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. 2025 Jan;13(1):143-154.e10.
doi: 10.1016/j.jaip.2024.10.027. Epub 2024 Nov 4.

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

Chun-Bing Chen  1 , Chuang-Wei Wang  2 , Chun-Wei Lu  3 , Wei-Ti Chen  4 , Bing-Rong Zhou  5 , Chia-Yu Chu  6 , Shang-Fu Hsu  7 , Cheng-Ta Yang  8 , John Wen-Cheng Chang  9 , Chan-Keng Yang  9 , Chih-Liang Wang  10 , Yueh-Fu Fang  8 , Ping-Chih Hsu  8 , Chung-Ching Hua  11 , Chiao-En Wu  9 , How-Wen Ko  12 , Kun-Chieh Chen  13 , Yi-Chien Yang  14 , Han-Chi Tseng  14 , An-Yu Cheng  14 , Li-Chuan Tseng  15 , Feng-Ya Shih  15 , Shuen-Iu Hung  16 , Cheng-Yang Huang  17 , Wen-Hung Chung  18
Affiliations

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

Chun-Bing Chen et al. J Allergy Clin Immunol Pract. 2025 Jan.

Abstract

Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment.

Objective: We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity.

Methods: We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (seven with severe SJS/TEN and 10 with mild maculopapular exanthema), 98 osimertinib-tolerant subjects, and 2,123 general population controls. We performed HLA genotyping, drug-induced lymphocyte activation test, and surface plasmon resonance assay.

Results: HLA-B∗51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but in only 3.3% of the general population controls (P = 2.8 × 10-7; corrected P = 6.9 × 10-6; odds ratio [OR] = 146), and 0% of osimertinib-tolerant controls (P = 6.5 × 10-8; corrected P = 1.6 × 10-6; OR = 707). The association of HLA-B∗51:01 and HLA-A∗24:02 with osimertinib-induced maculopapular exanthema patients, rather than with osimertinib-tolerant subjects (P = .002, OR = 15.7 for HLA-B∗51:01; and P = .003, OR = 9.5 for HLA-A∗24:02), was identified as a phenotype-specific association. Granulysin, the SJS/TEN-specific cytotoxic protein, was significantly higher in plasma of SJS/TEN patients (39.8 ± 4.5 ng/mL; P < .001) and in in vitro lymphocyte activation test (sensitivity = 83.3%; P < .01) compared with tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. Surface plasmon resonance results also confirmed that HLA-B∗51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs.

Conclusions: HLA-B∗51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B∗51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity.

Keywords: HLA-B∗51:02; Hypersensitivity; Osimertinib; Stevens-Johnson syndrome; Toxic epidermal necrolysis.

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