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M. Nakashima
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-013 - Association of PK/PG with Toxicity of Gefitinib in Patients with Advanced NSCLC (ID 150)
09:30 - 09:30 | Author(s): M. Nakashima
- Abstract
Background:
Gefitinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and is a key drug for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation. The orally administered gefitinib showed large interindividual variability in its pharmacokinetics. Some phase I studies have suggested there is a relationship between gefitinib plasma concentration and skin toxicity, diarrhea, and liver toxicity. The aim of this study was to evaluate the association of pharmacokinetics or pharmacogenomics with toxicity or effectiveness of gefitinib in patients with advanced NSCLC.
Methods:
The evaluation of pharmacokinetics was performed using sample obtained on day 1 at 0, 1, 3, 5, 8, 24 hour and day 8 and day 15 after start of gefitinib 250mg administration. Plasma concentration of gefitinib was analyzed by high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, ABCC2, CYP3A4, CYP3A5, CYP2D6 were analyzed by direct sequencing.
Results:
Thirty-five patients with advanced NSCLC (14 men and 21 women; median age, 72 years; range, 53 to 90 years) were enrolled. All patients were stage IV adenocarcinoma harboring EGFR mutation: 18 had exon 19 deletions, 16 had exon 21 L858R, and 1 had exon 18 G719A. The overall response rate was 82.9% (95% confidence interval 66.4-93.4%). The median survival time was 21.2 months, and the median progression-free survival time was 10 months. The common adverse events were rash or acne (68%), diarrhea (46%), and liver injury (63%). One patient died of drug induced interstitial lung disease (ILD). The median area under the plasma concentration-time curve of gefitinib estimated from 0 to 24 hour (AUC0-24) was 10.9 (1.5-31.3) µM·h. The peak plasma concentrations (Cmax) was achieved 5 hour after dosing, and the median was 0.84 (0.38-1.74) µM. There were no statistically significant association of pharmacokinetics or pharmacogenomics with response rate, survival, and toxicity, such as skin toxicity, diarrhea, liver injury, and ILD of gefitinib. However, one patient died of drug induced ILD showed the highest AUC and Cmax.
Conclusion:
The elevated gefitinib exposure could be associated with drug-induced ILD. Further studies of the association of pharmacokinetics or pharmacogenomics with toxicity of EGFR-TKI are needed.
