Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity

Area of Science:

• Pharmacogenomics
• Immunology
• Oncology

Background:

• Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is effective for lung cancer.
• Severe hypersensitivity reactions, such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), are common in Asian populations treated with osimertinib, limiting its use.

Purpose of the Study:

• To investigate the genetic human leukocyte antigen (HLA) predisposition and immune pathomechanism underlying osimertinib-induced hypersensitivity.
• To identify specific HLA alleles associated with different severities of osimertinib hypersensitivity.

Main Methods:

• Genotyping of human leukocyte antigen (HLA) alleles in 17 patients with osimertinib-induced hypersensitivity (7 severe SJS/TEN, 10 mild maculopapular exanthema), 98 osimertinib-tolerant subjects, and 2,123 general population controls.
• Performing drug-induced lymphocyte activation tests and surface plasmon resonance assays to assess immune response and drug-protein interactions.

Main Results:

• HLA-B∗51:02 was significantly associated with osimertinib-induced SJS/TEN (83.3% of patients vs. 3.3% of controls; P < 10^-6).
• HLA-B∗51:01 and HLA-A∗24:02 were associated with mild maculopapular exanthema.
• Elevated granulysin levels and positive in vitro lymphocyte activation confirmed SJS/TEN immunopathology. HLA-B∗51:02 showed higher binding affinity to osimertinib.

Conclusions:

• HLA-B∗51:02 is a strong genetic marker for severe osimertinib-induced hypersensitivity (SJS/TEN) in Asian populations.
• Preemptive screening for HLA-B∗51:02 may reduce the incidence of severe adverse reactions to osimertinib.
• Patients with hypersensitivity to osimertinib may tolerate other EGFR-TKIs, and HLA-B∗51:02 has a specific binding affinity for osimertinib.