Predicting immunotherapy response in advanced bladder cancer: a meta-analysis of six independent cohorts

Advanced bladder cancer patients show very variable responses to immune checkpoint inhibitors (ICIs) and effective strategies to predict response are still lacking. Here we integrate mutation and gene expression data from 707 metastatic bladder cancer patients treated with anti-PD-1/anti-PD-L1 to build highly accurate predictive models. We find that, in addition to tumor mutational burden (TMB), enrichment in the APOBEC mutational signature, and the abundance of pro-inflammatory macrophages, are major factors associated with the response. Paradoxically, patients with high immune infiltration do not show an overall better response. We show that this can be explained by the activation of immune suppressive mechanisms in a large portion of these patients. In the case of non-immune infiltrated cancer subtypes, we uncover specific variables likely to be involved in the response. Our findings provide novel information for advancing precision medicine in patients with advanced bladder cancer treated with immunotherapy. ### Competing Interest Statement Potential conflicts of interest: J. Bellmunt has served in consulting or advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bristol Myers Squibb, Genentech, Novartis, Pfizer, Pierre Fabre, and the healthcare business of Merck KGaA, Darmstadt, Germany; has received travel and accommodation expenses from Ipsen, Merck & Co., Kenilworth, NJ, and Pfizer; reports patents, royalties, other intellectual property from UpToDate; reports stock and other ownership interests in Rainier Therapeutics; has received honoraria from UpToDate; and has received institutional research funding from Millennium, Pfizer, Sanofi, and the healthcare business of Merck KGaA, Darmstadt, Germany.