Abstract
BackgroundAnti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) – that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs.MethodsWe conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Results190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 months vs. 5 months, p < 0.0001; OS, not reached vs. 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development.ConclusionsIn this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms.
Highlights
Programmed cell death protein 1 (PD-1) is a receptor expressed on activated T cells which binds to progressive disease (PD) ligand 1 (PD-L1, B7-H1) and PD ligand 2 (PD-L2, B7-dendritic cells (DCs)) [1,2,3,4]
To describe patterns of multiple Immune-related adverse events (irAE), we evaluated all patients with >1 irAE (N=44) that developed during treatment and/or follow-up period. irAE categories were grouped and betweencategory relationships were considered regardless of number, and/ or temporality and subsequently enumerated
190 patients with advanced/unresectable cutaneous, mucosal, or unknown primary melanoma who met the inclusion criteria were included in the present analysis (119 males, 71 females)
Summary
Programmed cell death protein 1 (PD-1) is a receptor expressed on activated T cells which binds to PD ligand 1 (PD-L1, B7-H1) and PD ligand 2 (PD-L2, B7-DC) [1,2,3,4]. Therapeutic blockade of the PD-1/PD-L1 interaction by immune checkpoint inhibitors (ICI) has transformed the management of advanced melanoma; with objective responses in 35-40% of patients [8, 9], with 35% progression-free at 1-year [10, 11], and 34% alive at 5-years [12]. Immune-related adverse events (irAE) represent a unique spectrum of toxicities observed in patients treated with ICIs targeting cytotoxic T-lymphocyte–associated protein 4 (CTLA4) and PD-1 receptors. IrAE occurrence has been associated with improved outcomes for patients treated with anti-PD-(L) or anti-CTLA-4 ICI primarily in the context of melanoma [15,16,17,18,19], non-small cell lung cancer (NSCLC) [13, 20, 21], and urothelial cancer [19]. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs
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