B.C. Agema1,2, G.D.Veerman1, D.A.C. Lanser1, C.M.J. Steendam3, T.Preijers2, C. Van der Leest4, B.C.P. Koch2, A.C. Dingemans3, R.H.J. Mathijssen1, S.L.W. Koolen1,2
1 Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam. 2 Dept. of Clinical Pharmacy, Erasmus University Medical Center, Rotterdam. 3 Dept. of Pulmonology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, 4 Dept. of Pulmonology, Amphia Hospital, Breda.
Objectives:
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 [1]. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. Given the importance of osimertinib treatment continuation, a preventive dose reduction could avoid severe toxicity for patients with no or minor impairment of treatment effectiveness. We hence 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 cohort study, patients with NSCLC treated with osimertinib were prospectively followed for severe toxicity (grade ≥3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination), progression-free (PFS) and overall survival (OS). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. To quantify individual exposure to osimertinib, a population-pharmacokinetic model was developed. Time to event analysis were performed using univariate and multivariate Cox proportional-hazard models and the Fine & Gray competing risk model. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure-efficacy relationship, defined as PFS and OS.
Results:
In total, 819 samples from 159 patients were included in the analysis with median follow-up of 11.5 months for pharmacokinetic analysis and 10.3 months for severe toxicity. A one-compartment model including inter-individual variability in clearance, with CRP, thrombocyte count, haemoglobin and alkaline phosphatase as covariates explaining variability in clearance best described osimertinib pharmacokinetics. Multivariate competing risk analysis showed osimertinib clearance (c.q. exposure) to be significantly correlated with severe toxicity (HR 0.91, 95% CI 0.83 – 0.99). An ROC-curve showed the optimal toxic limit to be 259 ng/mL osimertinib. This target concentration divides the cohort in two groups: the risk of severe toxicity in the >259 ng/mL group is 34% versus 14% in the <259 ng/mL group. A 50% dose reduction in the high-exposure group – i.e. 25.8% of the total cohort – would reduce the risk of severe toxicity by 53%. Correlation of the first plasma trough concentrations collected in the first two months of treatment, revealed a similar difference in severe toxicity (31% versus 17%), when dividing the cohort in two by the toxic limit of 259 ng/mL osimertinib. Additionally, out of the 21 patients who were dose reduced to 40 mg QD in this study, only three (14%) experienced re-occurrence of severe osimertinib toxicity. Osimertinib exposure was not associated with PFS nor OS.
Conclusions:
Osimertinib exposure is highly correlated with 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.
References:
[1] Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020; 383: 1711-1723.
Reference: PAGE 30 (2022) Abstr 9956 [www.page-meeting.org/?abstract=9956]
Poster: Drug/Disease Modelling - Oncology