A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV non-squamous non-small-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study)
Mené au Japon sur 307 patients atteints d'un cancer non épidermoïde du poumon non à petites cellules de stade IIIB/IV ne présentant pas de mutation du gène EGFR, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout de tivantinib à l'erlotinib
Backgrounds : A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, non-squamous non-small-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian non-squamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). Methods : A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary endpoint was OS. Secondary endpoints were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Results : Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively (hazard ratio [HR]=0.891, p=0.427). Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR=0.719, p=0.019). The commonly observed grade ≥3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). Conclusions : This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in non-squamous NSCLC patients with WT-EGFR.Trial registration number NCT01377376