Compared with earlier epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib delivers superior therapeutic activity and produces fewer grade 3 or higher adverse drug reactions (ADRs) in individuals with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations. Nonetheless, treatment responses to this agent have been shown to differ among ethnic groups. For this reason, additional investigation is required to determine how single-nucleotide polymorphisms (SNPs) within cytochrome P450 (CYP450) enzymes and transporter genes may influence therapeutic outcomes and ADR profiles among Thai recipients of osimertinib, with the aim of improving individualized cancer therapy. In this observational cohort incorporating retrospective and prospective data, 63 Thai NSCLC patients were treated with osimertinib monotherapy at a daily dose of 80 mg. Each subject was genotyped for seventeen SNPs within genes implicated in metabolism or transport of the drug. Chi-square and Fisher’s exact tests were applied to examine associations between genetic variants and clinical endpoints such as ADR occurrence and objective response rate (ORR). Additionally, Kaplan–Meier curves with log-rank analyses were used to explore links between genotype and median time to treatment failure (TTF) or progression-free survival (PFS).
Six genetic markers—rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and the CYP2A6 deletion allele (CYP2A64)—were found to significantly elevate ADR frequency. Two variants, rs2069514 in CYP1A2 and rs1057910 in CYP2C9, were connected with shorter median TTF, while rs28399433 in CYP2A6 and rs1057910 in CYP2C9 were associated with reduced median PFS. Notably, rs1057910 in CYP2C9 had simultaneous effects on ADR risk, TTF, and PFS. Furthermore, carriers of the CYP2A6 heterozygous non-4/*4 genotype demonstrated a markedly increased incidence of ADRs and exhibited a 27.0% rate of dose reduction. The study identified several SNPs that correlate with heightened ADR occurrence as well as diminished PFS and TTF in Thai NSCLC patients receiving osimertinib. The allele distributions of CYP2C9 (*3) and CYP2A6 (*4) differed from those seen in other populations and were linked to elevated ADR rates. These data emphasize the relevance of pharmacogenetic variability in NSCLC management and may support more personalized therapeutic strategies. Additionally, the incidence of ADRs and the frequency of dose modification exceeded those described in major trials such as FLAURA, AURA2, and AURA3, potentially reflecting genetic distinctions among populations.
