Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Key Points

Question

What is the association between immune-related adverse events (irAEs) and survival after immune checkpoint inhibitor (ICI) therapy initiation and human leukocyte antigen genes in patients with advanced malignant melanoma?

Findings

In this case-control study of 132 adults with advanced malignant melanoma treated with ICIs, patients with irAEs had improved treatment response rates and better survival. Distinct HLA-DR alleles were associated with specific irAEs.

Meaning

These findings suggest that the occurrence of irAEs after ICI therapy in patients with advanced melanoma is associated with improved treatment response, survival, and certain HLA-DR alleles.

Abstract

This case-control study examines the association between development of immune-related adverse events (irAEs) and response to therapy, survival, and human leukocyte antigen (HLA) class II genes in patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs).

Abstract

Importance

Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)–DR alleles in conferring irAE risk has not been well studied.

Objective

To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma.

Design, Setting, and Participants

This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis.

Exposures

Immune checkpoint inhibitors (anti–cytotoxic T-lymphocyte antigen 4, anti–programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma.

Main Outcomes and Measures

The association between irAEs and response to therapy, survival, and HLA-DR alleles.

Results

Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4.

Conclusions and Relevance

These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.