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S. Koolen



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    Optimizing targeted therapy in lung cancer (ID 56)

    • Event: ELCC 2018
    • Type: Poster Discussion session
    • Track:
    • Presentations: 1
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      132PD - Plasma concentrations of pemetrexed to predict clinical outcomes in patients with advanced NSCLC (ID 614)

      16:45 - 17:45  |  Author(s): S. Koolen

      • Abstract
      • Slides

      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
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      168P - Pemetrexed dosing regimens in patients with advanced NSCLC (ID 617)

      12:30 - 13:00  |  Author(s): S. Koolen

      • Abstract
      • Slides

      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.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.