Dr. Doug Johnson, clinical director of the melanoma program and assistant professor of medicine at Vanderbilt University Medical Center, discusses the management of immune-related adverse events refractory to standard therapies.

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TRANSCRIPT

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Welcome to the ASCO University Weekly Podcast. My name is Doug Johnson. I'm the clinical director of the melanoma program, assistant professor of medicine at Vanderbilt University Medical Center. Today we'll discuss management of immune-related adverse events refractory to standard therapies.

As a background to today's discussion, immune checkpoint inhibitor are active therapies and FDA approved in 15 different cancer types. Responses in patients who do respond can be quite durable. And these are enhanced further by combining immune checkpoint inhibitors-- specifically combining anti PD-1, or nivolumab or pembrolizumab, with anti CTLA-4, ipilimumab.

The side effect from these treatments, called immune-related adverse events, are caused by unleashing T cells not only against tumor but against host tissues. These inflammatory toxicities can affect any organ and may occasionally be life threatening. The cornerstone of managing immune-related adverse events in patients involves corticosteroid treatment, which are usually effective. More clinically severe events are treated with high-dose steroids.

For example, prednisone or methylprednisolone, 1 to 2 milligrams per kilogram per day. And less severe side effects may be managed by dose withholding, symptomatic management, or low-dose steroids-- 0.5 milligrams per kilogram or less. In addition, certain side effects have fairly well-established second line treatments. For example, patients with colitis that does not improve with steroids within three days should be considered for infliximab treatment. Similarly, hepatitis that fails to improve should also receive mycophenolate mofetil. For more information about steroid dosing, definitions of mild versus severe toxicities, and established second line treatments for refractory toxicities, please visit the ASCO Clinical Guidelines for managing immune checkpoint inhibitor toxicities.
So, as I mentioned, corticosteroids and established second line regimens are fairly effective. So what is the problem? What is the knowledge gap? Well, again, though most events fail to respond to corticosteroids, a subset fails to improve and requires even additional treatment regimens. Actually, approximately 1% of patients treated with combination ipilimumab and nivolumab actually experience fatal toxicities. Further, a small subset of patients develop chronic toxicities, such as neuropathy or arthritis, those developing more effective treatment regimens and more effectively using the treatment regimens we have is a real unmet need.

So let's talk about the data. Well, first of all, even the data for steroids for using steroids for these immune-related toxicities, as well as the fairly well-established second line treatments, like infliximab and mycophenolate, are largely based on anecdotal evidence and clinical experience. Thus, the data for use of additional agents on top of that for the very refractory toxicities are even more limited. But with that being said, let's discuss some approaches.
First, some general principles. Most immune therapy toxicities have a similar syndrome that's encountered outside of immune checkpoint inhibitor treatment. For example, immune checkpoint inhibitor colitis is quite similar to inflammatory bowel disease. Thus, we consider agents with activity in those situations.
Some immune toxicities actually appear virtually identical to their non-immune checkpoint inhibitor analog, including Guillain-Barre syndrome, myasthenia gravis, immune thrombocytopenic purpura, and several others. Again, these are managed with steroids plus appropriate disease-specific management. For example, IVIg or plasmapheresis for patients that have Guillain-Barre syndrome, in addition to steroids.

Now, let's go into a few specifics. What about colitis that's refractory to steroids and infliximab? Well, there are a number of case reports that show activity of the integrin inhibitor, vedolizumab, in colitis that does fail to respond to steroids and infliximab. It's important to keep in mind that this agent has a fairly slow onset, and improvement may be seen over a few weeks, similar to the experience in patients who have Crohn's disease.
How about pneumonitis refractory to steroids? Well, second line options here are less well established, but guidelines suggest either infliximab, mycophenolate, or IVIg as appropriate options. And if of these fails to work after a few days, it's reasonable to add a second agent.

Moving to hepatitis, if steroids and mycophenolate do not improve liver function, there've been anecdotal reports of anti-thymocyte globulin reversing even full-minute presentations. We generally avoiding anti-TNF alpha agents here, like infliximab, since they can actually rarely cause liver failure on their own.

Finally, myocarditis. This is a very challenging toxicity with a fatality rate as high as 50% in serious cases. We generally treat this very aggressively upfront when symptomatic and when associate with arrhythmias with very high doses of steroids-- up to 1 gram of methylprednisolone daily. Plus either mycophenolate, IVIg, or even ATG. Really, the best upfront regimen is not well defined.

To sum it up, immune checkpoint inhibitor to transformative treatments in some patients that produce durable responses. Their toxicities are usually manageable. But as we use these agents more often in the clinic, we'll increasingly see refractory and unusual toxicities that provide a clinical challenge. Understanding how to manage these events will be a key challenge for oncologists moving forward.

Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on immune therapy and the treatment of toxicities, please visit the ASCO Guidelines, as well as the Comprehensive eLearning Center at university.asco.org

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