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

• Published in: The journal of allergy and clinical immunology in practice (Cambridge, MA) Vol. 13; no. 1; p. 143
• Main Authors: Chen, Chun-Bing, Wang, Chuang-Wei, Lu, Chun-Wei, Chen, Wei-Ti, Zhou, Bing-Rong, Chu, Chia-Yu, Hsu, Shang-Fu, Yang, Cheng-Ta, Wen-Cheng Chang, John, Yang, Chan-Keng, Wang, Chih-Liang, Fang, Yueh-Fu, Hsu, Ping-Chih, Hua, Chung-Ching, Wu, Chiao-En, Ko, How-Wen, Chen, Kun-Chieh, Yang, Yi-Chien, Tseng, Han-Chi, Cheng, An-Yu, Tseng, Li-Chuan, Shih, Feng-Ya, Hung, Shuen-Iu, Huang, Cheng-Yang, Chung, Wen-Hung
• Format: Journal Article
• Language: English
• Published: United States 01.01.2025
• Subjects: Acrylamides - adverse effects; Adult; Aged; Aged, 80 and over; Alleles; Aniline Compounds - adverse effects; Antineoplastic Agents - adverse effects; Drug Hypersensitivity - diagnosis; Drug Hypersensitivity - genetics; Female; Genetic Predisposition to Disease; Genotype; HLA-B Antigens - genetics; Humans; Indoles; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lymphocyte Activation; Male; Middle Aged; Protein Kinase Inhibitors - adverse effects; Pyrimidines; Stevens-Johnson Syndrome - genetics; Stevens-Johnson syndrome; Toxic epidermal necrolysis; Osimertinib; HLA-B∗51:02; Hypersensitivity
• ISSN: 2213-2201
• DOI: 10.1016/j.jaip.2024.10.027

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. We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity. 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. 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 ; corrected P = 6.9 × 10 ; odds ratio [OR] = 146), and 0% of osimertinib-tolerant controls (P = 6.5 × 10 ; corrected P = 1.6 × 10 ; 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. 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.