Neoadjuvant TAR-200 Plus Cetrelimab versus Cetrelimab Monotherapy in Cisplatin-Ineligible Patients with MIBC

The treatment of muscle-invasive bladder cancer (MIBC) in patients who cannot receive or decline standard cisplatin-based neoadjuvant chemotherapy is particularly challenging. To address this clinical need, a recent interim analysis of the SunRISe-4 trial evaluated the efficacy and safety of combining TAR-200, an intravesical gemcitabine-releasing system, with cetrelimab, an anti-PD-1 antibody, compared to cetrelimab monotherapy in this patient population.

The SunRISe-4 study was a randomized, open-label, phase 2 trial conducted at 109 centers across ten countries. Eligible patients were aged 18 years or older with newly diagnosed muscle-invasive bladder cancer (stage cT2-cT4 N0M0) who were ineligible for or declined platinum-based neoadjuvant chemotherapy. Patients were randomly assigned in a 5:3 ratio to receive either four cycles of intravesical TAR-200 (225 mg gemcitabine) plus intravenous cetrelimab (360 mg) every 21 days or four cycles of intravenous cetrelimab monotherapy (360 mg) every 21 days. The primary endpoint was centrally confirmed pathological complete response in the efficacy-evaluable population.

The study assessed 196 patients for eligibility, and 122 were randomized (TAR-200 plus cetrelimab n=80, cetrelimab monotherapy n=42). The safety population included 120 patients who received at least one dose of the study drug. The mean age was 70.7 years (SD 7.9), with 102 (85%) male participants, 81 (68%) White patients, and 28 (23%) Asian patients.

In the efficacy-evaluable population (TAR-200 plus cetrelimab n=53, cetrelimab monotherapy n=31), the pathological complete response rate was 42% (22 of 53 patients; 95% CI 28-56) in the combination group compared to 23% (seven of 31 patients; 95% CI 10-41) in the cetrelimab monotherapy group. The pathological overall response rate was 60% (32 of 53 patients; 95% CI 46-74) versus 35% (11 of 31 patients; 95% CI 19-55), respectively. Treatment-related adverse events occurred in 57 (72%) of 79 patients in the TAR-200 plus cetrelimab cohort and 18 (44%) of 41 patients in the cetrelimab monotherapy cohort. Grade 3 or worse treatment-related adverse events occurred in nine (11%) patients in the combination group and two (5%) in the monotherapy group. The most common grade 3-4 treatment-related adverse event was hematuria (two [3%] patients) in the TAR-200 plus cetrelimab cohort. Serious treatment-related adverse events occurred in nine (11%) patients in the combination group and one (2%) patient in the monotherapy group. Discontinuation rates due to treatment-related adverse events were seven (9%) for TAR-200 and six (8%) for cetrelimab in the combination group, with no discontinuations in the monotherapy group. One treatment-related death occurred in the cetrelimab monotherapy cohort due to hyperglycaemic, hyperosmolar, non-ketotic syndrome.

The findings of this important study show localized intravesical therapy combined with systemic checkpoint inhibition as an effective treatment approach for this challenging patient population. An update with longer-term survival outcomes will be an important aspect of this novel treatment strategy.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

Necchi A, Guerrero-Ramos F, Crispen PL, Herrera-Imbroda B, Garje R, Powles T, 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 Aug 27. doi: 10.1016/S1470-2045(25)00358-4.

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