Systematic Review and Meta-Analysis of Response Rates in BCG-unresponsive Non–Muscle-Invasive Bladder Cancer: a Consensus Statement From the International Bladder Cancer Group

Abstract

There is a critical need to establish reference response rates following bladder-sparing therapies administered in the setting of bacillus Calmete-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). We sought to determine the efficacy of different interventions in recent trials accruing patients fulfilling the strict BCGunresponsive definition established by the US Food and Drug Administration. We performed a systematic review and meta-analysis for clinical trials in the BCG-unresponsive disease space to include published and presented results. The primary endpoints were complete response rate for CIS±Ta/T1 tumors, recurrence-free rate for patients with papillary-only disease, and disease-free rate in studies enrolling both papillary CIS tumors (Ta/T1/CIS). I2 was used for assessing heterogeneity. Eleven studies using 9 different therapeutic agents in a total of 909 patients with BCG-unresponsive NMIBC were identified. The resulting outcomes at 3, 6, and 12 months were 44%, 38%, and 25% complete response rate in CIS±Ta/T1 tumors; 73%, 58%, and 48% recurrence-free rate in papillary-only; and 48%, 22%, and 43% disease-free rate in combined Ta/T1/CIS, respectively. Relatively low levels of heterogeneity were observed amongst studies restricted to papillary-only or CIS±Ta/T1 tumors. Future randomized controlled studies are needed and will likely require stratification between papillary-only and CIS±Ta/T1 tumors. Introduction

Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

“…Among patients with papillary disease, 57% achieved a DFS rate at 12 months and 48% at 24 months 126,127 . Of all completed trials of BCG‐unresponsive disease, only ALT‐803 surpassed the proposed clinically relevant thresholds 128 . These results are promising but require further validation in larger prospective cohorts.…”

“…consider randomization to be an achievable approach in the present day that can be required for the evaluation of therapeutic options before regulatory approval. As a result, RCTs with an ideal control treatment are required to eliminate risks of bias and increase the reliability of meta‐analyses 128 . Furthermore, tumor characterization and subtype identification is becoming imperative for enriching our understanding of treatment response and disease biology.…”

“…FDA‐approved drugs for BCG‐unresponsive CIS ± Ta/T1 NMIBC, valrubicin, pembrolizumab, and, most recently, nadofaragene firadenovec‐vcng, have not achieved the clinically relevant outcomes of 6‐month 50% and 12‐month 30% CRR that were previously proposed by the FDA, IBCG, and American Urological Association. 27 , 128 , 183 Studies involving other novel ICIs are underway. The efficacy and safety of other ICIs including HX008, tislelizumab, and camrelizumab are currently under evaluation in multiple clinical trials.…”

“…According to Rose et al., 128 there is a lack of uniformity in clinical trials including BCG‐unresponsive NMIBC. This further diminishes the reliability of outcomes observed in the meta‐analysis of these agents.…”

“…As a result, RCTs with an ideal control treatment are required to eliminate risks of bias and increase the reliability of meta‐analyses. 128 Furthermore, tumor characterization and subtype identification is becoming imperative for enriching our understanding of treatment response and disease biology. The 2022 edition of the World Health Organization classification of tumors of the urinary tract underscores the need for reporting the presence and percentages of different subtypes in urothelial carcinomas.…”