Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the last decade. Despite the efficacy of ICIs, immune-related adverse events (irAEs) occur in over a third of treated patients and can cause lasting morbidity and mortality.1–3 Cutaneous irAEs (cirAEs) are the most frequently reported toxicities, occurring in 20–40% of treated patients. Though recent reports have investigated the prognostic significance of irAEs on cancer outcomes, little is known about the specific impact of cirAEs and their subtypes on cancer survival.4 In this landmark analysis, we present the first population-level study examining the influence of cirAE development following ICI therapy on the mortality of cancer patients.
Methods 7,008 patients who developed cirAEs after treatment with anti-programmed cell death receptor/ligand 1 (PD-1/PD-L1) therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract were identified through the TriNetX Diamond network along with 7,008 matched controls (table 1). The malignant neoplasms and cutaneous diagnoses for this study were identified from published literature and expert opinion.5 6 Looking at cutaneous eruptions within 6 months of the first instance of ICI administration, a 6-month landmark analysis using a Cox proportional hazards model was performed to determine the impact of cirAE on overall survival.
Results Presence of any cirAE (HR=0.695, p<0.0001), nonspecific rashes (HR=0.704 , p<0.0001), pruritus (HR=0.695, p<0.0001), drug eruption (HR=0.755, p=0.0013), and xerosis (HR=0.626, p=0.0013) were significantly protective of mortality using a Benjamini-Hochberg (BH) correction for multiple comparisons (table 2). Psoriasis (HR=0.703, p=0.0451) and lichen planus/lichenoid dermatitis (HR=0.511, p=0.0274) were nominally significant. Notably, though not reaching statistical significance, eczematous dermatitis (HR=0.0.612), vitiligo (HR=0.534), bullous pemphigoid (HR=0.524), and Grover's disease (HR=0.468) were associated with strong protective clinical effects. To explore the impact of landmark time on mortality, a sensitivity analysis was performed for cirAE onset within 3 months (HR=0.759, p<0.0001) and 9 months (HR=0.84, p<0.0001) of ICI initiation. A separate sensitivity analysis expanded to include all cancer types treated with ICI yielded similar results, with additional statistical significance reached for ICI-induced psoriasis (table 3).
Conclusions This is the first population-level study and largest analysis to date of the impact of cirAEs on mortality among patients with advanced cancer. With the exception of mucositis and hyperhidrosis, there was a strong clinically protective effect of cirAEs across all individual morphologies investigated. Our results demonstrate that cirAE development after ICI initiation is an important positive prognostic indicator of response to ICI therapy and patient survival.
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Wongvibulsin S, Pahalyants V, Kalinich M, et al. Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune checkpoint inhibitors: A United States population-level analysis. J Am Acad Dermatol. Published online 2021:1–10. doi:10.1016/j.jaad.2021.03.094.
Kalinich M, Murphy W, Wongvibulsin S, Pahalyants V, et al. Prediction of severe immune-related adverse events requiring hospital admission in patients on immune checkpoint inhibitors: study of a population level insurance claims database from the USA. J Immunother Cancer. 2021;9(3):e001935. doi: 10.1136/jitc-2020-001935. PMID: 33789879; PMCID: PMC8016099.
Ethics Approval Study utilized de-identified data from a multi-institutional registry and is exempt from IRB approval.
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