Improving the tolerability of osimertinib by identifying its toxic limit

Abstract

Background: Osimertinib is the cornerstone in the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer (NSCLC). Nonetheless, ±25% of patients experience severe treatment-related toxicities. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. Therefore, we aimed to study the relationship between osimertinib exposure and severe toxicity and to identify a safe toxic limit for a preventive dose reduction. Methods: In this real-life prospective cohort study, patients with NSCLC treated with osimertinib were followed for severe toxicity (grade ⩾3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure–efficacy relationship, defined as progression-free survival (PFS) and overall survival (OS). Results: In total, 819 samples from 159 patients were included in the analysis. Multivariate competing risk analysis showed osimertinib clearance ( c.q. exposure) to be significantly correlated with severe toxicity (hazard ratio 0.93, 95% CI: 0.88–0.99). An relative operating characteristic curve showed the optimal toxic limit to be 259 ng/mL osimertinib. A 50% dose reduction in the high-exposure group, that is 25.8% of the total cohort, would reduce the risk of severe toxicity by 53%. Osimertinib exposure was not associated with PFS nor OS. Conclusion: Osimertinib exposure is highly correlated with the occurrence of severe toxicity. To optimize tolerability, patients above the toxic limit concentration of 259 ng/mL could benefit from a preventive dose reduction, without fear for diminished effectiveness.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study

“…Albumin level was identified as a significant covariate for the clearance of the parent compound and AZ5104 (positive correlation), consistent with a previous report [ 29 ]. C-reactive protein (CRP) is a covariate of osimertinib clearance [ 21 ]. Decrease in albumin level and an increase in CRP level occur during inflammation, which can decrease CYP3A4 activity [ 30 – 32 ].…”

“…Funding This work was supported by the Research Foundation for Pharmaceutical Sciences, the Japan Research Foundation for Clinical Pharmacology (grant number 2018A20), JST SPRING (grant number JPMJSP2123), and the Keio University Doctorate Student Grant-in-exposure to osimertinib and efficacy, dose reduction up to 50% of mean exposure may be considered for patients experiencing AEs and high AUC 0-24 levels; however, further validation is needed [11,21,40,42].…”

“…While there have been reports on the association between exposure to osimertinib parent compound and its efficacy/ safety [11,21], no studies have explored the relevance of monitoring the two active metabolites of osimertinib for AE management. Additionally, germline polymorphisms in EGFR, ABCG2, ABCB1, or POR have a significant impact on the AEs of first-and second-generation EGFR-TKIs [13][14][15][16][17][18][19][20], but those of osimertinib have not been investigated.…”

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer

“…Agema et al reported 259 ng/ml as the osimertinib dose limit for toxicity in a prospective observational study of 159 patients with NSCLC in Netherlands (26). Major adverse events such as skin toxicities, creatinine kinase elevation, and pneumonia were significantly higher in patients with plasma osimertinib concentrations of >259 ng/ml; however, the authors did not observe a difference in efficacy possibly because the plasma osimertinib concentrations exceeded 211 ng/ml in most patients.…”

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

“…A more general approach, of boosting osimertinib exposure purely based on the plasma trough concentration, to improve osimertinib effectiveness is less evident, as a definitive exposure-response relation seems absent for osimertinib. Especially boosting in patients with initially high osimertinib exposure may be less ideal, as it could this could lead to a higher level of toxicity (≥259 ng/mL) [27]. However, inhibiting CYP3A-activity could theoretically increase the anti-tumor activity of osimertinib, as intratumoral CYP3A activity would be inhibited, which is increased in NSCLC-patients [28].…”