Dataset Information

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

ABSTRACT:

Aims

To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters.

Methods

PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF).

Results

A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state.

Conclusions

PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.

SUBMITTER: Brown K

PROVIDER: S-EPMC5427226 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

Brown Kathryn K Comisar Craig C Witjes Han H Maringwa John J de Greef Rik R Vishwanathan Karthick K Cantarini Mireille M Cox Eugène E

British journal of clinical pharmacology 20170206 6

<h4>Aims</h4>To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters.<h4>Methods</h4>PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was u ...[more]

PMID: 28009438

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Project description:BackgroundEpidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.MethodsTumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80?mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.ResultsEGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2?months (95% confidence interval 5.0-12.9?months; range 4.9-14.6?months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.ConclusionsThis study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

Dataset Information

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

Aims

Methods

Results

Conclusions

Publications

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

Similar Datasets

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