Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer

David R. Spigel, Thomas J. Ervin, Rodryg A. Ramlau, Davey B. Daniel, Jerome H. Goldschmidt, George R. Blumenschein, Maciej J. Krzakowski, Gilles Robinet, Benoit Godbert, Fabrice Barlesi, Ramaswamy Govindan, Taral Patel, Sergey V. Orlov, Michael S. Wertheim, Wei Yu, Jiping Zha, Robert L. Yauch, Premal H. Patel, See Chun Phan, Amy C. Peterson

Research output: Contribution to journalArticlepeer-review

381 Scopus citations

Abstract

Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Original languageEnglish
Pages (from-to)4105-4114
Number of pages10
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume31
Issue number32
DOIs
StatePublished - Nov 10 2013

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