Perspective on Managing Immune-related Adverse Events

As more patients are treated with single and combination immunotherapies for cancer, early identification and management of immune-related adverse events (irAEs) is critical to achieving desired outcomes with these new drugs. ACCCBuzz recently talked with Matthew R. Zibelman, MD, for perspective on irAE management in patients treated with immune checkpoint inhibitor therapy. Dr. Zibelman is a genitourinary medical oncologist at Fox Chase Cancer Center in Philadelphia, Pa., where he specializes in renal cell carcinoma and urothelial carcinoma with a particular clinical and research interest in immunotherapy. He is a member of the ACCC IO Institute’s Big Data Working Group.

ACCCBuzz: Why did you decide to get involved in the ACCC Immuno-Oncology Institute’s Working Group?

Dr. Zibelman: We’re obviously using immune checkpoint inhibitors more and more in the clinic these days, particularly in bladder cancer and kidney cancer where I am most focused. As a result, as we give more patients these drugs, we see a lot more of the side effects. Being able to recognize these toxicities, diagnose them properly, get patients on the appropriate treatment—and educate patients about what to look out for and how to troubleshoot issues that come up—is really important in using these drugs and helping to have good outcomes. Participating in the IO Institute Working Group is a great opportunity to get perspectives from other experts in the field including those who come from different backgrounds such as pharmacy and nurse practitioners. You see how others are thinking about and managing irAEs, and you try to come together for some consensus recommendations and to be able to provide guidance and oversight to people who are just learning to use these agents or who have questions. It’s been a great experience and hopefully will be helpful to the broader ACCC membership.

ACCCBuzz: With the guidance of the IO Institute Executive Committee and select Working Group members, ACCC has developed an irAE Workup Guidelines webpage that presents the existing guidelines organized by toxicity. How do you think providers in the community can benefit from this resource?

Dr. Zibelman: What I hope is that this resource brings a bit of insight and perspective that you can’t get just from trying to follow a flow-sheet guideline or a table guideline where you’re looking up something and pulling out a recommendation or a number.

The ACCC resource lists potential toxicities and points the user to where to find specific guidance on that toxicity within the existing clinical guidelines for managing adverse events with immune checkpoint inhibitors (i.e., ASCO, SITC, and NCCN). However, management of adverse events is not always as black and white as a guideline may make it seem.

ACCCBuzz: Can you elaborate on encountering patients who don’t fit into the guidelines?

Dr. Zibelman: I think checkpoint inhibitors have unique and complex toxicities that can be difficult for patients and providers to recognize. They are still relatively new and precipitate side effects that other drugs that we’ve used in oncology don’t do. It’s very challenging; you do your best to separate and tease out what a new complaint or side effect is.

What I’ve learned about checkpoint inhibitors is with anything new or different that a patient is experiencing, you need to think, “Could this be related to the immunotherapy?” If not, great and you move on. You have to also consider other causes of potential patient morbidity, such as progression of their cancer or infections, but you always want to keep in mind that these drugs can cause different kinds of unusual side effects at any point.

Secondly, the guidelines are written for pure immune checkpoint inhibition—using a single drug by itself or using a combination of checkpoint inhibitors. But we are now commonly using these drugs in combination with chemotherapy and/or targeted therapies. In renal cell carcinoma, for example, we are commonly using checkpoint inhibitors in combination with oral anti-angiogenic tyrosine kinase inhibitors (TKIs). TKIs also have side effects, and so it can be difficult to tease out the side effect from the more traditional drugs versus the checkpoint inhibitors. Clinicians have to use their own medical decision-making on top of the guideline recommendations to really make sure they are treating patients appropriately.

ACCCBuzz: Do the current guidelines for managing irAEs address patients with comorbid conditions receiving checkpoint inhibitors?

Dr. Zibelman: For many comorbidities there is not much guidance. I think that this is because there probably doesn’t need to be. One of the nice things about immune checkpoint inhibitors is that we can give them to people who are sometimes frail, sick, and have other co-morbid conditions. That does not preclude administration of these drugs for most patients. One exception would be people with a history of an autoimmune disease who may be at higher risk of developing an irAE. I think what is important is helping patients understand the risks and benefits and with the shared decision-making process—what are the other treatment options? Is it worth trying one of these drugs or not?

ACCCBuzz: Has your program implemented any algorithms for nursing staff or patients at home to support early identification of irAEs?

Dr. Zibelman: At Fox Chase I started a working group among different clinical providers that includes physicians, advanced practice providers, pharmacy, IT, and nursing. We’ve put into place some ways to educate patients and staff to better understand and recognize side effects of immunotherapy. For example, we have created our own patient IO wallet card that is drug and disease agnostic. Basically the card says: This patient is on immunotherapy. Please call this number. Patients can show the card to providers in emergency rooms and urgent care centers and make sure the providers contact us.

We’ve instituted prompts in our EHR (Epic) for staff to confirm that the patient has the IO wallet card with them. Patients are asked by the nurse at every visit if they have their card. If not, they are provided with a new one.

We also have a banner that appears in the EHR automatically as soon as the patient receives their first dose of immunotherapy. That banner is visible to anyone who logs in to that patient’s chart. It states that the patient has received an immune checkpoint inhibitor (ICI) and is at lifetime risk for immune adverse events. So if the patient is calling in with a side effect, the telephone triage nurse can easily know if they are on an immunotherapy, or radiologists trying to assess chest imaging can see that the patient is on ICI therapy.

Recently, we’ve also leveraged the existing patient portal so that patients receiving immune checkpoint inhibitors can gain access to a unique link specifically for patients on immunotherapy. This takes them to a new site with information about the drug that they are on, provides links to other websites, and a body map that includes information on the different side effects they may experience. These are just some of the steps we’ve taken to try to help patients understand the risk of side effects.

The irAE guidelines have helped establish a standard, or backbone, for managing the most common irAEs and the recommended way to think about the side effect. In setting a standard, the guidelines help everyone speak the same language. For example, guidelines help define a grade 1 or grade 2 irAE, but then providers have to adapt the guideline recommendations to the patient in front of them.

ACCCBuzz: Hypothetically, if a patient were to present with something that you would suspect is an irAE, but it’s not something you’ve seen a lot—how might you use the guidelines to inform your treatment decisions for that patient?  

Dr. Zibelman: I think what can be difficult is if someone comes in with somewhat non-specific symptoms that don’t fit into a specific guideline. For example, it’s easier when patients report normal bowel movements and then come in and tell you that for the last four days, they’ve had seven bowel movements a day. Then you can easily go to the diarrhea or colitis guidelines and use those to make recommendations.

It’s less clear when patients come in with symptoms that are non-specific: weakness or fatigue, or a little dizziness, or soreness. Depending on how the clinician asks the question and perceives things, it may take the provider to the adrenal insufficiency pathway, or the myopathy pathway, or the cardiac pathway. I think that is where it can get complicated. Providers need to make sure they ask clear questions. I definitely err on the side of having patients evaluated for a new symptom, because I think it can be hard to get a good understanding over the phone of what they are trying to describe. I find bringing them in the same day or the next day, getting to see them in the clinic, and examining them is the best way to understand what their symptoms are. Then, I think having a high suspicion that it may be immune related is important.

ACCCBuzz: What has surprised you in terms of immune-related side effects?

Dr. Zibelman: At this point nothing surprises me. I just recently saw a patient who developed adrenal insufficiency after not having received any immune checkpoint inhibitors for over eight months and not having had many side effects up until then. We’ve had a patient who developed a hearing loss as a result of immune checkpoint inhibitors, and it turned out basically the immune cells were attacking the inner ear cells. The patient’s hearing improved with intra-tympanic steroid injections, thus avoiding systemic steroid administration, and the patient’s cancer maintained a complete remission.

It’s helped me to see that these side effects can happen at any time. People can have long-delayed side effects, so your index of suspicion must remain high even after patients have stopped immune checkpoint inhibitors. I also think trials may under-represent the incidence of delayed side effects because the patients that go off trial are often not followed long enough to notice them [late side effects]. You just have to have a high dose of suspicion that when something unusual is going on, it may be an irAE.