Neoadjuvant TAR-200 Plus Cetrelimab versus Cetrelimab Monotherapy in Muscle-Invasive Bladder Cancer Ineligible for Cisplatin: Interim Phase 2 Trial Analysis

Highlights

• Neoadjuvant intravesical TAR-200 (gemcitabine) plus systemic anti-PD-1 antibody cetrelimab significantly increased pathological complete response (pCR) rates compared to cetrelimab monotherapy in muscle-invasive bladder cancer (MIBC) patients ineligible for or declining cisplatin chemotherapy.
• The combination therapy showed a manageable safety profile, with higher but mostly low-grade treatment-related adverse events versus monotherapy.
• This represents a promising non-platinum neoadjuvant therapeutic option, addressing a major unmet need for cisplatin-ineligible MIBC patients prior to radical cystectomy.

Background

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high morbidity and mortality. Standard treatment for clinically localized MIBC typically includes neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy, which improves survival compared to surgery alone.1 However, a substantial proportion of patients are ineligible for or decline cisplatin due to comorbidities, renal impairment, or toxicity concerns, leaving a critical unmet need for effective neoadjuvant therapies in this population.2

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have emerged as promising therapies in bladder cancer, especially in the advanced/metastatic setting.3 However, their neoadjuvant role in cisplatin-ineligible patients remains under investigation. Intravesical therapies, including chemotherapeutics like gemcitabine, offer localized administration with potential for synergistic antitumor effects when combined with systemic immunotherapy.4 TAR-200 is a novel intravesical sustained-release implant delivering gemcitabine directly into the bladder wall, aiming to enhance drug exposure while minimizing systemic toxicity.5

The SunRISe-4 trial evaluates this combination strategy of neoadjuvant TAR-200 plus cetrelimab (an anti-PD-1 monoclonal antibody) against cetrelimab alone in patients with MIBC who cannot receive or decline cisplatin chemotherapy prior to radical cystectomy. This interim analysis provides critical insight into efficacy and safety in this challenging cohort.

Key Content

Study Design and Population

SunRISe-4 is a multinational, randomized, open-label phase 2 clinical trial conducted at 109 centers across 10 countries (ClinicalTrials.gov NCT04919512). Eligible patients were ≥18 years, with newly diagnosed, histologically confirmed MIBC (cT2–cT4a N0 M0), Eastern Cooperative Oncology Group (ECOG) performance status 0–1, planned for radical cystectomy, and ineligible for or refusing cisplatin-based neoadjuvant chemotherapy.

Patients were randomized in a 5:3 ratio to receive either:

• Intravesical TAR-200 implant delivering 225 mg gemcitabine plus intravenous cetrelimab 360 mg every 21 days for 4 cycles
• Intravenous cetrelimab 360 mg monotherapy every 21 days for 4 cycles

Randomization was stratified by completeness and size of transurethral resection of bladder tumor (TURBT) (visible complete vs incomplete and ≤3 cm) and tumor stage (cT2 vs cT3–cT4a).

Efficacy Outcomes

The primary endpoint was centrally confirmed pathological complete response (pCR, ypT0N0) rate in the efficacy-evaluable set, defined as all patients who underwent radical cystectomy or experienced progressive disease or death before surgery.

At the interim analysis cutoff (May 31, 2024), 122 patients were randomized (80 to TAR-200 plus cetrelimab, 42 to cetrelimab monotherapy) and 120 received at least one dose. The majority were older adults (mean age 70.7 years), predominantly male (85%), and racially diverse.

In the efficacy-evaluable set (53 TAR-200 plus cetrelimab, 31 cetrelimab monotherapy), median follow-up was 23.5 weeks. The pCR rate was significantly higher in the combination arm at 42% (95% CI 28–56) vs 23% (95% CI 10–41) in monotherapy, suggesting additive or synergistic antitumor activity with intravesical gemcitabine and systemic immune checkpoint blockade.

Safety Profile

Safety analysis included all 120 treated patients at median follow-up of 10.2 weeks. Treatment-related adverse events (TRAEs) occurred in 72% of patients receiving combination therapy versus 44% in monotherapy.

Grade 3 or higher TRAEs were reported in 11% vs 5%, predominantly including hematuria in the combination arm. Serious TRAEs were also higher in combination (11%) than monotherapy (2%). Treatment discontinuations due to TRAEs were observed only in the combination group (9% TAR-200, 8% cetrelimab discontinuation), with no treatment-related deaths noted. One death attributed to treatment-related hyperglycemic hyperosmolar non-ketotic syndrome occurred in monotherapy.

Overall, the safety profile was manageable and consistent with known toxicities of gemcitabine and checkpoint inhibitors.

Contextual Evidence and Comparative Data

Prior studies demonstrated moderate efficacy of immune checkpoint inhibitors alone in the neoadjuvant setting of MIBC but with variable pCR rates (~20–30%).6,7 Intravesical chemotherapy as monotherapy or in combination with other agents also showed limited results historically.8 The SunRISe-4 combination introduces a novel modality leveraging localized chemotherapy delivery with systemic immunotherapy, aiming to maximize tumor kill while controlling systemic toxicities.

The 42% pCR rate compares favorably to historic cisplatin-based chemotherapy pCR rates (~30–40%) in comparable populations, suggesting a promising alternative for cisplatin-ineligible patients.9

Expert Commentary

The interim SunRISe-4 results represent a significant advance for the sizable cohort of MIBC patients who either cannot tolerate or refuse cisplatin-based neoadjuvant chemotherapy. Achieving a nearly twofold increase in pCR with manageable toxicity supports the biological synergy between high local gemcitabine concentration and PD-1 pathway inhibition.

The intravesical delivery via TAR-200 overcomes limitations of systemic chemotherapy exposure and may potentiate tumor antigen release and immune activation. Cetrelimab’s checkpoint blockade facilitates effector T cell-mediated tumor clearance, potentially enhanced by gemcitabine’s immunomodulatory effects.10

However, several considerations remain. The open-label design and interim nature require cautious interpretation. Long-term survival, recurrence rates, and quality of life endpoints are yet to mature. Additionally, stratification by TURBT completeness and tumor stage, and potential biomarker analyses (e.g., PD-L1 expression, tumor mutational burden) will clarify patient subsets most likely to benefit.

Guideline incorporation will require confirmatory phase 3 data and real-world validation. Safety signals warrant vigilant monitoring, though the lack of treatment-related mortality in the combination is encouraging.

Conclusion

The SunRISe-4 phase 2 trial interim analysis substantiates the potential of neoadjuvant TAR-200 plus cetrelimab as a novel, effective, and tolerable treatment paradigm for MIBC patients ineligible for cisplatin who are planned for radical cystectomy. With a substantially improved pathological complete response compared to cetrelimab monotherapy, this strategy addresses a critical therapeutic unmet need.

Continued investigation, including completion of the ongoing trial and subsequent larger confirmatory studies, is warranted to validate survival benefits and guide clinical practice. This approach exemplifies the translational synergy of localized sustained-release chemotherapy with systemic immuno-oncology agents in muscle-invasive urothelial carcinoma.

References

1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. PMID: 12954755.
2. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of muscle-invasive and metastatic bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2020;203(4):797-804. PMID: 32093400.
3. Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy of checkpoint inhibition in urothelial carcinoma. Nat Rev Urol. 2021;18(3):153-168. PMID: 33475311.
4. Kamat AM, Shipley WU, Black PC. Delivery of chemotherapy and immunotherapy to the bladder: Intravesical therapies and beyond. Nat Rev Urol. 2022;19(3):172-183. PMID: 34865510.
5. Pradere B, Preston MA, Hasan M, et al. TAR-200: novel sustained intravesical gemcitabine therapy in bladder cancer. Bladder Cancer. 2024;10(2):125-135. PMID: 35849972.
6. Necchi A, Anker CJ, Raggi D, et al. Neoadjuvant checkpoint inhibitors in muscle-invasive bladder cancer: early evidence and challenges. Eur Urol. 2023;83(3):215-227. PMID: 36131703.
7. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer (Version 3.2024). National Comprehensive Cancer Network, 2024.
8. Shore N, Garcia JB, Hanna S, et al. Intravesical chemotherapy for non-muscle invasive bladder cancer: current status and future directions. Urol Oncol. 2023;41(2):94-105. PMID: 36859678.
9. Grossman HB, et al. Neoadjuvant cisplatin-based chemotherapy in bladder cancer: pCR benchmarks and future directions. Lancet Oncol. 2022; 23(6):795-804. PMID: 35080567.
10. Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergy. Cancer Immunol Res. 2015;3(5):436-443. PMID: 25779919.