Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry.

Lina María Serna-Higuita,Claus Garbe,Lukas Flatz,Ulrike Leiter,Andrea Forschner,Olivia Seeber,Thomas Kurt Eigentler,Teresa Amaral,Ioannis Thomas,Peter Martus

doi:10.3390/cancers13236141

Abstract

Simple SummaryNivolumab combined with ipilimumab has improved the prognosis of patients with advanced melanoma. However, this therapy is frequently associated with immune-related adverse events. Published data suggested that objective responses rates appear to be superior in patients who developed immune-related adverse events. The primary aim of this study was to evaluate the association between immune-related adverse events and disease control rate, progressive-free survival, and overall survival in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. In this manuscript, we show that the presence of immune related side effects is related to better overall response and longer survival in patients with advance stage melanoma treated immuno-therapy, suggesting that immune-related adverse events might be a predictive factor of response in those patients.(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23–0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1–2 HRadj: 0.61 95% CI: 0.4–0.93, p = 0.02, irAEs grade 3–4 HRadj: 0.55 95% CI 0.31–0.99, p = 0.04), but not with PFS (irAEs grade 1–2 HRadj: 1.21 95% CI: 0.91–1.79, p = 0.16, irAEs grade 3–4 HRadj: 1.14 95% CI 0.83–2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.

Highlights

Monoclonal antibodies targeting the immune regulatory checkpoint receptors of anti-programmed cell death 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) have significantly improved the prognosis of patients with advanced melanoma [1–4]
We found that the development of immune-related adverse events (irAEs), as expressed by changes in laboratory values, is significantly associated with disease control in patients with stage IV melanoma treated with progressive disease (PD)-1-based immunotherapy indicating that irAEs can be a predictive factor for immune checkpoint inhibitors (ICIs)
The presence of irAEs was positively and significantly associated with disease control (DC) and overall survival (OS). This observation was stable in all the Cox regression models performed

Summary

Introduction

Monoclonal antibodies targeting the immune regulatory checkpoint receptors of anti-programmed cell death 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) have significantly improved the prognosis of patients with advanced melanoma [1–4]. Though the introduction of ICI improved the prognosis of patients with metastatic melanoma, this therapy is frequently associated with immune-related adverse events (irAEs) [8,10–12]. This can be explained as the ICIs play a role in maintaining immune homeostasis and preventing autoimmunity, their inhibition leads to increased activity of the immune system, resulting in a variety of irAEs that resemble autoimmune diseases in their clinical presentation [6,8,10–15]. These irAEs can involve any organ or tissue [16], ranging from mild to life-threatening toxicity [17]. The most commonly irAEs reported are rash, vitiligo, colitis, pneumonitis, hepatitis, thyroiditis, nephritis, and hypophysitis [13,18,19], leading to ICIs discontinuation in approximately 10–20% of patients [16]

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