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

J Clin Oncol 2013 Nov 7;31(32):4105-14. Epub 2013 Oct 7.

David R. Spigel, Thomas J. Ervin, and Davey B. Daniel, Sarah Cannon Research Institute; David R. Spigel, Tennessee Oncology, Nashville; Davey B. Daniel, Chattanooga Oncology Hematology Associates, Chattanooga, TN; Thomas J. Ervin, Florida Cancer Specialists, Fort Myers; Michael S. Wertheim, Hematology/Oncology Associates, Port St Lucie, FL; Rodryg A. Ramlau, Poznan University of Medical Sciences, Poznan; Maciej J. Krzakowski, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Jerome H. Goldschmidt Jr, Blue Ridge Cancer Care, Christianburg, VA; George R. Blumenschein Jr, The University of Texas MD Anderson Cancer Center, Houston, TX; Gilles Robinet, University Hospital Morvan, Brest; Benoit Godbert, Centre Hospitalier Universitaire Nancy, Vandoeuvre-lès-Nancy; Fabrice Barlesi, Assistance Publique-Hôpitaux de Marseille, Aix Marseille University, Marseille, France; Ramaswamy Govindan, Washington University School of Medicine, St Louis, MO; Taral Patel, Mid Ohio Oncology/Hematology, Columbus, OH; Sergey V. Orlov, St Petersburg Pavlov State Medical University, St Petersburg, Russia; Wei Yu, Robert L. Yauch, Premal H. Patel, and See-Chun Phan, Genentech; Amy C. Peterson, Medivation, San Francisco, CA; and Jiping Zha, Crown Bioscience, Taicang City, China.

Purpose: 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 And Methods: 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.

Results: 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.

Conclusion: 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.

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http://jco.ascopubs.org/content/early/2013/10/07/JCO.2012.47
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http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.47.4189
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http://dx.doi.org/10.1200/JCO.2012.47.4189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878106PMC
November 2013
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