In an interim analysis of a phase II trial (SunRISe-4) reported in The Lancet Oncology, Necchi et al found that the addition of neoadjuvant TAR-200—a targeted releasing system that provides sustained delivery of gemcitabine within the bladder—to the PD-1 inhibitor cetrelimab resulted in a higher complete pathologic response rate compared with cetrelimab alone in patients with muscle-invasive bladder cancer who were ineligible for or declined neoadjuvant cisplatin-based chemotherapy.
Study Details
In the international open-label trial, 120 eligible patients with planned radical cystectomy were randomly assigned 5:3 between July 2022 and May 2024 to receive TAR-200 with gemcitabine at 225 mg plus cetrelimab at 360 mg every 21 days for four cycles (n = 79) or four cycles of cetrelimab at 360 mg every 21 days for four cycles (n = 41). The primary outcome measure was pathologic complete response in the efficacy-evaluable set; because not all patients had completed treatment at time of analysis, the efficacy-evaluable set was defined as all patients who had radical cystectomy or progressive disease or death before radical cystectomy.
Key Findings
Among patients in the efficacy-evaluable set, at a median follow-up of 23.5 weeks (interquartile range = 8.6–42.0 weeks), pathologic complete response was observed in 22 (42%, 95% confidence interval [CI] = 28%–56%) of 53 patients in the TAR-200/cetrelimab group vs 7 (23%, 95% CI = 10%–41%) of 31 in the cetrelimab group.
Rates of pathologic overall response (downstaging to ≤ ypT1N0 at radical cystectomy) were 60% vs 35%.
Treatment-related adverse events of any grade occurred in 72% of the TAR-200/cetrelimab group vs 44% of the cetrelimab group; grade ≥ 3 events occurred in 11% (most commonly hematuria, in 3%) vs 5% of patients. Serious treatment-related adverse events occurred in 11% vs 2% of patients. Treatment-related adverse events resulted in discontinuation of TAR-200 in 9% and cetrelimab in 8% in the TAR-200/cetrelimab group, with no discontinuations in the cetrelimab group. One treatment-related death was observed in the cetrelimab group (due to hyperglycemic, hyperosmolar, nonketotic syndrome).
The investigators concluded: “Neoadjuvant TAR-200 plus cetrelimab showed a high [pathologic] complete response rate with a manageable safety profile. These results support continued investigation of TAR-200 in patients with muscle-invasive bladder cancer planned for radical cystectomy.”
Andrea Necchi, MD, IRCCS, of San Raffaele Hospital, Milan, Italy, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Johnson & Johnson. For full disclosures of all study authors, visit thelancet.com.
