First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group

8016 Background: Based on our promising results of phase II studies estimating gefitinib in NSCLC pts with sensitive EGFR mutations (JCO 2006, BJC 2006), this multicenter phase III trial compared progression free survival (PFS) of first line gefitinib versus first line chemotherapy in EGFR mutation positive pts with stage IIIB/IV NSCLC. Per protocol, an analysis for safety except response, PFS and overall survival were estimated. Methods: PNA-LNA PCR clamp test, which had been developed and validated by us (Cancer Res 2005, Cancer Sci 2007), was employed to detect EGFR mutations using cytological samples or histological samples. Pts having sensitive EGFR mutations, measurable site(s), ECOG PS 0–1, age of 20–75 years, and no prior chemotherapy were randomized (1:1 ratio; balanced for institution, sex, and stage) to receive Arm A: gefitinb (250 mg/ day) orally, or Arms B: CBDCA AUC 6 and TXL 200mg/m2 in 21-day cycles until disease progression. The primary endpoint was PFS, and the sample size was calculated to be 320 in total (alpha=5%, power=80%) to confirm the superiority of Arm A (hazard ratio = 0.69). Results: From April 2006 to July 2008, 155 pts were enrolled (Arm A=80; Arm B=75). Their characteristics were well balanced between arms: median age=65 years; 64% female; 77% Stage IV; 93% adenocarcinoma, 61% non-smoker. There were several differences in toxicities between Arm A and Arm B (grade 4 neutropenia: 1% vs. 29%, grade 3–4 liver dysfunction: 24% vs. 1%, grade 3 neuropathy: 0% vs. 5%, respectively, p<0.01). But these were tolerable in both arms. Furthermore, there were no interstitial lung disease and no toxic deaths in both arms. Analyzing both arms together, preliminary response rate and PFS of the 155 pts were 53.7% and 6.5 mos, respectively. Conclusions: This is the first prospective study to compare first line gefitinib with first line chemotherapy for advanced NSCLC pts harboring EGFR mutations. Due to acceptable toxicities, the independent safety committee decided to continue this study further. At the end of 2008, 200 pts have been entered to this study, and, per protocol, an interim analysis to investigate PFS will be performed in May 2009. No significant financial relationships to disclose.