Contributing Editors
- Jennifer H. Benbow, PhD
- Asim Amin, MD, PhD
- Emily Baldrige, MPH
- Edward S. Kim, MD
Overview
Discovery of immune checkpoint inhibitors has revolutionized the therapeutic landscape for the treatment of cancer. Development of immunotherapy for cancer is based on modulation of T cell function via manipulation of checkpoint proteins expressed on the cell surface. This manipulation results in T cell activation or prevention of T cells from switching off thus enhancing their ability to target and destroy cancer cells. Immune checkpoint inhibitors (ICIs) represent the largest and most frequently used type of immunotherapies.
Therapeutic targeting of immune-inhibitory and stimulatory pathways can alter the immune system’s tolerance for ‘self,’ resulting in damage to normal cells, known as immune-related adverse events (irAEs). As opposed to traditional chemotherapy that works by directly destroying rapidly dividing cells, irAEs occur when increased activation of immune effector cells/mechanisms result in damage to normal cells. Any organ system can be affected, and severity can range from mild grade 1–2 to severe grade 3-4 toxicities. Presenting symptoms for irAEs can be nonspecific and at times subtle making them difficult to be identified. It is critically important for both, patients and clinicians/practitioners to recognize these adverse events earlier in their course when appropriate measures can result in reversal of these events in 90% to 95% of cases. If these toxicities are not dealt with promptly and appropriately, irreversibility may ensue that can potentially lead to severe organ dysfunction (ie, colectomy) or even death.
The severity of adverse events is dependent on the agent/agents used. The combination of anti-PD1 antibody plus anti-CTLA4 antibody has been documented to elicit higher grade irAEs compared with anti-PD1/PD-L1 antibody monotherapy. Additionally, the dose of ICIs used may also impact the adverse event profile. The Checkmate 067 study used combination nivolumab (anti-PD1; Opdivo, Bristol Myers Squibb) at 1 mg/kg and ipilimumab (anti-CTLA4; Yervoy, Bristol Myers Squibb) 3 mg/kg for treatment of patients with unresectable/stage IV melanoma. In this study almost 60% of the patients who received the above combination experienced grade 3-4 irAEs. The Checkmate 511 study compared the above-mentioned combination with altered dosing of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg in the same patient population with significant reduction in the incidence of high-grade irAEs.
Distribution of irAEs by organ system may also vary with ICI being used. For instance, there is a higher incidence of colitis with anti-CTLA4 antibody compared with thyroid dysfunction that is more often observed with anti-PD1/PD-L1 antibodies.
Several factors including underlying or undiagnosed conditions can impact emergence of irAEs after treatment with ICIs. Those individuals with prior diagnosis of autoimmune diseases – including thyroid disorders, arthritis, skin conditions like psoriasis, inflammatory bowel disease, sarcoidosis etc. – are at very high risk for rapidly developing severe related toxicities, therefore they are usually excluded from treatment with ICIs. Additionally, some individuals may have a tendency toward developing an autoimmune disorder but have never been diagnosed. These individuals are at high risk for unmasking their autoimmune tendency and developing high-grade immune-related toxicities. While the median time of developing autoimmune breakthrough, adverse events vary from 3 to 12 weeks depending on the organ system involved, these toxicities may present themselves earlier in those with underlying conditions.
Novel immunotherapy combinations with chemotherapy or targeted agents/tyrosine kinase inhibitors are being assessed and developed for multiple indications that will add another layer of complexity to adverse events and their management. Here we provide an overview of irAEs described for current ICIs in clinical practice and their management based on review of published guidelines.
Objectives
Upon completion of this module, participants should be able to:
- Identify immune related adverse events associated with ICI-based therapy.
- Recognize signs and/or symptoms associated with these adverse events.
- Understand the principles of management and monitoring associated with the most common irAEs.
Thank you for participating in this module. Click below to download the certificate.