Pneumologie 2016; 70 - P79
DOI: 10.1055/s-0036-1572244

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin in advanced Non-Small Cell Lung Cancer (NSCLC) patient

J von Pawel 1, S Kraff 2, JR Fischer 3, W Eberhardt 4, T Gauler 4, L Müller 5, N Reinmuth 6, M Reck 6, M Kimmich 7, F Mayer 8, HG Kopp 8, DM Behringer 8, YD Ko 9, M Frueh 10, RA Hilger 11, M Roessler 4, B Moritz 12, U Jaehde 13, M Joerger 11
  • 1Asklepios Fachkliniken München Gauting
  • 2Institute of Pharmacy, University of Bonn
  • 3Klinik Löwenstein
  • 4University Hospital Essen
  • 5Oncological Practice Leer
  • 6Krankenhaus Grosshansdorf
  • 7Klinik Schillerhöhe, Stuttgart-Gerlingen
  • 8University Hospital, Tuebingen
  • 9Augusta-Kranken-Anstalt Bochum
  • 10Johanniter-Krankenhaus Bonn
  • 11Cantonal Hospital St. Gallen
  • 12Cesar Central Office, Vienna
  • 13University Bonn

Background: Variability of chemotherapy exposure may cause severe toxicity or lack of efficacy. Paclitaxel (PTX) exposure (time above a plasma concentration of 0.05mM, Tc > 0.05) has been shown to predict toxicity. Whereas carboplatin dose is adapted to kidney function, PTX dosing only accounts for body-surface area. We developed a PTX dosing algorithm for avoidance of supra- or subtherapeutic PTX exposure based on Tc > 0.05 determined from a single blood sample drawn 18 – 30 hours after starting PTX infusion. This study was initiated to validate PK-guided PTX dosing in advanced NSCLC patients.

Methods: 304 patients with advanced NSCLC were randomly assigned to receive up to 6 cycles of first-line 3-weekly carboplatin AUC 6 combined with PTX either at a standard dose of 200 mg/m2 (Arm A) or at a PK-guided dose (Arm B).

Initial PTX dose in Arm B was between 150 to 200 mg/m2 based on age and sex, and subsequent PTX doses were adjusted according to the previous cycle PTX Tc > 0.05 to target a Tc > 0.05 between 26 and 31 hours. Dose reductions were permitted in both arms for chemotherapy-associated toxicity. The study had a power of 90% to detect a 11% reduction of grade 4 neutropenia with PK-guided PTX dosing.

Results: Major patient characteristics were male gender in 67%, current smokers in 38%, ≥65 years of age in 50%, performance status of 2 in 8%, squamous-cell histology in 21%. Compared to standard dosing, PK-guided dosing of PTX reduced the incidence of grade 4 neutropenia (measured on day 15 of each cycle) (15% v 21%, P = 0.029), grade ≥2 neuropathy (14% v 27%, P < 0.001), and grade ≥3 neuropathy (1% v 8%, P < 0.001). Median PTX dose at cycle 6 was significantly lower with PK-guided dosing (132 v 197 mg/m2, P < 0.001), and the proportion of patients with supratherapeutic PTX exposure was reduced from 41% in cycle 1 to 2% in cycle 6. Objective response rate was 32% and 29% in Arms A and B (P = 0.70). Progression-free survival was 5.2 and 4.7 months in Arms A and B (hazard ratio 1.1, 95% CI 0.8 – 1.4, P = 0.54).

Conclusions:

PK-guided dosing of PTX improves the risk-benefit profile in patients with advanced NSCLC, primarily by a substantial reduction of PTX-associated neuropathy.