Immune checkpoint inhibitors have changed the treatment landscape for many cancer types. These immunomodulatory antibodies target the PD-1, PD-L1, and CTLA-4 pathways to help restore immune responses against tumors.
So far, the FDA-approved immune checkpoint–directed antibodies include ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).
Despite the important clinical benefits of immunotherapy, including increased overall survival, immune checkpoint blockade is associated with immune-related adverse events that can affect any organ system, most often the gastrointestinal tract, endocrine glands, skin, and liver.
“The wide range of potential immune-related adverse events requires multidisciplinary, collaborative management by providers across the clinical spectrum,” said Michael A. Postow, MD, and colleagues in their recently published review article on the topic (Postow MA, et al. N Engl J Med. 2018;378:158-168).
Because no prospective trials have defined strategies for effectively managing specific immune-related adverse events, clinical practice remains variable. Several organizations, however, are working to harmonize expert consensus on managing specific inflammatory side effects.
In their article, Postow and colleagues focused on the following questions that are relevant to clinicians in the management and treatment of immune-related adverse events in patients receiving immune checkpoint blockade.
Why Do These Adverse Events Occur?
The exact pathophysiology underlying immune-related adverse events is unknown, but is thought to correlate to the role that immune checkpoints play in maintaining immunologic homeostasis. For example, CTLA-4 works by inhibiting an immune response in several ways, such as attenuating T-cell activation at a proximal step in the immune response. Translational studies in patients with immune-related adverse events have demonstrated that T-cell, antibody, and cytokine responses may be involved.
How Are They Treated?
Because no prospective clinical trials have defined optimal treatment approaches, clinicians treating this patient population have to rely on recommendations based on consensus opinion. Most immune-related adverse events are effectively treated by delaying drug administration or by inducing temporary immunosuppression. Glucocorticoids are usually the first-line immunosuppressive therapy. If glucocorticoids are initially ineffective, additional immunosuppressive agents can be used.
When Do They Occur?
The onset of these events ranges from the first few weeks to months after treatment initiation; however, these events can occur at any time, even after treatment discontinuation.
Dermatologic adverse events are usually the first to appear, as reflected in studies of CTLA-4 and anti–PD-1 therapy.
According to the authors, it is still unknown whether immune checkpoint blockade creates later-term toxicity risk. However, this will become an important question as indications for treatment expand to patients who present with cancer at earlier stages, when life expectancy may be measured in decades.
Why Do Only Some Patients Have These Adverse Events?
It is unknown why some patients experience immune-related adverse events. Researchers are investigating whether factors such as germline genetics and the composition of host microbiota are related to risk. Preclinical and emerging clinical data suggest that certain bacterial species are linked with the efficacy of immune checkpoint blockade, which raises the possibility that variations in a patient’s gastrointestinal flora that affect host immunity influence the risk for immune-related adverse events.
Are These Events Linked to Treatment Efficacy?
The available data are conflicting regarding whether the incidence of immune-related adverse events is associated with improved treatment efficacy. The general consensus is that the occurrence of these events is not required for patients to see treatment benefit. The authors noted that specific events, such as vitiligo, may be more clearly associated with treatment efficacy.
Does Immunosuppression Reduce the Antitumor Efficacy of Therapy?
Retrospective studies have shown that clinical outcomes are similar in patients who require immunosuppression to treat immune-related adverse events and in those who did not require such treatment. Beneficial responses can persist despite the use of immunosuppression to treat immune-related adverse events. Studies investigating the potential relationship between the various aspects of immunosuppression (eg, timing and duration) and clinical outcomes are warranted.
Does Immunosuppression Have Unintended Effects?
Oncologists need to be aware that immunosuppression does carry additional risks. Specifically, the side effects of glucocorticoids can result in hyperglycemia, fluid retention, anxiety, and iatrogenic adrenal insufficiency.
Furthermore, immunosuppression is a risk factor for subsequent opportunistic infection, such as Aspergillus fumigatus pneumonia and cytomegalovirus hepatitis.
Is it Safe to Restart Therapy After a Serious Adverse Event?
Prospective data from clinical trials are limited on the safety of resuming immune checkpoint blockade after the adverse event has resolved. This is attributed to study protocols that often require that treatment be permanently discontinued if a patient experiences a serious immune-related adverse event.
Retrospective studies have shown that immune-related adverse events associated with the anti–CTLA-4 class may not necessarily recur during treatment with another agent, such as a PD-1 inhibitor. The safety of retreatment depends on the severity of the previous event, the availability of alternative treatment options, and the status of the cancer. However, retreatment should not start in the event of life-threatening toxicity, particularly cardiac, pulmonary, or neurologic toxicity.
Is It Necessary to Restart Treatment After Event Resolution?
Data on this point remain limited. Retrospective studies indicate that patients who had a favorable response to immune checkpoint blockade and discontinue treatment because of immune-related adverse events generally maintain responses. Prospective studies are needed to address whether restarting immunotherapy is necessary.
Is It Safe to Use These Drugs in Patients at Risk for Such Events?
Patients at increased risk for immune-related adverse events may still benefit from immune checkpoint blockade, such as patients with preexisting autoimmune disease. Age should not be a factor to exclude patients from treatment.
Subgroup analyses from prospective and retrospective trials of older adults suggest that the efficacy of immune checkpoint blockade is similar to the efficacy in younger adults, without an increase in immune-related adverse events.
Improving Adverse Events Management
The authors concluded by outlining 3 opportunities to improve the treatment of immune-related adverse events and to refine answers to the 10 questions they addressed.
Studies are needed to elucidate the mechanisms of action of immune-related adverse events to develop more precise treatments for these events.
Establishing international registries will help capture real-world data in patient populations that are underrepresented in clinical trials.
Finally, clinical experience with these agents is increasing; therefore, multidisciplinary clinical involvement is needed to share insights from various fields of medicine to realize the full potential of this cancer treatment.