Phase 3 Randomized Study (ARCHER 1050) of 1st-Line Dacomitinib vs Gefitinib for Advanced NSCLC with EGFR Mutation(S)

Abstract

Background: Dacomitinib (D) is an orally available, potent and selective irreversible inhibitor of all catalytically active members of HER family tyrosine kinases, and is active in preclinical studies on EGFR mutant cell lines, including gefitinib (G)-resistant lines. D has shown superior PFS to erlotinib as 2nd-line therapy in a randomized phase 2 trial of an 'unselected', predominantlyWestern population (Ramalingam et al 2012), and is currently being tested in a randomized double-blind global phase 3 study of similar design. In a previous phase 2 study, 45 NSCLC pts with confirmed EGFR exon 19 or 21 sensitizing mutations (m) who received 1st-line D achieved a 76% PR rate. The preliminary PFS rate was 77% at 1 yr; preliminary median PFS was 18 mo (Mok et al 2012). Method(s): A randomized, open label, phase 3 trial (ARCHER 1050; NCT01774721) will compare the efficacy of 1st-line D with G in pts with adv stage EGFR m-positive NSCLC. Approximately 440 pts with stage IIIB/IV pathologically confirmed NSCLC, with an activating EGFR m (either exon 19 deletion or exon 21 L858R m, permitting exon 20 T790M if in co-existence with activating m), radiologically measurable disease, ECOG PS 0-1 and no prior systemic therapy for NSCLC will be randomized (1:1) to receive D 45 mg or G 250 mg orally once daily. The primary endpoint is PFS by Independent Radiologic Review. Secondary endpoints include: OS, OS at 30 mo, best overall response, DR, safety and tolerability, and PRO of HRQoL and disease/treatment-related symptoms. The randomization will be stratified by race (Japanese vs mainland Chinese vs other East Asian vs non East Asian), and EGFR m status (exon 19 deletion vs exon 21 L858R m).With a minimum of 268 PFS events required, the study has 90% power to detect a >50% improvement in PFS (ie HR < 0.667) in pts receiving D vs those receiving G using the ITT analysis population.