Pathologic CR Rates in MIBC: TAR-200, Cetrelimab Versus Cetrelimab Alone in SunRISe-4

The SunRISe-4 trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024 by Dr. Andrea Necchi, enrolled 196 patients with muscle-invasive bladder cancer (MIBC) who were not eligible for or declined neoadjuvant cisplatin-based chemotherapy.

Patients received TAR-200 with the anti-PD1 agent cetrelimab (Cohort 1) versus cetrelimab alone (cohort 2). Patients had histologically confirmed cT2-T4a N0M0 bladder cancer with predominantly urothelial carcinoma histology and were scheduled for radical cystectomy (RC).

TAR-200, also known as the ‘pretzel device,’ which has been prevalent in the non-muscle invasive bladder cancer (NMIBC) setting in the last few years, is an intravesical releasing system designed for sustained, local delivery of chemotherapy in the bladder. The gemcitabine chemotherapy is delivered at 225mg every three weeks through an indwelling catheter in a 2-3 minute office procedure, for up to 12 weeks.

In terms of patient characteristics, about 66% of patients were White, 25% Asian, and 11% were of other races. Just over 33% of patients were ineligible for NAC, with the remaining 66% refusing NAC in both cohorts. In cohort 1, 20.3% of patients had variant histologies, while 26.8% of patients in cohort 2 had variant histologies.

In patients with MIBC undergoing RC, the pathologic stage is a prognostic factor for survival. The study met its primary endpoint of pathologic complete response (pCR) and showed pCR and pathologic overall response (pOR) rates of 42% and 60%, respectively. Interestingly, the pCR for patients with an incomplete TURBT was 56%, higher than the 39% pCR seen in patients with a complete TURBT.

In the cT2 subgroup, 48% of patients treated with TAR-200 plus cetrelimab achieved pCR, and 68% were downstaged to <T1 at RC. Cetrelimab monotherapy provided pCR and pOR rates of 23% and 35%, respectively.

The safety profile of this novel combination was manageable, with most adverse events (AEs) being low grade, most commonly dysuria, pollakiuria, urgency, and hematuria. The rate of discontinuation due to treatment-related AEs was 13%. There was one death on the cetrelimab monotherapy arm, reported as hyperglycemic, hyperosmolar nonketotic syndrome.

There was an update at the ESMO Congress 2024 on this combination in the high-risk BCG-refractory NMIBC setting (SunRISe-1 trial), which showed CR rates of 84% with TAR-200 monotherapy. In SunRISe-1, there was a more favorable risk-benefit profile for TAR-200 monotherapy compared with TAR-200 plus cetrelimab or cetrelimab monotherapy.

In summary, these results provide additional evidence for neoadjuvant therapy options for patients who are scheduled for RC, but cannot receive or decline neoadjuvant platinum-based chemotherapy. It will be important to identify biomarkers associated with durable responses to eventually select patients for bladder preservation and avoid RC altogether.

The landscape is likely to continue to change in the coming years, as we obtain data for perioperative enfortumab vedotin plus pembrolizumab for both cisplatin-eligible and -ineligible patients with MIBC.