Interim results from the Phase 2 SunRISe-4 trial indicate that neoadjuvant treatment with TAR-200, an intravesical gemcitabine-releasing system, combined with cetrelimab, an anti-PD-1 antibody, shows promising efficacy in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or refuse neoadjuvant platinum-based chemotherapy. The study, presented at the European Society of Medical Oncology (ESMO) 2024 Congress, highlights a potential new approach for treating this aggressive cancer.
The SunRISe-4 trial is a randomized, open-label study evaluating the efficacy and safety of TAR-200 plus cetrelimab versus cetrelimab alone in patients with MIBC scheduled for radical cystectomy. Patients were randomized in a 5:3 ratio to receive either TAR-200 (225 mg gemcitabine every 3 weeks) plus intravenous cetrelimab for 12 weeks or cetrelimab monotherapy for 12 weeks. The primary endpoint was pathologic complete response (pCR), with key secondary endpoints including recurrence-free survival, safety, pathologic objective response (pOR), and overall survival.
Efficacy Outcomes
The interim analysis included 122 patients, with 80 randomized to the combination arm and 42 to the cetrelimab monotherapy arm. Efficacy was evaluable in 53 patients in the TAR-200 plus cetrelimab arm and 31 in the cetrelimab monotherapy arm. The pCR rate in the combination arm was 42% (95% CI, 28-56), while the pOR rate was 60% (95% CI, 46-74). In contrast, cetrelimab monotherapy resulted in a pCR rate of 23% (95% CI, 10-41) and a pOR rate of 36% (95% CI, 19-55).
Subgroup analysis revealed that in patients with cT2 disease, the pCR rate with TAR-200 plus cetrelimab was 48%, and the pOR rate was 68%. However, in patients with cT3-4a disease, the pCR and pOR rates were lower, at 23% and 39%, respectively. The efficacy of TAR-200 also appeared to improve with the number of doses administered, with pCR rates increasing from 27% to 50% in patients receiving 1-2 doses and 4 doses, respectively.
Safety Profile
The combination of TAR-200 and cetrelimab demonstrated a manageable safety profile. Immune-related grade ≥3 adverse events were observed in 6.3% of patients in the combination arm and 5% in the monotherapy arm. Overall, grade ≥3 treatment-related adverse events occurred in 11.4% and 5% of patients in the combination and monotherapy arms, respectively. Treatment discontinuation due to adverse events was observed in 13% of patients in the combination arm and none in the monotherapy arm. The median time to radical cystectomy was 13.7 weeks in the combination arm and 12.6 weeks in the monotherapy arm.
Clinical Significance
Muscle-invasive bladder cancer is an aggressive disease with a high recurrence rate and poor survival outcomes. Radical cystectomy, often combined with neoadjuvant chemotherapy, is a standard treatment approach. However, up to 50% of patients are ineligible for neoadjuvant chemotherapy. The SunRISe-4 study addresses this unmet need by evaluating a novel combination therapy in patients who cannot receive or refuse chemotherapy.
Dr. Andrea Necchi, from Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy, emphasized that the study was not designed to compare the two arms directly but to describe the efficacy outcomes in each arm. The results suggest that the addition of TAR-200 to cetrelimab may offer a significant benefit in terms of pathologic response compared to cetrelimab alone, potentially improving surgical outcomes and reducing the risk of recurrence.
Future Directions
The SunRISe-4 study is ongoing, and further data on recurrence-free survival and overall survival are awaited. However, the interim results support the potential of TAR-200 plus cetrelimab as a neoadjuvant therapy for patients with MIBC who are ineligible for or refuse neoadjuvant chemotherapy. This innovative approach could potentially change the treatment paradigm for bladder cancer, offering a more effective and tolerable option for a significant proportion of patients.
