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P. de Bruijn
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Optimizing targeted therapy in lung cancer (ID 56)
- Event: ELCC 2018
- Type: Poster Discussion session
- Track:
- Presentations: 1
- Now Available
- Moderators:F. Cappuzzo, N. Peled
- Coordinates: 4/12/2018, 16:45 - 17:45, Room W
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132PD - Plasma concentrations of pemetrexed to predict clinical outcomes in patients with advanced NSCLC (Now Available) (ID 614)
16:45 - 16:45 | Author(s): P. de Bruijn
- Abstract
Background:
Currently, there are no clinically useful predictors of efficacy and toxicity to pemetrexed (PMX) in advanced non-small-cell lung cancer (NSCLC). Using population pharmacokinetic (pop-PK) modelling, we explored whether total exposure to PMX predicts for progression-free and overall survival (PFS/OS) and occurrence of (severe) chemotherapy (CTx)-related adverse events (AEs).
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV NSCLC receiving first- or second-line PMX(/platinum) were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle PK). In a subgroup, blood samples were also collected at 10, 30 minutes and 1, 2, 4, 8, 24 hours after start of PMX infusion (24h PK). With pop-PK modelling total exposure (AUC) to PMX per patient was estimated. The relation between AUC during cycle 1 (AUC~1~) and OS/PFS in treatment-naïve patients was examined using Cox regression analyses and in all patients we compared the difference in mean AUC~1~ between patients with and without grade ≥3 CTx-related AEs (CTCAE 4.03) during total treatment of 4 cycles.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). Median estimated AUC~1~ was 201 mg·h/L (interquartile range: 179–224). In treatment-naive patients (n = 95), AUC~1~ did neither univariably predict for OS/PFS, nor multivariably when adjusted for prognostic factors sex, disease stage and WHO performance score (OS, HR = 1.05, 95%CI: 1.00–1.11; PFS, HR = 1.03, 95%CI:0.98–1.08). Compared to patients without ≥ grade 3 CTx-related AEs (n = 51), patients with ≥ grade 3 CTx-related AEs (n = 55) had significantly higher AUC~1~ values (220 vs 191, p < 0.001). When seperating ≥ grade 3 CTx-related AEs into clinical and laboratory AEs, identical results were found.
Conclusions:
Total systemic exposure to PMX does not predict for PFS/OS, but is significantly associated with more frequent occurrence of severe CTx-related AEs. Although the impact of peak concentrations on efficacy remains unclear, our findings suggest that lower dosage might prevent severe toxicity with preservation of efficacy.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of Scientific Committee ELCC 2018; consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.
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Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Track:
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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168P - Pemetrexed dosing regimens in patients with advanced NSCLC (Now Available) (ID 617)
12:50 - 12:50 | Author(s): P. de Bruijn
- Abstract
Background:
There is a lack of rationale to use body surface area (BSA)-based dosing if BSA is not a predictor of systemic clearance and thus total systemic exposure (AUC). Using population pharmacokinetic (Pop-PK) modelling, we evaluated the influence of BSA and renal function on pemetrexed (PMX) clearance and compared different dosing strategies.
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) receiving PMX(/platinum) first- or second-line were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle-PK) and glomerular filtration rate (eGFR) was estimated. In a subgroup, sampling was also performed at 10,30 minutes and 1,2,4 and 8 hours after start of PMX infusion (24h PK). With the ultimate Pop-PK model, we simulated different dosing strategies and compared differences in median AUC (interquartile range [IQR]) and interindividual variability (coefficient of variation [CV]) of AUC to standard BSA-based dosing.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). A two-compartment model (population estimate (%standard error of the estimate) in terms of PMX clearance (CL; 4.58L/h (3.1%)), central distribution volume (V~1~; 15.9L (3.3%)), peripheral distribution volume (V~2~; 21.6L (5.0%)), intercompartimental clearance (Q; 0.05L/h (4.7%)) and between-patient variability of CL (16.7%), fitted PK data appropriately. Covariate eGFR significantly reduced between-patient variability in CL from 20.2% to 16.7% (p < 0.005), while BSA did not. Compared to BSA-based dosing (CV 22.5%, AUC 206 (IQR 178–240)), simulation of eGFR-based dosing (CV 18.5%, AUC 206 (IQR 183–232)) and fixed dose of 900 mg with 25% dose reduction if eGFR < 60 (CV 19.1%, AUC 197 (174–224)) both showed less interindividual variability of AUC.
Conclusions:
Although we currently dose PMX based on BSA, our data show better rationale for eGFR-based dosing as it offers additional control of systemic exposure to PMX, indicated by the decreased variability. Using fixed dose of 900 mg with 25% dose reduction if eGFR < 60 may be an acceptable alternative in clinical practice.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of scientific committee ELCC 2018 consultant/advisory role with Eli Lilly and Company All other authors have declared no conflicts of interest.
