Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)

Publication

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)

Journal Paper/Review - Aug 8, 2016

Jörger Markus, Behringer D M, Ko Y-D, Hilger R A, Roessler M, Kloft C, Henrich A, Moritz B, Miller M C, Salamone S J, Kopp H-G, Mayer F, von Pawel J, Kraff S, Fischer J R, Eberhardt W, Gauler T C, Mueller L, Reinmuth N, Reck M, Kimmich M, Jaehde U

Citation

Jörger M, Behringer D, Ko Y, Hilger R, Roessler M, Kloft C, Henrich A, Moritz B, Miller M, Salamone S, Kopp H, Mayer F, von Pawel J, Kraff S, Fischer J, Eberhardt W, Gauler T, Mueller L, Reinmuth N, Reck M, Kimmich M, Jaehde U. Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 2016; 27:1895-902.

Type

Journal Paper/Review (English)

Journal

Ann Oncol 2016; 27

Publication Date

Aug 8, 2016

Issn Electronic

1569-8041

Pages

1895-902

Brief description/objective

BACKGROUND
Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure.

PATIENTS AND METHODS
Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS).

RESULTS
Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682).

CONCLUSION
PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC.

CLINICAL TRIAL INFORMATION
NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).