Based on a review of immune checkpoint inhibitor mechanisms of action and clinical trial data, SITC has published a clinical practice guideline, which provides key recommendations for managing immune-related adverse events.
The management of immune-related adverse events (irAEs) resulting from treatment with immune checkpoint inhibitor (ICI) monotherapy or in combination regimens was probed by an expert panel brought together by the Society for Immunotherapy of Cancer (SITC). Based on the review, SITC has published a clinical practice guideline, which provides key recommendations for managing irAEs.1,2
According to research, IRAEs contribute significantly to the toxicity profile of immunotherapies. Specifically, programmed death-ligand 1 (PD-L1) inhibitors lead to irAEs in 74% of patients and these irAEs are grade 3 or higher for 14% of patients. The incidence of irAEs is even higher with anti-CTLA-4 agents at 84%. Anti-CTLA-4 therapies also have a 34% incidence of grade 3 or higher irAEs. ICI combination regimens led to irAEs in 90% of patients with 55% being grade 3 or higher in severity.
“Over the past decade or so, the role of immuno-oncology has expanded dramatically, particularly with the introduction of immune checkpoint inhibitors, Marc Ernstoff, MD, chief of the ImmunoOncology Branch at the NCI Division of Cancer Treatment and Diagnosis, Developmental Therapy Program at the National Institute of Health told Targeted Oncology (TO), in an interview.
“The use of these agents is now in many different cancers, and the spectrum of toxicities associated with immune checkpoint inhibitors is unique and differs dramatically from the standard chemotherapy or radiation. It's critical that SITC as well as other societies put forward understanding the mechanism, the breath mechanism, and treatment of these toxicities,” Ernstoff added.
In characterizing irAEs associated with ICI therapy further, it was shown that more common events like thyroiditis and dermatitis, are different from chemotherapy-related AEs, and the timing of these irAEs is less predictable. The unique mechanisms of action found with ICIs combined with data from clinical trials make clinical practice guidelines for managing irAEs an important need for oncologists.3
The experts modeled the clinical practice guidelines according to The Institute of Medicine’s (IOM) Standards for Developing Trustworthy Clinical Practice Guidelines. Literature review along with open communication and scientific debate was used by the experts to develop the recommendations, then a draft of the clinical practice guidelines was released to the public for comment before being finalized. The finalized SITC panel clinical practice guidelines included general panel recommendations, recommendations by type of toxicity, and recommendations for the use of ICI combinations.
First, the general panel recommendations provide guidance around treatment hold and discontinuation, timing and dosing for corticosteroids and similar agents, baseline screening and testing, and what to do for patients who have various grade levels of irAEs.
For oncologists, the panel recommends performing a complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), free thyroxine (fT4) before beginning any ICI therapy. In addition, urinalysis should be performed for patients who have kidney disease at baseline to evaluate their condition. The panel also advises that oncologists should consider performing an electrocardiogram for patients who have a higher probability of developing myocarditis. Troponin test at baseline may also be appropriate if a patient has potential for future cardiac toxicity.
During treatment, oncologists should also carry out CBC with differential, CMP, TSH, and fT4 tests intermittently for patients being treated with ICIs.
Oncologists are also encouraged to counsel their patients well regarding irAEs and the possibility of exacerbation or flare-ups that may follow ICI therapy if they have a history of a non-life-threatening autoimmune disease.
For patients with cancer, treating physicians should encourage contraception while giving immunotherapy and fertility should be discussed before treatment. The risk-benefit profiles of ICI therapy should be discussed with patients with an autoimmune disease before they are treated. During ICI therapy, patients should be referred to a specialist in the event of grade 3 toxicity that does not respond to steroids.
In terms of continuing, holding, or discontinuing ICIs, the expert panel advises that grade 1 irAEs do not warrant holding or discontinuing therapy, but the issue should be monitored for worsening symptoms. In the case of grade 2 irAEs, treatment should be temporarily withheld, and patients should receive corticosteroids if appropriate.
Regarding re-challenging patients with ICI, the recommendations are that the decision is thought through to consider the potential threat on the patient’s life, prolonged or multiple immunosuppressants, history of long-term therapy on an ICI, and whether patients have had complete responses or durable clinical benefit when previously on the ICI. For patients who have a grade 3 or 4 irAE, the oncologist should weigh the benefits and risks before re-challenging.
The final general panel recommendation states that any grade myositis, myocarditis, or neurological toxicities in patients performing erythrocyte sedimentation rate, C reactive protein, creatine kinase, antibody tests acetylcholine, muscle-specific kinase, striational, aldolase, troponin, EKG, nerve conduction, and electromyography testing on patients. Frequent pulmonary assessment and the usual irAE treatment should be performed on patients. All recommendations should be followed unless otherwise specified.
“The toxicities of these agents are different and unique, and the identification and diagnosis of the toxicities, therefore, become important to recognize. The treatment or the management of the toxicities are also different than other standard therapies. It needed to be outlined for individuals and that the toxicity profile is such that it's not always immediate and doesn't necessarily follow immediately upon therapy but can be delayed. Also, the management of the toxicities many times requires multiple specialties,” Ernstoff stated.
Aside from the general panel recommendations, the toxicity type-based recommendations offer more in-depth details on what oncologists should do if a patient with cancer who is receiving ICI therapy experiences the following toxicity types:
Covering the section in its totality, Ernstoff told TO, “independent of whether the toxicities are gastrointestinal, or skin, or related to the central nervous system, the grading of the toxicities are significant. The toxicities associated with each of organ that can be involved is critical because it could be life-threatening. Although it's exceedingly rare, bullous formation in skin toxicity could be potentially life-threatening, if not recognized early and managed. Cardiomyocyte and the development of type 1 diabetes can be life-threatening, if not identified, and associated gastrointestinal toxicity, which is usually diarrhea associated with colitis, if not recognized can cause perforation and catastrophic events, explained Ernstoff. “So, it's important to recognize that while many of these agents, particularly single-agent therapies are well tolerated in general, we shouldn't be lulled into complete compliance complacency in querying our patients and making sure we follow them closely for the development of the side effects.”
Ernstoff further explained the treatment of irAEs in patients with cancer often requires the expertise of more than just the treating oncologist.
“The first identification of the event and the severity of the event many times requires a collaboration with a multidisciplinary team. Recognizing early in the development of toxicity, whether it be gastrointestinal, cardiovascular, or neurological, that collaboration with appropriate subspecialty is critical in managing that toxicity,” said Ernstoff.
The key concern related to the use of ICI combinations is that patients are at a higher risk of experiencing toxicities in comparison to patients being treated with a single agent. The panel recommends counseling patients about this fact, especially if 1 of the agents in their regimen is ipilimumab (Yervoy) dosed at 3 mg/kg. These patients should also be monitored frequently for signs of irAEs.
The panelists recommend counseling patients to monitor their blood pressure regularly when receiving the combination of pembrolizumab (Keytruda) and axitinib (Inlyta). Patients who develop hypertension because of an ICI combination should receive medication for hypertension and the axitinib should be held if the event is grade 2 or higher.
Moreover, the recommendations state that physicians should uncover the source of the irAEs because in the event that the irAE is not related to ICI therapy, the dose does not require reduction. Patients should be referred to a specialist if the oncologist cannot determine the origin of the irAE.
“Managing toxicities is a complicated area. The key message is that one must recognize that this is a different therapy that has its unique toxicities. To be able to use ICI therapies effectively, one has to be able to recognize and manage those toxicities,” Ernstoff concluded about the clinical practice guidelines.
1 Society for Immunotherapy of Cancer publishes clinical practice guideline on immune checkpoint inhibitor-related adverse events. News release. July 14, 2021. Accessed July 18, 2021. https://prn.to/3kE0cFY
2 Brahmer JR, Abu-Sheih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6): e002435. doi: 10.1136/jitc-2021-002435.
3 Hargadon KM, Johnson CE, Williams CJ, et al. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39. doi:10.1016/j.intimp.2018.06.001