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

INTRODUCTION: 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. EVIDENCE ACQUISITION: 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 clinicaltrials.gov to explore ongoing trials on the subject. EVIDENCE SYNTHESIS: 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. CONCLUSIONS: 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.