Dr. Misha Rosenbach discusses identifying and managing the broad range of cutaneous side effects from checkpoint inhibitors used to treat skin cancers and other malignancies.
Misha Rosenbach, MD, is Associate Professor of Dermatology and Internal Medicine, at the University of Pennsylvania Department of Dermatology, Philadelphia, Pennsylvania .
“Checkpoint inhibitors cause dermatology,” said Misha Rosenbach, MD, who presented “Immune Checkpoint Inhibitor-induced Autoimmunity” at Masterclasses in Dermatology 2022.
“These are drugs that dermatologists have been loosely familiar with over the past decade. Originally these cancer agents were developed and approved for treatment of advanced stage melanoma.”
Checkpoint inhibitor medications as a category include CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors, said Dr. Rosenbach.
“These drugs basically work by unleashing the immune system. For melanoma patients, they are transformative.”
For skin cancers alone, immune checkpoint inhibitors and combination therapies with the inhibitors have been approved for melanoma, squamous cell carcinoma, and Merkel cell carcinoma. Trials are underway for use of the drugs in basal cell carcinoma, cutaneous T-cell lymphoma, and other rare cutaneous neoplasms, said Dr. Rosenbach.
“These are drugs that dermatologists will see used to treat their patients with advanced disease. But also, these drugs are being studied for just about every type of malignancy, so the other part of this is you’ll see increasing numbers of trials with monotherapy and combination therapies for increasing numbers of tumors and with increasing numbers of medication approvals,” said Dr. Rosenbach.
Cutaneous AEs are Common
Patients treated with immune checkpoint inhibitors commonly experience immune-related cutaneous adverse events, according to Dr. Rosenbach.
“It’s not just a rash or one skin reaction or one pattern of eruption, but the patients who get checkpoint inhibitors get a lot of side effects and get a lot of skin side effects.”
Studies suggest more than 50% to nearly 90% of patients experience some sort of immune-related adverse event, according to Dr. Rosenbach.
“The skin is very commonly impacted. Depending on which drug and which combination, sometimes a quarter to almost 50% of patients will develop some sort of skin immune-related adverse event, and the skin involvement can precede other organ involvement.”
There are two things that are important for dermatologists to know, according to Dr. Rosenbach: “… one, immune-related adverse events from checkpoint inhibitors can cause a wide range of eruptions. Two, that might have … prognostic implications, and that’s really important for patients who are undergoing treatment for malignancies with these agents.”
Patients undergoing cancer treatment often are medically complicated and seeing a skin reaction can be scary to the patient and oncologists, according to Dr. Rosenbach.
“So, it’s important that dermatologists help make themselves available to help co-manage these patients and are available to see these patients quickly,” he said.
Whereas oncologists may be inclined to reach for systemic corticosteroids, dermatologists, with more focus on management of skin disease, have a variety of safer, more effective tricks up their sleeves for treating some of the more common reactions from checkpoint inhibitors, including eczematous reactions, pruritic eruptions, and xerosis, said Dr. Rosenbach.
Types of Skin Reactions
Some of the more common cutaneous reactions from immune checkpoint inhibitors are morbilliform, or maculopapular reactions; itchiness or just pruritus; xerosis; psoriasiform rashes; eczematous rashes; and lichenoid reactions. Uncommon reactions may include diseases such as bullous pemphigoid, vitiligo-like depigmentation, or alopecia areata, according to Dr. Rosenbach.
“Importantly, these drugs can also cause rare, severe reactions. You can get an intense … blistering that can resemble Stevens-Johnson syndrome. You can get a drug reaction with eosinophilia and systemic symptoms (DRESS) spectrum reaction; vasculitis, diseases similar to idiopathic connective tissue diseases; granulomatous reactions; and more.”
Vitiligo is one of the more interesting reactions, according to Dr. Rosenbach.
“Patients who have advanced melanoma and are getting treated with checkpoint inhibitors sometimes will develop incidental disappearance of some other pigmented lesions…. At least in melanoma patients getting checkpoint inhibitors, when they develop some of these disease reactions, in particular when they develop vitiligo, it seems to portend a better response and better outcomes.”
“Some of the more robust reactions, like lichenoid reactions, blistering eruptions or in some small studies psoriasiform eruptions, may be an indicator of potentially better treatment response. And these reactions don’t necessarily happen immediately. It can be 4 to 14 days for a morbilliform reaction, or on the order of weeks to months for some severe reactions,” said Dr. Rosenbach.
“There are also some studies to suggest that, if you biopsy [checkpoint inhibitor reactions] at one time point, you can see what looks like lichenoid dermatitis. But, if the rash persists and progresses over time, in some cases their clinical and pathologic picture might progress to look more like a true connective tissue disease like subacute cutaneous lupus.”
According to Dr. Rosenbach, key articles can help dermatologists to become familiar with adverse events caused by immune checkpoint inhibitors,1 as well as treatments.2
“I think [Nadelmann et al. is] a really nice reference for dermatologists to be aware of because it walks through what oncologists are thinking about in terms of management of these different reactions and when dermatologists should get involved. Notably for us, if you look at that table, it says ‘consult dermatologist’ for almost every reaction unless it’s super mild.”
Treatment Take-Homes
Almost any rash can be attributed to a checkpoint inhibitor, and it can occur quickly or be a delayed response. Studies are just beginning to show which reactions occur at which timepoints, according to Dr. Rosenbach.
“What’s really exciting about the future for our field is that some of the work that is being done–instead of broadly using corticosteroids for the entire immune response–if we see a specific cutaneous reaction, we might soon use our dermatology skills to initiate therapy with a specific targeted inhibitor for that response. Though, this is not yet the approach, it’s exciting to think about the future of less toxic, more targeted, supportive oncodermatology.”
Should you stop a checkpoint inhibitor in a cancer patient because of cutaneous reactions? Not necessarily, said Dr. Rosenbach.
“First, try to suss out, is this reaction related to the drug or something else? Second, you should try to say, does this reaction portend something? Is it a sign of their immune system turning on?”
If so, have a conversation with the patient’s oncologist about the benefits, risks and alternatives, said Dr. Rosenbach.
“Patients undergoing treatment for cancer have a problem list that goes: cancer, cancer, cancer… then rash; our job is to help the patient and the oncologist best manage the whole case.”
Disclosures: Dr. Rosenbach reports no relevant disclosures.
References:
- Quach HT, Johnson DB, LeBoeuf NR, Zwerner JP, Dewan AK. Cutaneous adverse events caused by immune checkpoint inhibitors. J Am Acad Dermatol. 2021;85(4):956-966. doi:10.1016/j.jaad.2020.09.054.
- Nadelmann ER, Yeh JE, Chen ST. Management of Cutaneous Immune-Related Adverse Events in Patients With Cancer Treated With Immune Checkpoint Inhibitors: A Systematic Review. JAMA Oncol. 2022;8(1):130–138. doi:10.1001/jamaoncol.2021.4318.