Immune checkpoint inhibitors for BCG-resistant NMIBC: the dawn of a new era.

High risk non-muscle invasive bladder cancer (NMIBC) is a recurring and potentially lethal disease. To date, with the exception of radical surgery, there are no validated strategies for patients not responding to intravesical BCG therapy. Immune Checkpoint Inhibitors (ICI) are currently being tested for BCG-resistant NMIBC. We report current available data and ongoing trials exploring the efficacy and safety of ICI in this setting.

A narrative search was performed including the combination of the following words: ((immunotherapy) AND ((BCG AND resistant) OR (non-muscle AND invasive)) AND (bladder AND cancer)). Three search engines (PubMed, Embase®, and Web of Science) were queried up to November 1, 2020. Congress abstracts reporting results and not only trials' design were also referenced. The US National Library of Medicine was queried via to explore ongoing trials on the subject.

Pembrolizumab demonstrated a promising 40.6% (95% CI, 30.7-51.1) complete response within the KEYNOTE-057, with a median duration of response of 16.2 months. Preliminary data in the phase II SWOG S1605 trial with Atezolizumab showed a 41.1% complete response at 3 months. Avelumab is being tested in the PREVERT phase II study exploring ICI with radiotherapy (60-66 Gy) of the whole bladder. CheckMate 9UT analyzes Nivolumab monotherapy versus Nivolumab + BMS-986205 (IDO-1 inhibitor) with or without BCG in patients with BCG-unresponsive, carcinoma in situ with or without papillary component. Finally, Durvalumab is being studied in the BCG resistant space with radiotherapy in the ADAPT-BLADDER study. After proving its safety profile in the phase 1, the trial will randomize patients to Durvalumab + BCG, Durvalumab + radiation therapy (6Gy 3x) or BCG rechallenge.

Pembrolizumab has received FDA approval in the treatment of BCG-resistant NMIBC. All five other ICI molecules are currently being extensively tested within clinical trials. The results of the currently ongoing studies are awaited with impatience by the uro-oncologic community and will probably open a new era in the treatment of BCG-resistant NMIBC.

Minerva urology and nephrology. 2021 Mar 29 [Epub ahead of print]

Simone Albisinni, Nieves Martinez Chanza, Fouad Aoun, Romain Diamand, Georges Mjaess, Jean-Michel Azzo, Francesco Esperto, Joaquim Bellmunt, Thierry Roumeguère, Cosimo DE Nunzio

Urology Department, University Clinics of Brussels, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium - ., Oncology Departments, University Clinics of Brussels, Hôpital Erasme and Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Urology Department, University Clinics of Brussels, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium., Urology Department, Hôtel Dieu de France - Université Saint Joseph, Beyrouth, Liban., Urology Department, Università Campus Biomedico, Rome, Italy., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Urology Department, Sant'Andrea Hospital, Università degli Studi di Roma La Sapienza, Rome, Italy.