Individualization of docetaxel (DTX) treatment in East-Asian advanced non-small cell lung cancer (NSCLC) patients based on pharmacokinetically (PK)-guided dosing strategy: an open-label randomized clinical trial

Aim/Background

BSA dosing leads to great inter-individual DTX PK variability, which is a major contributor for severe toxicity, especially in East-Asian populations. DTX exposure measured by area under plasma concentration-time curve (AUC) could positively predict DTX related neutropenia. We conducted a randomized clinical trial to assess the value of PK-guided DTX dosing on relieving toxicity.

Methods

To date, 99 Asian advanced NSCLC patients were randomly assigned to receive single agent 3-weekly DTX chemotherapy for up to 6 cycles, either at a fixed standard dose of 75 mg/m² by BSA (arm1) or at a PK-guided dose (arm2) with a same starting dose. AUC is calculated from a published PK model. Dose of subsequent cycles of arm2 patients is calculated base on previous cycle, according to optimal AUC target (2.5–3.7 µg•h/mL) algorithm. Dose reductions were permitted in both arms for toxicities. The study had a power of 80% to detect a 23% reduction of grade >3 neutropenia with PK-guided arm.

Results

Patients' major characteristics were male (62.6%), non-smoker (58.6%), ECOG 0 (80.8%) and adenocarcinoma (74.7%). 1^st cycle of dosing 75 mg/m² for all patients show 11 folds of PK variability, with mean AUC of 4.53 (range 1.8-20.3, CV = 56%), only 29.2% were in the target. Major patients (59.4%) were over exposed to DTX, experienced 18.5% higher of grade ≥3 neutropenia incidence. PK-guided dosing strategy could significantly reduce the dose of DTX, with a reduction of 8.6 mg/m² (64.4 vs. 73.0, p < 0.001) in 2^nd to 6^th cycles. Patients therefore experienced 25.4% lower of grade ≥3 neutropenia incidence in PK-guided dose arm (47.5% vs. 72.9%, p = 0.002). Overall response rate showed no differences between arm2 and arm1 (20.0% vs. 17.5%, p = 0.769), so is progression free survival (4.6 vs. 3.4 months, p = 0.567).

Conclusions

Majority of East-Asian NSCLC patients were over-exposed to DTX at a dose of 75 mg/m². PK-guided dosing strategy could reduce DTX related neutropenia without efficacy damage.

Clinical trial identification

NCT01891123

Disclosure

All authors have declared no conflicts of interest.