Immunotherapy in urothelial cancer: current status and future directions

ABSTRACTIntroduction Since 2016, the progressive use of immune checkpoint inhibitors (ICIs) starting from second-line treatment has led to an improvement in overall survival in locally advanced and metastatic urothelial cancer (UC). Clinical trials are underway testing the role of ICIs since the first stages of the disease, alone or in combination with standard therapies.Areas covered This review summarizes the current updated evidence regarding the role of ICIs in the different stages of UC, the ongoing clinical trials exploring the potential benefit of immunotherapy alone or in combination with standard-of-care therapies, as well as the promising association of ICIs with antibody-drug conjugates (ADCs).Expert opinion In the first-line setting, ICIs alone in platinum-unfit patients have shown unconvincing results; the ongoing EV-302 trial will probably suggest enfortumab vedotin plus pembrolizumab as a new effective option. The optimal duration of maintenance immunotherapy is still to be determined, finding a balance with the risk-benefit profile. The clinical benefit of ICIs as second-line treatment is limited to a subset of patients that cannot be definitively established yet. In the next 5 years, a lot of new ADCs will likely emerge for the treatment of UC.KEYWORDS: Antibody-drug conjugatesatezolizumabavelumabdurvalumabimmune checkpoint inhibitorsnivolumabpembrolizumaburothelial cancer Article highlights Immune checkpoint inhibitors (ICIs) have recently changed the standard-of-care of locally advanced and metastatic urothelial cancer thanks to the introduction of avelumab as maintenance treatment after first-line platinum-based chemotherapy and pembrolizumab in the second-line therapy, although predictive biomarkers of response to ICIs still lack.Immunotherapy has shown promising results since the first stages of the disease: intravesical administration of the IFNα-expressing adenovirus nadofaragene firadenovec and pembrolizumab are FDA (not EMA) approved in BCG-unresponsive non-muscle-invasive bladder cancer.While adjuvant nivolumab is FDA and EMA approved in cisplatin-ineligible patients or in case of poor response to neoadjuvant chemotherapy, in the neoadjuvant setting several ongoing phase III trials are comparing ICIs alone or in combination with chemotherapy or antibody-drug conjugates (ADCs) against standard treatment.Pembrolizumab or atezolizumab monotherapy can be considered a first-line option in patients cisplatin-unfit and whose tumors express PD-L1; the addition of immunotherapy to standard-of-care chemotherapy has not shown benefits in Imvigor130 and KEYNOTE-361 trials, but results from NILE and CheckMate-901 are awaited.Aside from pembrolizumab, current second-line options include atezolizumab in Europe and avelumab and nivolumab in the USA; the combination ipilimumab + nivolumab is under study in CheckMate-032 and TITAN-TCC trials.Several studies are investigating enfortumab vedotin, sacituzumab govitecan, and other ADCs, alone or in combination with ICIs or target therapies: considering the ability of ADCs to modulate the immune system, it is reasonable to assume that the association of ICIs and ADCs can lead to significant anti-tumoral response.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper received no funding.