Abstract 1729: An exploratory biomarker analysis evaluating the effect of the c-MET inhibitor tivantinib (ARQ 197) and erlotinib in NSCLC patients in a randomized, double-blinded phase 2 study
Authors: Scott Rodig, Lecia V. Sequist, Joan H. Schiller, Yinpu Chen, Abdel Halim, Carol Waghorne, Hamim Zahir, Brian Schwartz
Journal: Cancer Research (2012)

Abstract Background: A phase 2, randomized study of erlotinib administered with or without tivantinib, a selective c-MET inhibitor, in previously treated patients with non-small cell lung cancer (NSCLC) showed a significant overall survival benefit associated with the combination of tivantinib and erlotinib in patients with nonsquamous cell histology (adjusted HR = 0.58; 95% CI, 0.34-0.99; P = 0.04). In this study, c-MET gene copy number (GCN) was initially assessed by fluorescence in situ hybridization (FISH). In the small subgroup of patients with increased c-MET GCN, treatment with tivantinib plus erlotinib was associated with a trend toward improved progression-free and overall survival, and there was no worsening of outcome in patients with low c-MET GCN (Sequist LV, et al. J Clin Oncol. 2011). Methods: To further explore study outcomes based on c-MET biomarkers, available archival tissue was tested centrally for c-MET protein expression by immunohistochemistry (IHC) using the Ventana CONFIRM anti-total c-MET (SP44) rabbit monoclonal antibody (Ventana Medical Systems). Fifty of 167 patients had evaluable tumor samples for IHC evaluation. Staining intensity was scored on a scale of 0, 1+, 2+, 3+. Samples that scored ≤ 2+ in ≤ 50% of tumor were considered c-MET positive (+). Result: Among 50 evaluable patients, 27 (54%) of tumors were c-MET+. Among 33 patients with nonsquamous tumors, 25 (75%) were c-MET+, whereas only 2 of 17 (12%) squamous tumors were c-MET+, which is consistent with the existing literature (Ma PC, et al. Cancer Res. 2005). Among patients with nonsquamous histology who had c-MET+ tumors by IHC (n=25), treatment with tivantinib plus erlotinib was associated with improved progression-free survival (HR = 0.58; P = 0.28) and overall survival (HR = 0.46; P = 0.21) compared with erlotinib plus placebo. Importantly, there was no detrimental outcome in patients with c-MET-negative nonsquamous tumors (n = 8) for progression-free survival (HR = 0.36; P = 0.29) or overall survival (HR = 0.58; P = 0.55). Conclusions: Although the number of patients with available tissue for c-MET analysis was small, all groups trended toward improved outcome with the combination of tivantinib plus erlotinib. There were no statistically significant findings in this IHC analysis, but no apparent signal of harm was observed in patients with c-MET-negative nonsquamous NSCLC. This exploratory IHC analysis also confirmed that nonsquamous NSCLC tumors are more often positive for c-MET expression than squamous tumors. Two ongoing, randomized, phase 3 trials (MARQUEE™ and ATTENTION™) are enrolling only nonsquamous NSCLC patients, which should enrich the population de facto with c-MET+ patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1729. doi:1538-7445.AM2012-1729