Overcoming toxicity challenges in immune checkpoint inhibitor treatment of high-risk metastatic cancers.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have become a cornerstone of cancer treatment and induce durable responses in many patients with advanced cancer. However, they cause immune-related adverse events (irAEs) which result in symptoms related to autoimmunity, chronic sequelae, and occasionally death. Balancing toxicity and efficacy considerations remains a major challenge in ICI treatment. AREAS COVERED: We provide an overview of the pathophysiology, risk factors, and clinical presentation of irAEs. Next, we discuss potential approaches to manage these events. Finally, we discuss novel strategies to detect, prevent, and mitigate severe irAEs and thus optimize the benefits of ICI therapy for patients with cancer. EXPERT OPINION: irAEs, along with lack of response, remain the major challenge in ICI therapy. These constraints are not unrelated, as more aggressive combinations result in higher response rates (at least in some tumors), but increase irAEs as well. Novel multidrug regimens with immune modulators may 'thread the needle' to optimize both response and toxicity concerns.