utDNA and ctDNA Are Predictive of Residual Disease After TAR-200 in MIBC

The gemcitabine intravesical system (formerly TAR-200; Inlexzo) represents a promising therapeutic strategy in the neoadjuvant setting when combined with cetrelimab in patients with muscle-invasive bladder cancer (MIBC), according to Andrea Necchi, MD.

Findings from the primary analysis of the phase 2 SunRISe-4 trial (NCT04919512), which were presented at the 2025 ESMO Congress, showed that the gemcitabine intravesical system plus cetrelimab induced higher pathologic complete response (pCR) and 12-month recurrence-free survival (RFS) rates compared with cetrelimab monotherapy.¹ Exploratory analyses also showed that urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) should be further investigated as predictive biomarkers for residual disease after neoadjuvant therapy.

“This, to my knowledge, is one of the first times that utDNA data have been reported, at least within a prospective study of neoadjuvant therapy in this patient population,” Necchi said in an interview with OncLive® during the conference.

These findings build on data from the phase 2b SunRISe-1 trial (NCT04640623), which led to the September 2025 FDA approval of the gemcitabine intravesical system as monotherapy for adult patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors.^2,3 In SunRISe-1, patients who received the gemcitabine intravesical system achieved a confirmed CR rate of 82% (95% CI, 72%-90%), and 52% of patients had a duration of CR of 1 year or longer.³

In the interview, Necchi discussed the findings and implications of the SunRISe-4 trial in addition to ways that utDNA and ctDNA may operate as key biomarkers in the MIBC landscape, and future directions for research with the gemcitabine intravesical system across bladder cancer management settings.

Necchi is a medical oncologist, associate professor, and director of Genitourinary Medical Oncology at San Raffaele Hospital and Scientific Institute in Milan, Italy.

OncLive: What previously reported data led to the design of the SunRISe-4 study?

Necchi: The SunRISe-4 study is part of a platform with multiple other studies testing the gemcitabine intravesical system alone or in combination with the checkpoint inhibitor cetrelimab in multiple clinical stages [of bladder cancer], including non–muscle-invasive disease and muscle-invasive disease.¹ The SunRISe-1 study was the study that led to the FDA approval of the gemcitabine intravesical system in CIS [NMIBC] tumors that were unresponsive to BCG.^2,3 Building on the results that have already been presented from the preliminary findings in muscle-invasive disease, [at ESMO 2025], we reported the primary biomarker results from SunRISe-4.¹

What was the design of SunRISe-4?

SunRISe-4 is a study that [enrolled patients with] T2-T4, N0M0 MIBC who refused or were unfit for cisplatin-based chemotherapy. The study provided combination therapy with intravesical the gemcitabine intravesical system and cetrelimab, or cetrelimab monotherapy in a randomized fashion before cystectomy, given for 4 courses every 3 weeks. The primary end point was pCR rate, and biomarker [analyses are] ongoing. At [ESMO 2025], we presented the primary clinical outcomes and biomarker results in terms of the ctDNA and utDNA assessments within the study. These biomarkers were evaluated at baseline and post-therapy at week 12, so after neoadjuvant therapy and before radical surgery.

What key efficacy findings have been presented from SunRISe-4?

The pCR rate with the gemcitabine intravesical system and cetrelimab was 38% [95% CI, 28%-49%]. This was compelling compared with [findings from] other ongoing studies in this field. The pathologic overall response rate [ORR] was [53% (95% CI, 43%-64%)]. With cetrelimab monotherapy, we lost a bit [of efficacy] with a 28% [(95% CI, 16%-44%) pCR rate and a] 44% [(95% CI, 29%-59%) pathologic ORR]. There was an improvement with adding an intravesical therapy to systemic checkpoint inhibition without adding too much regarding safety.

What is the safety profile of TAR-200 plus cetrelimab in MIBC?

The other good point for the combination therapy was also confirmed in SunRISe-1 and other ongoing studies in this platform.³ There was no extra toxicity of any significance in the [patients who received the gemcitabine intravesical system].¹ Most of the grade 3/4 adverse effects were effects of intravesical or local irritation and were manageable. [There is] nothing [notable regarding] tolerability compared with the data that have been already reported with the gemcitabine intravesical system.

What were the outcomes of the biomarker analyses of SunRISe-4?

Regarding biomarkers, an interesting story was presented [at ESMO 2025] because utDNA assessed at week 12—post-neoadjuvant therapy—was associated with pCR. Clearance of utDNA [at week 12] in patients who were utDNA positive at baseline and had an assessment and matched samples post-therapy was seen in [47.7%] of the patients; this was associated with pCR. On the other side, ctDNA was confirmed to be associated with RFS, as was reported in other studies in this setting. Interestingly, ctDNA was not associated with pCR or pathologic response.

We have 2 different end points that are providing us with different information. utDNA [analyses inform the local efficacy of the gemcitabine intravesical system in] the bladder for the interim end point pCR. ctDNA analyses inform us about the outcomes of the patients. Altogether, the informational biomarkers utDNA and ctDNA inform us about the possible potential next steps that indicate a way for blood-sparing [biomarker] approaches in the near future.

What is the significance of the SunRISe-4 study reporting utDNA analysis outcomes in the MIBC setting?

When evaluating intravesical therapy, considering utDNA becomes important because [it shows] the local situation. Interestingly, we started with a population of [approximately] 20% of patients in both arms who had a visible complete resection of the tumor judged by local investigators. In this patient population, the utDNA positivity baseline rate was [82.1%], meaning that despite the apparent complete regression or resection of the tumor, most—if not all—of the patients presented with positive utDNA results. This is one of the most important points.

The other point is related to the response to treatment. When evaluating the bladder with a local medium seems to be more reliable compared with systemic evaluation of residual disease in the blood. Minimal residual disease assessment of urine samples is a newer way to measure [treatment] activity and to predict the efficacy of newer intravesical therapy in these patients.

Now that TAR-200 is FDA approved for patients with NMIBC, how might future research continue to support the addition of this intravesical therapy in the bladder cancer treatment paradigm?

Based on the results of SunRISe-1, which were published in the Journal of Clinical Oncology [in July 2025], the gemcitabine intravesical system as monotherapy has been FDA approved for patients with BCG-unresponsive [NMIBC with] CIS with or without a papillary component.^2,3 The results were outstanding regarding CR and duration of response, because most of the CRs that have been reported with the gemcitabine intravesical system were maintained over time. There was no decline in CR duration [compared with that] reported with, for example, the use of standard systemic immune checkpoint inhibitors [ICIs] or other drugs that are approved in this setting. [The gemcitabine intravesical system is] the ideal backbone, and starting to add other drugs—systemic therapy or intravesical therapy—is a good background benchmark by which we can start treating this disease.

Research in the SunRISe platform is already looking at the frontline setting, which is new for immunotherapy. We have conflicting data emerging [with immunotherapy in the BCG-naive, high-risk NMIBC setting]. Regarding the phase 3 CREST study [(NCT04165317) of sasanlimab plus BCG] and the POTOMAC study [(NCT03528694) of durvalumab (Imfinzi) plus BCG, at ESMO 2025, these studies showed positive results] by combining ICI with standard BCG therapy. Other studies like the phase 3 ALBAN study [(NCT03799835) of atezolizumab (Tecentriq) plus BCG] were negative, and the incremental improvements in disease-free survival were significant but not huge.

There is a way of maybe changing the way we treat these patients, for example, by removing the BCG backbone and the BCG limitations in availability, toxicity, etc., by testing different combination therapies. Two phase 3 studies in this platform: SunRISe-3 [NCT05714202] and SunRISe-5 [NCT06211764], are evaluating combinations with the gemcitabine intravesical system and immunotherapy in comparison with the BCG backbone [in patients with high-risk NMIBC]. These are exciting trials that may in the future [result in the] removal of the BCG component [of standard therapies]. It would be hard, but the objective is compelling.

Disclosures: Necchi reported receiving grants or institutional research funding from AstraZeneca, Bristol Myers Squibb, Gilead, Ipsen, and Merck; receiving consulting or advisory fees from Astellas, AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Johnson & Johnson, Samsung Bioepis, Bicycle Therapeutics, and Merck; serving in a leadership role for the Global Society of Rare Genitourinary Tumors; and serving as an associate editor for the Journal of Clinical Oncology.

References

1. Necchi A, Guerrero-Ramos F, Crispen PL, et al. Neoadjuvant gemcitabine intravesical system (TAR-200) + cetrelimab (CET) or CET alone in patients (pts) with muscle-invasive bladder cancer (MIBC): SunRISe-4 (SR-4) primary analysis and biomarker results. Ann Oncol. 2025;36(suppl 2):S1652-S1653. doi:10.1016/j.annonc.2025.09.131
2. U.S. FDA approval of Inlexzo (gemcitabine intravesical system) set to transform how certain bladder cancers are treated. News Release. Johnson & Johnson. September 9, 2025. Accessed January 13, 2026. https://www.multivu.com/johnson-and-johnson/9342851-en-johnson-and-johnson-fda-approval-inlexzo-gemcitabine-intravesical-system
3. Daneshmand S, Van der Heijden M, Jacob J, et al. TAR-200 for bacillus calmette-guérin–unresponsive high-risk non–muscle-invasive bladder cancer: results grom the phase IIb SunRISe-1 Study. J Clin Oncol. 2025;43(33):3578-3588. doi:10.1200/JCO-25-01651