Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jonathan S. Leventhal

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in the field of oncology due to their effective antineoplastic properties for various cancers. Though revolutionary in cancer treatment, their use is limited by various immune-related adverse events (irAE). Cutaneous immune-related adverse events (cirAE) are the most common type of irAE and encompass a spectrum of dermatological manifestations. These include lichenoid reactions, psoriasiform eruptions, eczematous dermatitis, immunobullous disorders, granulomatous reactions, pruritus (with or without a primary eruption), vitiligo, and severe cutaneous adverse reactions such as Stevens–Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

The standard approach in the treatment of high-grade or refractory cutaneous immune-related adverse events often involves high-dose systemic corticosteroids. However, systemic corticosteroid use can lead to the potential disruption of antitumor responses and has associated medical complications. To address this, corticosteroid-sparing targeted immunomodulators have been explored as therapeutic alternatives. Biologic agents have been commonly utilized for non-cutaneous immune-related adverse events, such as immunotherapy-induced colitis. As such, these agents are being investigated in treating various patterns of cutaneous immune-related adverse events. Biologics have been increasingly recognized as effective in the management of cirAE; however, more data is needed to establish the efficacy and safety of these agents. Safety regarding oncologic outcomes is of particular importance, as further research is necessary to explore biologic therapy’s long-term effects on antitumor responses.

In this thesis, our primary aim was to perform a comprehensive literature review to characterize the use of biologic agents in the management of different cutaneous immune-related adverse event patterns. Our second aim was to describe the efficacy and safety of cirAE treated with biologic agents in our own cohort at the Yale Oncodermatology Clinic. Finally, our third aim was to evaluate tumor response and oncologic safety in this same cohort at the Yale Oncodermatology Clinic.

In the first aim, our literature review consolidates all cirAE treated with biologic therapy from the English-language literature on PubMed. For our second and third aims, the retrospective case series includes patients with an ICI-associated cirAE treated with a biologic agent at the Yale Oncodermatology Clinic. All data collection was performed manually given the lack of accurate and standardized classification codes for the various cirAE. All data was recorded in a secure Yale Box folder. Descriptive analyses and basic statistics were performed using Microsoft Excel Version 16.92.

Aim 1 (Literature Review): Overall, 163 out of 183 (89.1%) cases in the literature of cirAE with a reported response to biologic agents had at least a partial response. In many cases, biologic therapy often led to a complete or near-complete resolution of cirAE in our study.

Aim 2 (Retrospective Case Series – Biologic Efficacy and Safety): Of patients treated at the Yale Oncodermatology Clinic, 26 patients were included in the cohort based on inclusion criteria of having an ICI-associated cirAE with subsequent treatment with biologic therapy. All 26 (100.0%) patients exhibited at least a partial response of their cirAE to biologic therapy, and 17/26 (65.4%) patients exhibited a complete response. No adverse events from biologic therapy were reported.

Aim 3 (Retrospective Case Series – Oncologic Outcomes): Of the patients treated at the Yale Oncodermatology Clinic, ICI therapy was disrupted in most cases (20/26 patients, 76.9%) due to cirAE severity. Most patients (11/20, 55.0%) were able to resume ICI therapy while their cirAE remained controlled on biologic therapy, with all patients (26/26, 100%) exhibiting at least partial clinical response to therapy. 16 patients (62%) experienced no progression of oncologic disease, while 10 patients (38%) had progression of disease while on biologic therapy.

Given that ICIs will continue to be increasingly employed for various malignancies, it is of utmost importance to manage cirAE effectively and explore the use of biologic therapy as a steroid-sparing alternative for this patient population.

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This is an Open Access Thesis.

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