Yes, It’s Urgent: Timely Care of Immune-Related Adverse Events

The face of cancer care has changed dramatically with the use of immune checkpoint inhibitors (ICIs), also known as immunotherapy. ICIs currently approved by the FDA include: pembrolizumab, nivolumab, cemiplimab, and dostarlimab (anti-PD-1); atezolizumab, avelumab, and durvalumab (anti-PD-L1); and ipilimumab (anti-CTLA-4). It is now estimated that over 1 in 3 patients with cancer will be eligible for one of these ICIs at some point during their care.¹ ICIs trigger an attack against tumors with high somatic mutation burden, helping to overcome a Trojan horse trick that cancer uses to evade our immune system. While ICIs do not carry the same type of scorched-Earth-style toxicities we see with traditional chemotherapy, they can trigger attack against self-antigen, resulting in immune-related adverse events (irAEs) mediated by the same mechanism with which the immune system kills cancer—friendly fire.

In this feature, I share three key tips to help you facilitate more timely care collaboration for irAEs in your respective health systems. My first tip for you is based on an ancient quote from the famed military strategist Sun Tzu: Know your enemy. When patients on ICIs present in places where health care providers are not familiar with what an irAE might look like, it clearly presents a problem. Thus, what we must first overcome is a general lack of awareness of the potential for irAEs to occur in patients being treated with an ICI. To give a personal example, one of my family members was recently diagnosed with a rare health condition secondary to a viral infection. They presented to the emergency room (ER) with all of the hallmark symptoms of this rare syndrome. However, the diagnosis was not identified, and they were sent home without answers. It was only later that the condition was discovered and the diagnosis made. This experience is similar to that of many of my patients who have presented to a general ER, hospital floor, or other health care setting with all of the hallmark symptoms of an irAE, only for the irAE to not be recognized simply because it was not on the list of differential diagnoses being considered. Awareness of irAEs and the immunosuppressive drugs used to treat them is half the battle.

Beyond awareness, there is also a need for recognition of irAE acuity. This leads to my second tip for you: Know the urgency. I often tell those who are less familiar with immunotherapy that irAEs are the “new age” version of oncologic emergencies. Not the soothing type of sleep-inducing new age music, but rather something much more insidious. A fascinating and terrifying aspect of irAEs, as opposed to other chemotherapy AEs, is that their trajectory is often that of inevitable, exponential worsening, even in the absence of continued ICI dosing. When these irAEs occur, they often spiral into a more severe state unless stopped by immunosuppression. This is due to unchecked immune activation. In an ideal world where all irAEs were addressed in the safest, most responsible way, we would catch irAEs at the point when they worsen no further than grade 2, treat them early enough with immunosuppression to calm immune activity against self-antigen before it cascades out of control, then hope for the potential to continue immunotherapy later. Allowing an irAE to worsen to a severe level (grade 3 or 4) is not preferred, as it can lead to steroid-resistant irAEs, longer duration of immunosuppression, and less likelihood of continued ICI therapy.

As with the “old” oncologic emergencies (e.g., hypercalcemia, tumor lysis syndrome), the management of irAEs should usually be viewed as semi-urgent even when symptoms are relatively moderate. Why? I would liken a patient with a moderate irAE to a ticking time bomb; you suspect you know what is happening (irAE is occurring), you know what is coming should you not intervene (higher grade irAE), and you wish you knew how to stop it (appropriate workup and initiation of immunosuppression). What is there to do? My final tip for you: Know your friends. In many cases, particularly in the non-oncology realm, consider a specialist consult as a useful bridge to expedite workup and management of irAEs. Ideally, consult with the treating oncology team themselves. If that is not feasible, look to national guidelines and local or remote consultation with organ system specialists (whether it be gastroenterology, dermatology, hepatology, pulmonology, cardiology, neurology, endocrinology—you name it). You will likely receive resistance, perhaps even pushback, as you try to expedite your referrals in irAE cases. Be the persistent one. Explain what is happening (irAEs affect organ systems in a way that is usually more accelerated than other naturally occurring autoimmune disorders, and thus require more urgent evaluation). Call in the favors. As a health care profession, we must together accept that irAE management is different, and it requires mobilization in ways to which most disciplines are not accustomed. Improve your system one case at a time. Your patients will benefit from it.

Even those like myself who work with irAEs every day cannot expect to know the nuances of all irAEs, as each case is unique. That is why timely care collaboration is imperative. Be the advocate for irAE awareness in your health system. Learn who the key players are who might be able to help, should an irAE arise. Get to know the pathways that might help your team expedite referral. Recognize free guideline resources like those published by the National Comprehensive Cancer Network (NCCN) and other professional organizations, and use them.^2-4 Get to know the drugs used to slow down the immune system to the point that friendly fire stops (e.g., prednisone, methylprednisolone, infliximab, mycophenolate). You may not feel comfortable with these drugs, but they may be the only thing between your patient and a poor outcome.

Know your enemy. Know the urgency. Know your friends. If you do these three things, you will be well on your way to helping improve the consistency of care collaboration on irAEs across the spectrum of health care disciplines.

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