LBA20_PR - Phase III multi-centre, randomised, double-blind, placebo-controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemot...
|Date||29 September 2012|
|Event||ESMO Congress 2012|
|Session||Gastrointestinal tumors, non-colorectal|
D. Ferry1, S.J. Dutton2, W. Mansoor3, J. Thompson4, M. Harrison5, H. Abbas1, A. Dahle-Smith6, A. Chatterjee7, S. Falk8, A. Garcia-Alonso9, D.W. Fyfe10, R. Hubner3, T. Gamble4, L. Peachey11, M. Davoudianfar11, S.R. Pearson11, P. Julier11, J. Jankowski12, R. Midgely11, R. Petty13
There is no standard systemic therapy for metastatic esophageal cancer progressing after 1st/2nd line chemotherapy (Thallinger et al, 2011, JCO, 4709-14). High EGFR expression is associated with poor prognosis in esophageal cancer. A phase II trial of the EGFR kinase inhibitor gefitinib showed good tolerance with 11% partial responses and a trend towards improved survival (Ferry et al. Clin Cancer Res 2007, 13: 5869-75). Four other phase II trials showed objective responses with gefitinib or erlotinib. Cancer Research UK funded this pivotal phase III trial with free study drug provided by Astra Zeneca UK.
Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status (PS) 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: overall survival (OS) - an increase from 10-18% in 1yr OS is detectable with 450 patients, power 82.5%, significance level 5%, analysed with Kaplan-Meier and log-rank test. Secondary outcomes include safety, PFS, HRQL (EORTC QLQ-C30 and QLQ-OG25) and predictive biomarkers.
Recruitment of 450 patients from 51 UK centres occurred Mar2009-Nov2011. Baseline characteristics were well-balanced - median age 64 years; 83% male; 76% adenocarcinoma; 78% esophageal; PS0 25%, PS1 54%, PS2 21%. Median PFS was P 35 days, G 49 days (HR=0.795, 95%CI 0.66, 0.96, p=0.017). Median OS was P 3.60 months, G 3.73 months (HR=0.90, 95%CI 0.74, 1.09, p=0.285). No significant safety concerns emerged. PS is a highly significant prognostic factor for both PFS (median PFS: PS0 1.8, PS1 1.4, PS2 1.0 months) and OS (median OS: PS0 6.0, PS1 3.9, PS2 2.0 months). Disease control rate at 8 weeks in patients with measurable disease was P 16.0%, G 25.5% (p=0.014). HRQL was assessed for the pre-specified outcomes of QoL, dysphagia, eating and odynophagia, the latter of which was improved for gefitinib (p=0.004).
COG is the first large randomised trial in the 2nd/3rd line setting in esophageal cancer. Although the primary OS endpoint was not acheived, there was significant PFS improvement and palliation. Durable responses were seen, and the translational study (Trans-COG) is investigating the correlation of benefit with biomarkers.