Taking Steps to Manage Adverse Events Associated with Checkpoint Inhibitors

Igor Puzanov, MD, MSCI, FACP

Director, Early Phase Clinical Trials Program

Chief of Melanoma Section

Co-Leader, CCSG Experimental Therapeutics Program

Professor of Oncology in the Department of Medicine

Roswell Park Cancer Institute

Immune checkpoint inhibitors significantly improve clinical outcomes in numerous malignancies, and combination therapy with ipilimumab and nivolumab has been shown to improve both objective response rate and progression-free survival in patients with melanoma. However, along with this increased efficacy, we have seen an increase in immune-related adverse events, leading to a discontinuation rate of 30% to 40%. Interestingly, a majority of these patients experienced a durable response even after they discontinued therapy. And while they are rare, some high-grade, potentially fatal events have been identified as well.

The good news is that these side effects are not a deal-breaker for using these critical new therapies. However, it is essential to know about them, monitor patients for early warning signs, and manage them appropriately. Characterizing these toxicities and grading them accurately is a priority for the practicing oncologist, as more patients with many types of malignancies will be treated with these therapies.

Most of the adverse events are low-grade, including skin rashes and diarrhea. However, some cases involve inflammation of the lungs, bowel, pancreas, or liver, potentially leading to pneumonitis, colitis, pancreatitis, diabetes, and liver damage. Endocrine effects such as irregular levels of thyroid, adrenal, and/or pituitary hormones have been observed. These events are generally completely reversible in over 90% of patients through treatment with high-dose glucocorticoids. Among these patients, up to half will require hormone replacement for life despite early steroid therapy.

Prepare a Pathway to Treatment

Rarely, severe and potentially fatal side effects can occur, including immune-mediated myocarditis. For patients on combination immunotherapy with ipilimumab/nivolumab, it is advised that physicians monitor baseline and weekly troponin levels during weeks 1 through 12, and continue careful monitoring throughout active treatment. Proper monitoring, detection, and therapy are a subject of active research at Roswell Park and other experienced immuno-oncology cancer centers.Clinicians must educate their patients and provide written instructions with a list of warning signs, as well as what actions to take in the event that they experience side effects between clinic visits. For patients who do not live in the vicinity of a treatment center, physicians make every effort to get them in touch with nurses to help elucidate how severe their symptoms may be. Sometimes, physicians can begin treatment by calling in glucocorticoids to their local pharmacy. Other times, physicians ask the patient to go to a local emergency room or to come to the clinic to have an in-person evaluation by a physician.

Continuing Treatment

Putting it into Perspective

We must remember that these therapies are new. Personal communication between oncologists and primary care physicians, emergency care providers, hospitalists, and other frontline medical professionals is critical for appropriate care and evaluation of the patients and optimal treatment selection.For 60% of patients on ipilimumab/nivolumab therapy, immune-related events can be properly treated with steroids, and the immune therapy subsequently restarted. However, it is encouraging to see that a majority of patients for whom immunotherapy had to be stopped continued to respond once therapy was discontinued. These data and the analysis showing that use of steroids did not lower response rates or duration of response are reassuring.Cancer therapies, whether chemotherapy, genetic-mutation-targeted therapy or immunotherapy, have side effects. Adverse events with chemotherapy and radiotherapy are well documented, and unfortunately common. Targeted therapies—which by their mechanism of action spare the majority of, but not all, healthy cells—are associated with adverse events in 25% of patients, including cardiac-related side effects that are well described with many of them. Anti-VEGF inhibitors are a prime example, with up to 10% of patients experiencing cardiac-related side effects.

The observed adverse events that have been associated with immunotherapy, especially immunotherapy combinations, have to be properly assessed against their clearly improved efficacy in patients with otherwise dismal prognosis from stage IV cancers. As we gain more experience with these drugs, as more treatments become standard of care, and as we analyze the data to determine guidelines for predicting and ameliorating adverse events, the benefits of immunotherapies will continue to grow.