment-related adverse effect (TRAE) of any grade; these effects were grade 3 or higher for 26.8% of patients. The most common TRAEs reported in this arm were dysuria (any grade, 26.0%; grade ≥ 3, 0.4%), urinary tract infection (24.8%; 6.3%), pollakiuria (20.9%; 0%), hematuria (12.6%; 0.4%), hypothyroidism (10.6%; 0.4%), anemia (4.7%; 0.4%), fatigue (4.3%; 0.8%), diarrhea (4.3%; 0.4%), constipation (2.4%; 0%), asthenia (2.4%; 0.4%), nausea (2.0%; 0%), lymphopenia (2.0%; 0%), thrombocytopenia (1.6%; 0%), neutropenia (1.6%; 0.4%), and decreased appetite (1.6%; 0.4%).

TRAEs led to treatment discontinuation for 15.0% of those in the Gem-iDRS/cetrelimab arm vs 9.5% of those in the CRT arm. No treatment-related deaths occurred in the Gem-iDRS arm vs 1 in the CRT arm.

“There were no unexpected safety findings,” Necchi concluded.

Disclosures: Dr Necchi disclosed employment with Bayer, stock and ownership interests in Bayer, and serving in a consulting or advisory role for AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Catalym, Genenta Science, Gilead Sciences, Incyte, Johnson & Johnson/Janssen, Merck Serono, Merck Sharp & Dohme, Peerview, PeerVoice, Samsung Bioepis, and Seattle Genetics/Astellas. Research funding was provided by Bristol Myers Squibb/Celgene, Gilead Sciences, and Merck Sharp & Dohme. Travel, accommodations, and expenses were provided by AstraZeneca, Gilead Sciences, Janssen, and Merck Sharp & Dohme.

References

1. Necchi A, Williams SB, Tran P, et al. Gemcitabine intravesical system (Gem-iDRS) in combination with cetrelimab (CET) versus chemoradiotherapy (CRT) in muscle-invasive bladder cancer (MIBC): SunRISe-2 final results. J Clin Oncol. 2026;44(suppl 7):635. doi:10.1200/JCO.2026.44.7_suppl.635
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
4. US FDA approval of INLEXZO (gemcitabine intravesical system) set to transform how certain bladder cancers are treated. News release. Johnson & Johnson. September 9, 2025. Accessed February 28, 2026. https://www.multivu.com/johnson-and-johnson/9342851-en-johnson-and-johnson-fda-approval-inlexzo-gemcitabine-intravesical-system
5. Inlexzo. Prescribing information. Johnson & Johnson; 2025. Accessed February 28, 2026. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INLEXZO-pi.pdf