Systematic review of neoadjuvant therapy by immune checkpoint inhibitors before radical cystectomy: where do we stand?

Introduction: After demonstrating their efficacy in metastatic urothelial cancer (UC), immune checkpoint inhibitors (ICI) are currently being tested in the neoadjuvant setting before radical cystectomy. In this systematic review, we analyze current available data and ongoing trials exploring the efficacy and safety of ICI neoadjuvant therapy in UC.

Evidence acquisition: A systematic search was performed including the combination of the following words: (["neoadjuvant" AND "immunotherapy"] AND ["bladder" AND "cancer"]). Three search engines (PubMed, Embase^®, and Web of Science) were queried up to January 1, 2020. Study selection followed the PRISMA guidelines. After screening, 9 articles and abstracts fully compatible with the PICOS were included in the systematic review.

Evidence synthesis: The PURE-01 trial showed a 37% complete response (pT0) after neoadjuvant pembrolizumab. In the ABACUS trial, atezolizumab determined a complete response in 31% of patients. In both trials, an increased expression of PD-1 or PD-L1 was associated to an improved response to ICI. Moreover, ICI are well tolerated with grade III-IV adverse events in 6% of cases. In the PURE-01 trial, radical cystectomy after neoadjuvant ICI presents a similar complication rate compared to neoadjuvant chemotherapy, with fever (N.= 35, 52%) and ileus (N. = 21, 31%) being the most common postoperative complications. Numerous trials are currently recruiting to test ICI in the neoadjuvant setting, either alone, in combination immunotherapy or with chemotherapy.

Conclusions: Pembrolizumab and atezolizumab single agent demonstrated favorable results for ICI in the neoadjuvant setting. Patients with a higher tumor expression of PD-L1 appear to experience a higher response to ICI, although the adequate biomarker remains to be identified. Radical cystectomy appears to be safe after ICI treatment. The results of the currently ongoing prospective trial are awaited with impatience by the uro-oncologic community.