WASHINGTON, DC — and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.
“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.
cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.
And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.
A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.
At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.
Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.
The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.
“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.
A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.
“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”
The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.
The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.
Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.
This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.
Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.
Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.