Coordinator of Oncology Concentration
Yale University School of Nursing
Oncology Nurse Practitioner
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut
Marianne Davies, DNP, CNS, ACNP-BC, AOCNP, has disclosed that she has received fees for non-CME/CE services from AstraZeneca, Bristol-Myers Squibb, Genentech, and Merck.
As immunotherapies become more widely used in oncology, managing the associated immune-related adverse events (irAEs) has become a critical part of maximizing patient outcomes. In this commentary, I discuss examples of how I manage irAEs in patients with solid tumors in my clinic who are receiving immune checkpoint inhibitors.
Immune-Related Adverse Events: Overview
The most common irAEs I see are rash; pneumonitis, which occurs more frequently in the lung cancer population vs melanoma; endocrine dysfunction, such as hypothyroidism; and gastrointestinal toxicities such as diarrhea. We sometimes see some subtle changes in bloodwork such as impaired liver function (increased alanine aminotransferase and aspartate aminotransferase) or pancreatic function (increased amylase and lipase). Most cases are mild and asymptomatic. The irAE symptoms that are most obvious to patients will be diarrhea, rash and pruritus, lung pneumonitis, and hypothyroidism.
It is important that all our clinicians use common grading toxicity criteria (ie, CTCAE) very closely. This allows all clinicians to communicate objectively about the toxicity and provides the framework for treatment. Some patients receiving checkpoint inhibitors may require steroids to manage their irAEs if the toxicity is grade 2 or higher. In our clinic, we wait to start tapering down off steroids until the irAE has declined to grade 1, per guideline recommendations. In general, the taper is over a month, but some patients might require longer. It is important to not taper too rapidly to avoid a flare of the toxicity.
Case Study 1: Durvalumab in Stage IIIA Non-Small-Cell Lung Cancer (NSCLC)
I treat a 75‑year‑old woman with stage IIIA NSCLC who underwent standard induction therapy with chemotherapy and concurrent radiation therapy. She experienced the common AEs of esophagitis and fatigue over the course of treatment. These toxicities resolved within a few weeks of treatment completion.
We started maintenance therapy with the PD-L1 inhibitor durvalumab, which was well tolerated until cycle 4 when she developed a very mild rash. Rash is an expected toxicity of durvalumab and is usually well controlled. It was associated with some pruritus, and I initially prescribed her an oral antihistamine. However, the rash spread to a larger portion of her body (grade 2), and we prescribed clobetasol propionate cream, which is a moderate topical steroid, with initial resolution of the rash. These are management recommendations for this patient from the CCO irAE decision support tool:
Her rash tends to wax and wane, so if it does flare, we restart the clobetasol, but if it is under good control, then topical emollients are sufficient.
At the beginning of cycle 5, she experienced significant fatigue affecting her activities of daily living and was spending most of her time sleeping. We obtained thyroid function tests, concerned that she was probably experiencing an endocrine toxicity. As expected, her thyroid-stimulating hormone level was rising and her thyroxine (T4) level was decreasing. Because she was symptomatic, we initiated the hormone replacement levothyroxine, and within a few weeks, she had significant improvement in her symptoms. Currently, we are titrating up her levothyroxine to reach a therapeutic level.
This patient is very fortunate, as both toxicities can be very well controlled. She was worried that the toxicities would impede her ability to continue with treatment. Fortunately, we were able to reassure her that these irAEs are manageable and she could successfully continue with durvalumab treatment.
Case Study 2: Atezolizumab in Metastatic NSCLC
I treat a gentleman with NSCLC who progressed on platinum-containing chemotherapy and was treated with second‑line atezolizumab (a PD-L1 antibody). After several cycles, he developed grade 1 diarrhea. We were able to control this initially with diet modification and occasional loperamide. However, after a few more cycles, he came in with abdominal cramping, discomfort, and change in the number and the quantity of stools (grade 2 diarrhea). At that time, we held the atezolizumab and obtained stool cultures to rule out infection.
He needed stronger intervention, so we started him on prednisone, per management recommendations for this patient from the CCO irAE decision support tool:
Despite initial improvement of his irAE to grade 1, he did not do well with the taper and kept having toxicity flares that increased to grade 3. We instituted additional immunosuppression with the TNF-alfa antibody infliximab, which worked quite well and provided an opportunity to taper off the prednisone.
Because he had stable disease after almost 1 year of the atezolizumab, we discontinued his immunotherapy. Unfortunately, he eventually progressed. He really wanted to go back on immunotherapy, but given the grade 3 toxicity that was not easily controlled, we opted for chemotherapy. Fortunately, he is doing well and responding to chemotherapy at this time.
Case Study 3: Nivolumab in Recurrent RCC
Another of my patients is a woman in her 70s with renal cell carcinoma who progressed on an antiangiogenic regimen. She was treated with nivolumab for approximately 10 months and then developed moderate arthralgias with noticeable swelling in her hands and joints and shoulder pain. This AE began to interfere with her activities of daily living (eg, she needed help getting dressed). These are the guideline-based management recommendations for this patient from the CCO irAE decision support tool:
We held her therapy for a month, but the arthralgias and swelling continued. We started her on prednisone, which after a long course was tapered down to a fairly low dose, but she was not able to completely taper off. We often consult with our rheumatologists when we encounter a toxicity of this type that we are not able to easily manage. The rheumatologists evaluated the patient and obtained blood work that confirmed rheumatoid arthritis. As a result, they recommended additional immunosuppressant therapy.
Nivolumab is commonly associated with mild arthralgias or myalgias (ie, joint or muscle aches or pains). These AEs are usually well tolerated and accompanied by mild fatigue. In my experience, although we do monitor for it, fewer than 5% of patients receiving PD-1/PD-L1 checkpoint inhibitors develop significant arthralgias that require steroids.
We do see an increase in toxicities such as diarrhea and rash when combining CTLA-4 and PD-1 antibodies, such as ipilimumab plus nivolumab. These patients require unique irAE management strategies according to current guidelines. If the CTLA-4 antibody is considered to be the causative agent, patients may be able to resume their PD-1 inhibitor.
Counseling Patients About irAEs
Before we start any patient on an immune checkpoint inhibitor, we do a full review of their medical history to assess for underlying autoimmune conditions that checkpoint inhibitors could exacerbate. Although patients with autoimmune conditions were excluded from the clinical trials, now that checkpoint inhibitors are approved, the discussion becomes a shared decision-making risk–benefit analysis with the patient. There is consideration as to whether it is in their best interest to receive a therapy with the risk of exacerbating the autoimmune disease. We also conduct a medication review and reinforce with patients at each visit to not start any steroid‑based medication or other immune‑modulating agent that might interfere with their therapy.
We ensure that patients are fully educated about potential irAEs so they have clear expectations about treatment. Immune-related AEs are different than AEs from cytotoxic agents and targeted therapies. We explain the mechanism of action, including how the immune system is unleashed and can cause inflammation of any body system or organ, from head to foot. Sometimes the patients will have symptoms, but other times the start of an irAE will first be noted on their routine bloodwork, through our exam, or on diagnostic imaging, such as CT scans. It can be startling for patients to be told, for example, “We’re looking at your bloodwork and it indicates an elevation in some of these numbers. We will keep a close eye on it and may need to hold therapy.” This, of course, makes them very concerned.
Patients must understand the need to have close communication with us, notifying us at the onset of any symptoms and not ignoring them. We need to determine if their symptoms are from the checkpoint inhibitor or possibly another cause. For instance, if lung pneumonitis is drug induced, we would treat with steroids. But if it were due to a community‑acquired pneumonia, the steroid could actually exacerbate the infectious process. Moreover, if a drug‑induced pneumonitis is mistaken for a respiratory infection and treated with an antibiotic, the pneumonitis could get worse. Managing irAEs requires critical thinking and a differential diagnosis to find the etiology of the toxicity.
Patient Barriers and Resources
One of the barriers in helping patients manage irAEs is the patients’ fear that their treatment will be discontinued if the toxicity is significant enough, especially if they are responding to therapy. We reassure them that, as demonstrated in clinical studies, they can still benefit from the therapy even with a treatment interruption because an activated immune system can provide long, durable responses. We explain that there is a balance of keeping them safely on therapy without potential lifelong complications.
We provide a variety of resources to help patients monitor their symptoms at home, such as toxicity monitoring and recording charts, symptom management instructions, and contact numbers. Patients are instructed to carry a medication identification card that describes the immunotherapy they are receiving. This can be essential to inform other providers if the patients find themselves in an emergency department or at another provider’s office. The card includes our contact information so the treating provider can collaborate with us on how to best manage the patient’s symptoms. Overall, we encourage patients to call with any questions at all at any time. Accessible telephone triage is critically important to evaluate potential irAEs and provide direction to patients. For ongoing assessment, we typically see most patients in person at least monthly, some every 2‑3 weeks.
What challenges have you encountered in managing checkpoint inhibitor–associated toxicities? Share your experience in the comment box below.