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FAQ: irAEs in Solid Tumors
Management of Immunotherapy-Related Adverse Events in Solid Tumors: Highlights and Answers to Your Frequently Asked Questions

Released: May 06, 2025

Expiration: November 05, 2025

Suzanne McGettigan
Suzanne McGettigan, MSN, AOCN, ANP-BC
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Key Takeaways
  • Key toxicities associated with immune checkpoint inhibitor (ICI) and ICI combination therapies include diarrhea and colitis.
  • A combined use of current guidelines and expert recommendations may help to accurately address how to manage steroid-refractory disease.

Early identification and effective management of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI) and ICI-based combinations are key for maintaining quality of life and improving care of patients with cancer. This commentary provides experts’ guidance on managing common irAEs and answers to FAQs posed at a live webinar designed to strengthen advanced nursing strategy insights for managing irAEs.

Expert Case Guidance: A Patient Case
A 47-year-old woman with grade 3 ICI-related hepatitis who was started on prednisone 1 mg/kg and tapered by 10 mg weekly presents to your clinic. It would appear that the taper was conducted prematurely, and the patient had to restart steroid treatment. What would you recommend as next steps?

Suzanne McGettigan, MSN, CRNP, AOCN, ANP-BC:
This patient is more likely steroid refractory than nonresponsive. The level of inflammation can vary among patients. One patient may have a liver function test (LFT) showing elevated liver enzymes of 800 U/L and started on 1 mg/kg and tapered every week and/or twice weekly. Within 4 weeks, this patient is off steroids, with normal LFTs, and is able to resume ICI therapy. By contrast, another patient may also present with elevated LFTs (ie, in the 800s), but upon tapering, LFTs levels rise again. In this patient, second-line immune-modulating irAE management therapy is needed to bring LFTs to normal levels. For example, we see this quite often in patients with ICI-related colitis.

In patients receiving an ICI combination for metastatic melanoma, how would you educate them on what to expect regarding the timing and severity of irAEs?

Suzanne McGettigan, MSN, CRNP, AOCN, ANP-BC:
When using a combination of ICIs, we see more intense toxicity develop earlier on. It is important as healthcare professionals to educate our patients as well as other staff members so that they are aware of much earlier toxicities associated with the use of 2 ICIs vs 1 ICI. For example, colitis tends to peak approximately week 6 following the initiation of either ipilimumab or nivolumab alone, but when these are combined, colitis tends to peak closer to Week 5. After initiating nivolumab, pneumonitis tends to peak around Week 12, but with the addition of ipilimumab, it tends to be observed earlier at approximately Week 7.

It is also important to note that the incidence of irAEs differs depending on the immunotherapy dose, and in particular, the CTLA-4 combinations. In renal cell carcinoma (RCC), the standard dose is ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, whereas in non-small cell lung cancer, the standard dose is ipilimumab 1 mg/kg every 6 weeks and nivolumab 3 mg/kg, which results in increased incidences of some of the more common irAEs like dermatitis, pneumonitis, and hepatitis. In melanoma, the standard dose is ipilimumab 3 mg/kg plus nivolumab 1 mg/kg for a total of 4 doses, and the incidences of irAEs are somewhat in between the other 2 regimens, with the exception of diarrhea and hepatitis, which are nearly triple those observed in RCC. We also know from clinical trials that as the dose of the CTLA-4 antibody is increased, the risk of developing irAEs also increases.

Managing AEs Associated With:

With any immunotherapy, AE grade should be taken into consideration when managing irAEs. Most patients receiving single-agent ICI are asymptomatic. Supportive care (eg, steroids) is helpful for those with grade 2 irAEs if moderate but persistent. For those with grade 3 irAEs, intervention is required. Such intervention typically includes holding the immunotherapy with potential for discontinuation, and managing with systemic steroids with prolonged taper. For those with grade 4 or life-threatening irAEs, we may consider urgent intervention such as discontinuing ICI, systemic steroids with prolonged taper, and consideration for use of other immunosuppressants.

When managing AEs in this context, the approach depends on the causative agent. Chemotherapy-related toxicity tends to be consistent and cyclical. Chemotherapy doses can be adjusted, held, or reduced, or discontinued (if severe), or a new and less toxic chemotherapy can be introduced. ICI-related toxicity may occur after several cycles and persist over time; immunotherapy dose may be held but not dose-reduced and no change of ICI agent, but steroids could be considered, as well as ICI permanent discontinuation if irAE is severe.

When a patient is receiving multiple ICIs, as in patients receiving nivolumab (PD-1 inhibitor) and ipilimumab (a CTLA-4 inhibitor), the CTLA-4 inhibitor can be stopped while the PD-1 inhibitor can be continued. However, we most often do not reduce the dose of the PD-1 inhibitor, and we never switch to another ICI because there are no data showing a benefit to the patient using that approach.

In patients receiving an ICI plus VEGF inhibitor for metastatic RCC, a common overlapping toxicity is diarrhea/colitis. In patients with grade 2 diarrhea while receiving ICI (avelumab or pembrolizumab) and VEGF inhibitor axitinib, toxicity can often be mitigated by stopping axitinib for 24-48 hours and determining whether symptoms improve over the course of several days. If no improvement is observed after stopping axitinib, the ICI can be held, and corticosteroids (prednisone/intravenous methylprednisolone) can be initiated. If after corticosteroids AEs improve, consider restarting axitinib followed by ICI rechallenge. For grades 3/4 diarrhea, hold both agents and consider immediate intervention/hospitalization; for initial grade 3, consider rechallenge upon improvement, but for grade 4 permanently discontinue ICI and VEGF inhibitor therapy even after improvement.

Managing irAEs always starts with educating patients, their caregiver(s), and the care team. It is essential for patients to know how and when to reach out for help and what to expect throughout their treatment course, including a clear understanding of the potential AEs and typical timelines for each drug they receive. It is also important to be aware of overlapping toxicities and to consider the half-lives of the medications being used. In our clinic, when patients develop an immune-mediated toxicity and they start on a long steroid taper, we see them weekly until symptom resolution. Specialists can and should get involved early in the evaluation, particularly if there is uncertainty about which drug is the causative agent. A biopsy may be needed to determine the source of the AE(s). Ultimately, it is important to start treatment promptly. Do not wait for the biopsy results. Once you have the results, pivot as needed.

How do you address potential steroid resistance or intolerance in patients receiving immunotherapy?

Denise Rouse, MS, PA-C:
Steroid-sparing immunosuppressive drugs are available, but it is not a one-size-fits-all approach. Mycophenolate works in the liver, but infliximab works in the colon, and intravenous immunoglobulin can be used in the lungs. The answer to this question depends on what cells you are trying to target. Where is the toxicity occurring? The American Society of Clinical Oncology guidelines for ICI management include an appendix that details steroid-sparing options for immunosuppression, including where they can be used; the recommended dosing; and special considerations. Choosing something other than a steroid is fine, but if one is needed (eg, in the case of steroid resistance), a specialist should be included in the discussion. By contrast, if steroids are not working, they cannot be tapered. However, if a patient has brittle diabetes, we want to move to a steroid-sparing agent. In this setting, I always collaborate with a specialist, and we look to other medications to suppress the immune system. I recommend referencing the guidelines, as options are continually changing, so this will allow you to see the best options available.

Steroid resistance/intolerance can also be complicated by patient factors. Prophylaxis for Pneumocystis jirovecii pneumonia can be considered for patients receiving prednisone equivalent of at least 20 mg/day for at least 4 weeks or more than 30 mg for at least 3 weeks. Vitamin D or a calcium supplement may also be beneficial, as might valacyclovir for varicella-zoster virus. This is why it is important to meet with patients on a weekly basis and educate them on their options.

Suzanne McGettigan, MSN, CRNP, AOCN, ANP-BC:
I think some patients hesitate to report such symptoms, because they are afraid of what might happen if their therapy is held. Convincing patients that holding, or even stopping, therapy could be beneficial by citing trials showing favorable outcomes with these recommendations can provide reassurance. If patients let us know about these toxicities as soon as they notice something, it is often much easier to reverse them.

Is there an association between developing an irAE and having a durable response to immunotherapy in terms of cancer control?

Suzanne McGettigan, MSN, CRNP, AOCN, ANP-BC:
The short answer is no. However, there is much controversy surrounding this question. When trying to convince patients that it is okay to hold their therapy, I tell them that their immune system has been “revved up,” and we need to hold the ICI therapy to let it settle.

Do you initiate high-dose steroids with hypophysitis, or do you supplement with thyroid cortisol or testosterone?

Suzanne McGettigan, MSN, CRNP, AOCN, ANP-BC:
Before starting any hormone treatment, a baseline pituitary panel is needed. Quite often if the adrenal glands are not functioning properly, other hormone levels are affected. In these cases, the adrenal insufficiency should be corrected before thyroid or other hormone treatments.

In general, cortisol can be replaced with a physiologic dose of prednisone, but if patients are symptomatic from their hypophysitis, the dose of steroids can be slightly higher than the physiologic dose to target inflammation in the pituitary gland. Once the inflammation in the pituitary gland is reduced, the dose should be tapered very quickly to a physiologic dose. However, prednisone 1-2 mg/kg or equivalent only for hypophysitis is not needed.

Your Thoughts
What are your thoughts and biggest challenges on managing irAEs in patients with solid tumors? Visit the program page to access more education materials from the APPlexus series including downloadable slides and an on-demand webcast with a recording from the live event.

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