Randomized Phase II Trial of Irinotecan with Paclitaxel or Gemcitabine for Non-small Cell Lung Cancer: Association of UGT1A1*6 and UGT1A1*27 with Severe Neutropenia

Hypothesis:Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC.Patients and Methods:Previously untreated patients with adequate organ function who gave written informed consent were randomly assigned to receive irinotecan (50 mg/m2 on days 1, 8, and 15) plus paclitaxel (180 mg/m2 on day 1) every 4 weeks (IP group) or irinotecan (100 mg/m2 on days 1 and 8) plus gemcitabine (1000 mg/m2 on days 1 and 8) every 3 weeks (IG group). The primary endpoint was the response rate. We also evaluated the relationship of response and toxicity to polymorphisms of the uridine diphosphate glucuronosyltransferase (UGT) gene.Results:Eighty patients were enrolled, and 78 patients were eligible (38 in the IP group and 40 in the IG group). The response rate was 31.6% (95% confidence interval: 17.5–48.7%) in the IP group and 20.0% (9.1–35.6%) in the IG group. The median progression-free survival time was 86 days and 145 days, respectively. Both regimens were well tolerated. The most common severe adverse event was grade 4 neutropenia (36.8% and 10.0%, respectively), which was associated with UGT1A1*6 and UGT1A1*27. UGT polymorphisms did not correlate with response.Conclusions:Irinotecan plus paclitaxel may be more active against NSCLC than irinotecan plus gemcitabine. The UGT1A1*6 and UGT1A1*27 genotypes might be useful predictors of grade 4 neutropenia in patients who receive irinotecan-based chemotherapy.