An overview of immune checkpoint inhibitor toxicities in bladder cancer

Abstract

Bladder cancer is the tenth most prevalent malignancy worldwide, with a significant mortality burden. Urothelial carcinoma (UC) is the most common histological subtype, and treatment options are guided by whether the disease is muscle-invasive (MIBC) or non-muscle-invasive (NMIBC), with subsequent risk group stratification. The growing popularity of immune checkpoint inhibitors (ICIs) to treat MIBC and NMIBC as either monotherapy or combined with intravesical agents, may radically change the treatment paradigm of UC. Current treatments for NMBIC includes intravesical chemotherapy after trans-urethral resection of the bladder tumour, intravesical bacillus Calmette-Guerin (BCG) or radical cystectomy. Cisplatin-based chemotherapy is widely regarded as the first-line treatment for metastatic UC due to its beneficial response and survival rates when compared to alternative therapies. However, up to 70 % of metastatic UC patients are ineligible, and the prognosis of these patients remains poor, with a median survival of 13-16 months. For NMIBC and MIBC, ICIs provide a promising alternative for cisplatin-ineligible patients. In UC, ICIs including atezolizumab, nivolumab, avelumab, and pembrolizumab are Food and Drug Administration (FDA)-approved for monotherapy, and have demonstrated promising results, particularly in those who cannot receive cisplatin-based chemotherapy, and as a second-line treatment option for recurrent UC following platinum-based chemotherapy. It is important to consider that some patients may experience adverse events (AEs) with limited clinical benefit. Infusion-related reactions and immune-mediated AEs (imAEs) such as colitis, endocrinopathies, hepatitis, pneumonitis, interstitial lung disease, renal dysfunction, nephritis, cutaneous and neurological toxicities must be monitored for. Currently, there is no clear consensus on the role of a 'two-year stopping rule' in reducing the risk of imAEs, with further research on the optimal treatment duration of ICIs required. With increased ICI use, vigilance regarding their side effects is imperative. This review aims to provide an updated overview of ICI toxicities in bladder cancer, to assist clinicians in their therapeutic decision-making, with consideration of patient characteristics and the clinical context.

Keywords: Bladder Cancer; CTLA-4; Immune Checkpoint Inhibitor; PD-1; PD-L1; Toxicity.

Mechanism of action of anti CTLA-4 and anti PD-1/PD-L1 agents. Immune-mediated adverse events seem to result from an exaggerated immune response, due to the breakdown of immunological self-tolerance. TCR: T-cell receptor, MHC: major histocompatibility complex, CD80/86: cluster of differentiation 80/87, PD1: programmed cell death protein 1, PD-L1: programmed death-ligand, CTLA-4: cytotoxic T-lymphocyte associated protein 4