CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 09, 2023
Expiration: May 08, 2024
Spectrum of irAEs
Bethany Withycombe, PharmD, BCOP:
As already demonstrated, anti–PD-1 treatments are the preferred choice of systemic therapy for advanced NMSC. However, they are not without their drawbacks, which include the spectrum of AEs unique to ICIs. Therapeutics like cemiplimab and pembrolizumab that have been approved for the management of NMSCs work to reactivate or stimulate the immune system. This is a good thing when the immune system is becoming reactivated to help fight cancer cells. However, not so much if the immune system becomes so active that it starts mounting an attack on healthy tissue.
Patients must be educated on these potential reactions for early recognition to allow for prompt diagnosis and treatment. It is also important for patients to understand that the toxicity profile of ICIs is distinct from traditional cytotoxic chemotherapy. Traditional chemotherapy is associated with nausea, vomiting, and myelosuppressive effects that occur upfront. However, irAEs have a delayed onset, are inflammatory or autoimmune in nature, and have the potential to occur in any healthy tissue within the body. A good way to remember this is to think of irAEs as commonly ending in “itis,” which signifies inflammation. irAEs include things like dermatitis, colitis, hepatitis, hypophysitis, pneumonitis, nephritis, and even inflammation of the eye known as uveitis. Rare neurologic irAEs such as myasthenia gravis-like syndromes also can occur.
Patient Education is Key
Bethany Withycombe, PharmD, BCOP:
I cannot stress enough how important patient education is when starting ICI therapy. Early recognition and management of these irAEs is key. The treating team should obtain an understanding of the patient's baseline symptoms and baseline bowel habits before starting ICI therapy. Patients also should consider keeping a wallet card with them, which includes the name of the treatment they are receiving. This can be helpful if they present to an outside hospital that may not be familiar with the patient’s case and the therapy they are currently receiving and may help prevent any confusion regarding their treatment. For example, if a patient presents at outside emergency department stating they are receiving chemotherapy when in fact they are receiving ICI therapy, this could potentially change the differential for that treating emergency department team.
It is also important that patients know how to reach their provider and/or clinic nurses if they experience any new or abnormal symptoms while receiving immunotherapies. As a part of patient education, it is sometimes helpful for patients to know that there is a plan in place to manage any irAEs that arise.
Timing and Type of irAEs
Bethany Withycombe, PharmD:
When anti–PD-1 therapy is used alone, irAEs typically occur within 6 months of anti–PD-1 initiation but may ultimately occur at any point in time during therapy and even after treatment has been discontinued.36,37
Of interest, certain irAEs tend to occur at certain time points in therapy.36 For example, skin toxicities, are the most prevalent irAEs seen with immunotherapy and typically occur within the first several weeks of treatment, with most cases being low grade and manageable with a topical steroid. Colitis is the second most common irAE, and it typically develops within 5-10 weeks of starting anti–PD-1 treatment. Like with mild skin toxicities, mild colitis also may be managed without systemic steroids. Mild colitis can be managed using over-the-counter loperamide and with non-pharmacologic interventions such as the BRAT diet. The BRAT diet incorporates bland foods like bananas, rice, applesauce, and toast, and recommends avoiding foods that may further exacerbate symptoms like spicy foods, greasy, fatty foods, or foods high in sugar. And of course, one needs to keep up with hydration and electrolyte replacement during that time as well. Liver toxicity occurs at a lower rate than colitis but is a well-documented irAE that can occur with asymptomatic elevations in liver enzymes being the most common presentation. It has an onset that ranges from 6-12 weeks from the start of anti–PD-1 treatment but also can occur many months later. Finally, endocrine toxicities such as changes in thyroid function or hypothyroidism and lung toxicity such as pneumonitis typically occur further into treatment after several doses of anti–PD-1 therapy.
Any-Grade Toxicities Observed With Anti–PD-1 Therapy
Bethany Withycombe, PharmD, BCOP:
As mentioned previously, irAEs may occur anywhere in the body. We discuss the management of some of the more common toxicities, including skin rash and pruritus, colitis, diarrhea, and hepatotoxicity and thyroid dysfunction, as well as the less common but potentially serious irAE of pneumonitis, which has been associated more with anti–PD-1 therapy than anti–CTLA-4 therapy.36
General Guidance for Management of irAEs: Start by Ruling Out Other Potential Causes
Bethany Withycombe, PharmD, BCOP:
Early recognition of symptoms and prompt intervention are key to managing immunotherapy-related toxicity. The management of these irAEs depends on the severity. Grading of the severity of various irAEs is done using the Common Terminology Criteria for Adverse Events, or CTCAE.38 The grading scale ranges from 1-5 scale, with 5 being the most severe, that is, death.
In general, for patients experiencing a grade 1 toxicity, immunotherapy may be continued with close monitoring, except for more serious toxicities that are hematologic, cardiac, or pulmonary related. For grade 2 toxicities, the general recommendation is to hold and consider initiating 0.5-1 mg/kg/day of prednisone, which would be tapered over time. For more serious toxicity (grade 3/4 toxicity), high-dose steroids should be considered such as 1-2 mg/kg/day of prednisone or the equivalent tapering during at least 4-6 weeks.
Although patients are receiving steroid tapers, it is important to remember supportive care measures that need to be taken into consideration.39 First, there is a possibility of hyperglycemia. This is especially important for our patients with a history of diabetes. Second, gastritis may occur, and we need to consider patients for gastrointestinal prophylaxis with H2 blockers or a proton pump inhibitor while they are receiving high-dose steroid taper. Third, you need to consider the risk of opportunistic bacterial or fungal infections. Patients receiving ≥20 mg/day of prednisone for ≥4 weeks should be considered for Pneumocystis pneumonia prophylaxis, whereas those receiving the same amount of steroid for ≥6 weeks should be considered for prophylaxis against fungal infections with fluconazole as per the treatment management guidelines. In addition, antiviral prophylaxis may be considered for select patients to prevent herpes zoster reactivation. For patients on prolonged steroid tapers, ensuring that they have appropriate vitamin D and calcium supplementation is important for maintaining bone health as well.
Patients may be rechallenged on immunotherapy once they recover from an irAE. However, caution should be used when reinitiating therapy, especially in patients who have early onset irAEs, those who do not rapidly respond to steroid taper, and those who experience high-severity toxicity.
Management of irAEs: Skin Rash/Pruritus
Bethany Withycombe, PharmD, BCOP:
When working up skin toxicity, it is important to collect a pertinent history from the patient to rule out other possible causes.36,39,40 The physical examination should include an evaluation of the oral mucosa and blister formation. It should consider the body surface area that is involved.
In general, patients should follow nonpharmacologic supportive care measures such as using a topical emollient to keep the skin moisturized and less irritated and avoiding topical products that may be irritating to the skin. This would involve avoiding products with any kind of scent or fragrance or anything topical that contains alcohol. Patients also should avoid scalding hot showers, as this may further irritate the skin.
Sun safety measures also should be reinforced.
For low-grade skin toxicity, a topical steroid should be used for management. For grade 1, you may be able to use over-the-counter hydrocortisone cream and continuation of immunotherapy, although patients may end up needing a higher potency steroid cream like triamcinolone acetonide cream. I also would like to note here to take caution with the location of the skin rash, as higher-potency steroids should not be used on more sensitive skin areas like the face, axilla, and groin areas. If patients are unresponsive to topical management, consider a low-dose prednisone taper.
For grade 3/4 rash, starting a high-dose steroid taper of 1-2 mg/kg/day of prednisone or the equivalent should be considered, and immunotherapy should be withheld. A topical steroid cream should assist with managing any itching, and oral antihistamines also may be considered clinically appropriate.
Management of irAEs: Colitis/Diarrhea
Bethany Withycombe, PharmD, BCOP:
For the workup of colitis and diarrhea, again, a pertinent history should be collected to rule out other possible causes.36,39,40 Patients also should be asked about any other accompanying symptoms of the watery loose stool. The treating team also may consider collecting stool studies to rule out infection, as well as checking fecal lactoferrin and or fecal calprotectin. When either of these is positive, an endoscopy examination should be considered. In addition, serial monitoring of fecal calprotectin levels may help guide treatment duration and timing of immunotherapy rechallenge if that is deemed appropriate as per the management guidelines.
For patients with grade 1 diarrhea or colitis, consider withholding immunotherapy and using the supportive care mentioned previously. However, if symptoms persist or progress, patients should be managed as grade 2. For grade 2 diarrhea, withhold immunotherapy and start with 1-2 mg/kg/day prednisone with a 4- to 6-week taper. At some institutions, providers opt for a 0.5-1 mg/kg/day taper over 4-6 weeks. If there is no response after 2-3 days of steroid therapy, steroid doses should be maximized. If there is still no response, the addition of a biologic agent like infliximab or vedolizumab should be considered. If an anti-TNF biologic agent like infliximab is needed, the patient should be tested for tuberculosis and viral hepatitis, as they may be at risk for reactivation. However, these tests should not delay biologic therapy per management guidelines.
For patients with more severe diarrhea or colitis (grade 3/4 in severity), high-dose steroids (1-2 mg/kg) should be used until resolution to grade 1 and then tapered off for 4-6 weeks. Patients with dehydration or electrolyte imbalance may need to be considered for inpatient admission for high-dose IV steroids, rest, and additional support. For grade 4 diarrhea, the immunotherapy would be permanently discontinued.
Management of irAEs: Thyroid Dysfunction
Bethany Withycombe, PharmD, BCOP:
When endocrine toxicities such as hypothyroidism occur, replacement with levothyroxine should be considered for grade 2 toxicity.39,40 Some patients also may require physiologic hormone replacement with oral hydrocortisone if there is any concern for central hypothyroidism or hypophysitis. A thyroid panel should be carried out regularly throughout therapy, approximately every 4-6 weeks.
Management of irAEs: Hepatotoxicity
Bethany Withycombe, PharmD, BCOP:
A complete blood count with differential and a complete metabolic panel including liver function tests (LFTs) and bilirubin monitoring should be carried out before each treatment.39,40 When a patient presents with elevated LFTs, it is again important to collect a pertinent history to rule out other possible causes. For those with grade 1 elevations, defined as <3 times the upper limit of normal, immunotherapy in general can be continued with close monitoring of the LFTs. However, once patients start to experience elevations of grade 2 or higher, consider withholding immunotherapy and initiating steroids. The steroid dosing is based on the degree of severity of that elevation. Again, labs should be monitored closely to ensure LFTs and/or the bilirubin levels are improving. For those with more severe grade 3/4 toxicity, the use of high-dose steroids would be indicated. If a patient does not respond to high-dose steroids within 48 hours, additional immunosuppression with mycophenolate should be considered. Please note that infliximab is not recommended for hepatitis because of additional hepatotoxicity risk in this setting.
Management of irAEs: Pneumonitis
Bethany Withycombe, PharmD, BCOP:
When suspecting pneumonitis, collection of a pertinent patient history is necessary to rule out other causes of new onset or worsening shortness of breath or cough. In our clinic, if a patient presents with these symptoms, the team often conducts a walking and resting pulse oximetry test to see if the patient's oxygen levels drop with activity, as well as imaging of the chest for further evaluation.
The guideline recommendations for the management of pneumonitis differ from the other irAEs we have discussed. Here, grade 1 toxicity itself warrants consideration of holding immunotherapy. For grade ≥2, high-dose steroids should be considered. And of course, for more severe cases, hospitalization should be considered with involvement and guidance from the pulmonary and infectious disease teams.
NCCN Guidelines for Managing Immune Checkpoint Inhibitor–Related Toxicities: An Interactive Decision Support Tool
Bethany Withycombe, PharmD, BCOP:
CCO also has created an Interactive Decision Support Tool application in collaboration with the National Comprehensive Cancer Network for the management of irAEs. You can check this out by going to your cell phone's app store and searching for CCO Decision Support or visiting this link.
Management of Adverse Events as a Team
Bethany Withycombe, PharmD, BCOP:
Management of irAEs is a multidisciplinary team effort to correctly identify, grade, and treat these unique toxicities. As a team, we ensure patients have appropriate supportive care measures in place. We also ensure patients have appropriate follow-up ordered as further escalation of care may be needed pending treatment response.
Future of Immunotherapy in Nonmelanoma Skin Cancers
Zeynep Eroglu, MD:
The treatment landscape for NMSCs is rapidly evolving. In disease states where immunotherapy trials were started earlier, such as in melanoma, there are now FDA-approved anti–PD-1 drugs in the adjuvant setting. We see this for stage IIB/C and III melanomas. Neoadjuvant anti–PD-1 therapies also are being incorporated into clinical trial guidelines, having shown superiority to adjuvant-only approaches. I think we will see the same happen in NMSCs as data from some of the adjuvant and neoadjuvant trials with anti–PD-1/PD-L1 drugs mature, especially in MCC and cSCC. I also think we will see increasing use of immunotherapies in earlier-stage NMSCs. In the metastatic setting, we are looking forward to data with some of the previously mentioned investigational drugs. The data regarding oncolytic viruses are interesting and promising. Studies looking at combinations of immunotherapy with immunomodulatory drugs, those looking at where radiation fits in, and those investigating adoptive cellular therapy can all be potentially exciting findings in the future. There are a lot of new developments in the advanced NMSCs landscape to look forward to.
irAEs Key Takeaways
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