Q: Can you give us a little background about dermatologic side effects from immunotherapies?
A: Dermatologic adverse events to immunotherapies are of topmost importance because they are usually the first to appear, within approximately 3 weeks of the patient starting therapy. They are also among the most common: about 30% to 40% of all patients treated with immunotherapies will develop some type of dermatologic side effect. Some of the most common include rash, itching, skin color changes, and hair loss. However, the most common, by far, are itching of the skin without presence of a rash and rashes that can present in various ways. These generally occur within the first couple of months, but they can occur at any time during immunotherapy treatment, even years after the patient has finished therapy.
Q: How are patients best monitored for immunotherapy treatment–induced dermatitis?
A: It’s important to ask patients if they have any preexisting skin conditions, because any conditions that are considered to be immunologic in origin may be exacerbated by immunotherapy treatment. These include psoriasis, eczema, atopic dermatitis, vitiligo, and alopecia areata—any immune-mediated skin disease. It is important to have a dermatologist on the multidisciplinary care team, if possible, to closely follow the patient.
In almost every case, you can still treat a patient who has lung cancer and a co-existing skin disease with immunotherapy, even if the comorbid skin condition predated the cancer diagnosis. You should be able to mitigate or manage most skin diseases so that patients can receive the precise immunotherapy needed. Sometimes an oncologist refers a patient to me who has psoriasis, for example, and asks whether this patient can receive immunotherapy. In the great majority of these cases, the skin diseases will not be fatal, but the cancer could be fatal. So I, as the dermatologist, can deal with this skin condition, and the oncologist, who is the treating physician, can continue the treatment, which is, of course, the most important determinant of the patient’s overall survival.
It is also important when patients are starting therapy to counsel them against excessive sun exposure, because any inflammatory condition, like a sunburn, will be a lot worse while they are on active immunotherapy. Gentle skincare is also important—fragrance-free detergents and soaps, protective clothing, sunscreen when outside, and so on. In addition, it is very important for physicians and patients to have good communication and that patients raise a red flag as soon as he or she experiences itching or rash; oncologists should also be sure to ask about itching or rash that might have occurred between visits.
Q: In your experience, how do immunotherapy-related rashes or dermatitis differ from skin conditions associated with other treatments such as the EGFR TKIs?
A: In the lung cancer realm, we have been accustomed to acneiform rash as an adverse event associated with of treatment with EGFR inhibitors. Although immunotherapies can cause an acneiform rash, this happens very infrequently. The acneiform rash usually affects the face and chest, whereas the immunotherapy rashes affect mainly the trunk and extremities. In addition, immunotherapy rashes differ in appearance from acneiform—they present more like psoriasis, like eczema, or like hives.
Q: How often do you see the scalp involved?
A: We see it mostly when it is itching. One of the most common side effects, and to me, one of the most interesting, with immunotherapies is the itching, because there is no rash. Patients are very bothered, even unable to sleep, because of this itch. It is very hard for most of us to empathize with that, as opposed to when someone complains of pain, to which we can all relate. Most oncologists do not have access to specific treatments for this side effect, so they are at a loss for what to do. This is one of the most unique side effects, but in dermatology, we do have tools that can be effective for this.
Q: What tools, and what would be the optimal therapeutic approach?
A: In general, for grade 1 or 2 rashes, high-potency, topical steroids are used—strong topical steroids, not an over-the-counter solution. It is important to keep in mind that many of these steroids come in 30-gram or 60-gram tubes, which is like a small tube of toothpaste. However, the patient may have a rash covering her entire back, so the entire prescription is used in one application. It is important for the primary oncologist to work closely with the pharmacist or dermatologist on the multidisciplinary care team to ensure that the appropriate volume of cream is provided to the patient.
We also know that lung cancer incidence is greater in men than in women (although incidence rates are increasing in women). I find that many men have never applied a cream or a topical medication to their bodies in their entire lives. When they are told they need to apply a cream all over their backs, chests, and arms twice a day, they may not want to do it. As an alternative, some topical steroids are now available as a spray. It takes the patient only 10 or 20 seconds to apply and often this formulation leads to better adherence. For grade 2 rashes, we also might prescribe oral medications. For itching, I would use either antihistamines or GABA agonists. In addition, drugs like pregabalin have been shown to be superior to antihistamines for the control of severe itch.1
For grade 3 rashes, of course, oral steroids are often effective—for example, prednisone at approximately 0.5 to 1 mg/mg/kg per day, tapered over a course of 4 weeks. However, if the rash recurs after that, you should consider using a steroid-sparing agent, usually a biologic agent. Just as in oncology there are biologic therapies that target, for example, PD-1 or CTLA-4, in dermatology there are antibodies to block cytokines that contribute to inflammatory skin diseases. It would be difficult for an oncologist to become familiar with all of those agents, so that is where a dermatologist can play a role.
We treat conditions according to the way they look—we treat them based on their phenotype—and this has proven effective in most cases. For example, if the patient has a psoriasis-like, grade 3 rash, we treat them with any of the biologics that are approved for psoriasis. If it looks like eczema, we treat it as such, and so forth. For something like severe pruritus, omalizumab could be used. This agent is approved for hives and itch and was also shown to be effective in approximately two-thirds of patients with immunotherapy-related pruritus.2
Q: When someone presents with a dermatologic condition years after immunotherapy, would the condition be treated in the same way?
A: A recent paper showed that the most common conditions that appear later are alopecia areata, an autoimmune type of hair loss; the itching that we discussed; and vitiligo. Another condition that commonly appears later is an autoimmune blistering disorder that attacks a protein in the base of the skin, causing the skin to bubble up. It can be quite bothersome, but we have good treatments for it—again, usually steroids and biologic agents.
Q: In your opinion, are there certain treatments that are underutilized, or treatments in the pipeline that look promising?
A: I think one of the most underutilized treatments are GABA agonists for pruritus—pregabalin, for example. In randomized studies, pregabalin has been shown to be the most effective agent for patients suffering from uremic pruritus, an itching caused by chronic kidney disease. When the dermatology community was unsure about optimal management for the itching caused by immunotherapy, we looked to the pregabalin research. Unfortunately, many agents that have yielded success for conditions similar to immunotherapy side effects are off patent, or generic, so it is difficult to get industry-supported research data to see how well they work for this particular population of patients. Also promising are biologics, such as omalizumab, which is approved for hives. We have found it to be effective for the pruritus as well. Many biologics have been approved for psoriasis, and we use them in patients that have a psoriasis-type rash. Dupixent is another valuable biologic, approved for eczema in children as young as 6 years of age. So all these biologic drugs used in the non-cancer population are very effective for skin conditions in the cancer population as well.
Q: Are there any tips or pearls for oncologists who have not yet encountered dermatologic side effects from immunotherapy?
A: It is helpful to ask patients to take pictures of a rash when they first notice it so that they can send it to their oncologist, who can forward the pictures to a dermatologist. The dermatologist can help assess the nature of the rash but also whether the patient should be seen immediately or deferred for a week or two.
I would say again that because most dermatologic conditions are not life-threatening but, unfortunately, a substantial number of lung cancers are, there is very rarely sufficient reason as to why a patient could not continue their immunotherapy when they have a skin reaction. So always consult with the dermatologist before deciding to stop an immunotherapy because of a skin disorder. If you are not convinced, consider consulting with another dermatologist who may be more familiar with these conditions, as not every dermatologist will have experience working with patients on immunotherapy.
In my opinion, oncologists are probably the specialists who have the most diverse knowledge in medicine; they have to understand not only cancer but every organ system because of the complex array of adverse events associated with cancer therapies. Because not every multidisciplinary team includes a dermatologist, oncologists would be ideally positioned to learn about the specialized medicines used to treat these disorders and implement them when necessary.
- 1. Phillips GS, Wu J, . Hellmann, MD, et al. Treatment Outcomes of Immune-Related Cutaneous Adverse Events. J Clin Oncol. 2019;37(30):2746-2758.
- 2. Barrios DM, Phillips GS, Geisler AN, et al. IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies. Ann Oncol. 2021;32(6):736-745.
