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 Blood for pharmacokinetic analyses was withdrawn during every out-patient visit.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.

Keywords: NSCLC; exposure–efficacy relationship; exposure–toxicity relationship; osimertinib; preventive dose reduction.

Figure 1.

Relative operating characteristic (ROC) curve to determine the optimal osimertinib trough level threshold for toxicity.

Figure 2.

Kaplan–Meier estimates of toxicity-free survival. Patients were stratified as having a higher or lower median osimertinib trough concentration compared to the toxic limit of 259 ng/mL.

Figure 3.

Dose reduction effectively lowers osimertinib trough levels. (a) Distribution of osimertinib trough levels in a simulation cohort consisting of 1000 patients. The proposed toxic limit is visualized as a black vertical line (259 ng/mL). (b) Simulated distribution if the proposed 50% dose-reduction is applied for patients who were above the toxic limit in part (a).