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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Exposure-response modelling of osimertinib in patients with non-small cell lung cancer
Martin Johnson1, Yu-Wei Lin2, Henning Schmidt3
1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Science, R&D, AstraZeneca, Cambridge, UK.
Aims:
Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events.
Methods:
Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis.
Results:
E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control.
Conclusions:
E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.
Insights
Higher osimertinib exposure in EGFR-mutated NSCLC patients did not improve efficacy but may increase adverse events like ILD, rash, and diarrhea. Doses of 80mg or higher are unlikely to offer additional benefit.
Area of Science:
- Oncology
- Pharmacology
- Clinical Medicine
Background:
- Osimertinib is an effective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for EGFR-mutated non-small cell lung cancer (NSCLC).
- Understanding the exposure-response relationship is crucial for optimizing treatment and managing adverse events.
Purpose of the Study:
- To assess the relationship between plasma osimertinib levels and its efficacy in EGFR-mutated NSCLC.
- To evaluate the association between osimertinib exposure and safety events, including interstitial lung disease (ILD), left ventricular ejection fraction (LVEF) events, rash, and diarrhea.
Main Methods:
- Comprehensive pharmacokinetic exposure-response (E-R) modeling using steady-state area under the curve (AUCss) data from 1689 patients across various treatment lines.
- Survival analysis using proportional hazard models.
- Analysis of ILD and LVEF events using penalized logistic regression and graphical methods.
- Descriptive analysis for rash and diarrhea events.
Main Results:
- No clear trend of increased efficacy with higher osimertinib AUCss was observed; efficacy was superior to control across all exposure quartiles.
- A potential relationship between increased osimertinib exposure and higher probability of ILD events was identified, particularly in Japanese patients.
- Increased probabilities of rash and diarrhea were associated with higher osimertinib exposure.
- LVEF event probabilities showed overlapping confidence intervals between osimertinib ≤80mg and control.
Conclusions:
- Exposure-response modeling indicates that higher osimertinib exposure does not enhance efficacy in EGFR-mutated NSCLC.
- Increased osimertinib exposure may be linked to a higher occurrence of adverse events such as ILD, rash, and diarrhea.
- Long-term treatment with osimertinib doses ≥80mg is unlikely to provide additional therapeutic benefit and may increase risks.
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