RESUMO
Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.
RESUMO
Current retrospective data have found up to 20% of COVID-19 infection had developed into severe cases with hyperinflammatory pulmonary symptoms. Interleukin 6 (IL-6) is recognized as a key mediator of hyperinflammation previously mentioned in cytokine release syndrome. This leads to implementing IL-6 pathway inhibition in severe COVID-19. This review aimed to explore the clinical evidences of using IL-6 antagonists in COVID-19 infection based on most recent available data. Relevant studies were searched through PubMed, scopus, and ISI databases focusing on interleukin-6 antagonists in cytokine release syndrome and prospective data on COVID-19 infection. Only papers in English were included in the search. There were several studies conducted to evaluate the potential efficacy and safety of IL-6 antagonists and mostly with tocilizumab. After the search, we found that studies recruited patients with severe COVID-19 and elevated inflammatory mediators such as C-reactive protein (CRP), IL-6, or ferritin to receive tocilizumab, situximab or sarilumab in combination with other medications. Result showed that these agents may provide a clinical advantage as patients were able to refrain from invasive ventilation support after initiating IL-6 antagonists. In summary, IL-6 pathway inhibition in severe COVID-19 may be an emerging candidate to subside pulmonary complication. These agents may carry benefits in COVID-19 infection as well as safety risks such as bone marrow suppression. Current pharmacists' role is to provide most recent update information as well as intensive monitoring plan in patients who receive IL-6 inhibitor. However, robust clinical evidences are warranted to confirm efficacy and safety of IL-6 antagonists.
