Gemcitabine intravesical system plus cetrelimab shows strong efficacy in MIBC

Treatment of muscle-invasive bladder cancer (MIBC) with combination gemcitabine intravesical system (Inlexzo, formerly known as TAR-200) plus cetrelimab yielded high pathologic complete response (pCR) as well as strong recurrence-free survival (RFS), according to data from the SunRISe-4 study (NCT04919512) presented at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.¹

In his presentation, Andrea Necchi, MD, 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 although the current standard of care for MIBC (T2-T4a N0M0) consists of radical cystectomy and neoadjuvant chemotherapy (or chemoradiation in some patients),^2,3 some patients with MIBC are candidates for radical cystectomy and not neoadjuvant chemotherapy, representing an unmet need.

The open-label, multi-center, parallel cohort phase 2 SunRISe-4 study evaluated adult patients with histologically confirmed cT2-T4a N0M0 MIBC, who had predominant urothelial carcinoma histology, ECOG performance status of 0-1, were ineligible for or refused cisplatin-based chemotherapy, and who were scheduled for radical cystectomy. Patients were stratified by visible residual disease at transurethral resection of the bladder tumor (TURBT) (complete vs incomplete [≤ 3 cm]) and tumor stage at MIBC diagnosis: cT2 vs cT3a. Patients were randomly assigned 5:3 to cohort 1, consisting of gemcitabine intravesical system 225 mg gemcitabine every 3 weeks (indwelling) for 12 weeks plus cetrelimab monotherapy (360 mg intravenously every 3 weeks for 12 weeks), or cohort 2, consisting of cetrelimab monotherapy (360 mg intravenously every 3 weeks for 12 weeks). Patients underwent radical cystectomy at week 12 and were followed every 4 weeks until week 12 post cystectomy and every 12 weeks until week 108 post cystectomy.

The primary end point was pCR (ypT0N0). Secondary end points included recurrence-free survival (RFS) and safety. Exploratory end points included pathologic OR rate (≤ypT1N0), overall survival, time to symptomatic progression, quality of life per FACT-BI, pharmacokinetics, and biomarker analysis. At ESMO 2025, Necchi reported the primary analysis from SunRISe-4 as well as exploratory biomarker analyses of urine tumor DNA (utDNA) and circulating tumor DNA (ctDNA) minimal residual disease (MRD).

In reviewing baseline patient characteristics, Necchi pointed out that 55 (54.5) patients in cohort 1 and 36 (62.1%) patients in cohort 2 refused radical cystectomy, most patients presented with T2 tumor stage at initial diagnosis—79 (78.2%) patients in cohort 1 and 49 (84.5%) patients in cohort 2—and 19 (18.8%) patients in cohort 1 had residual disease as evidenced by visibly incomplete TURBT compared with 8 (13.8%) patients in cohort 2.

Necchi reported a pCR rate of 38% (95% CI: 28-49) for cohort 1 vs 28% (95% Ci: 16-44) for cohort 2. The 12-month RFS rate was 77% (95% CI: 67-85) for cohort 1 vs 64% (95% CI: 47-77) in cohort 2.

The investigators did not observe any new safety signals for the gemcitabine intravesical system, cetrelimab, or the combination of both. Treatment-related adverse events (TRAEs) of any grade were observed in 82 (81.2%) patients in cohort 1 and 30 (51.7%) patients in cohort 2. TRAEs included dysuria, pollakiuria, micturition urgency, fatigue, hematuria, hypothyroidism, hyperthyroidism, urinary tract infection, and pruritus. Serious TRAEs of any grade occurred in 14 (13.9%) patients in cohort 1 and 3 (5.2%) patients in cohort 2. No patient had a TRAE leading to death in cohort 1 vs 1 patient in cohort 2. In cohort 1, 21 (20.8%) patients experienced a TRAE leading to treatment discontinuation; no patient in cohort 2 experienced a TRAE leading to treatment discontinuation.

Necchi then turned to the utDNA analysis, reporting that at baseline 82.1% of patients were utDNA positive 17.9% were utDNA negative. At week 12, 52.3% of patients were utDNA positive and 47.7% were utDNA negative. Necchi reported that an associated between week 12 utDNA MRD status and pCR. Twenty-two of 27 (81.5%) patients who achieved a pCR were found to be utDNA negative at week 12 vs 7 of 33 (21.2%) patients who did not achieve a pCR. Similarly, Necchi reported that utDNA clearance from baseline to week 12 was also associated with pCR.

Regarding ctDNA, the investigators reported an association between ctDNA negative status at baseline and longer RFS at week 12, but there was no association seen with pCR.

DISCLOSURES: Necchi noted grants/institutional funding from AstraZeneca, Bristol Myers Squibb, Gilead, Ipsen, and Merck; consulting/advisory fees from Astellas, AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Johnson & Johnson, Samsung Bioepis, Bicycle Therapeutics, and Merck.

REFERENCES

1. Necchi A, Guerrero-Ramos F, Crispen P, et al. Neoadjuvant gemcitabine intravesical system (TAR-200) + cetrelimab or cetrelimab alone in patients with muscle-invasive bladder cancer: SunRISe-4 primary analysis and biomarker results. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA112. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA112.html.pdf

2. Holzbeierlein J, Bixler BR, Buckley DI, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/SUO guideline (2017; Amended 2020, 2024). J Urol. 2024;212(1):3-10. doi:10.1097/JU.0000000000003981

3. Witjes JA, Bruins HA, Carrión A, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2023 Guidelines. Eur Urol. 2024 Jan;85(1):17-31. doi:10.1016/j.eururo.2023.08.016