Dual EGFR Inhibition in combination with anti-VEGF treatment in colorectal cancer
Gerald S. Falchook1, Aung Naing2, Jennifer J. Wheler2, Apostolia M. Tsimberidou2, Ralph Zinner2, David S. Hong2, Siqing Fu2, Sarina A. Piha-Paul2, Filip Janku2, Kenneth R. Hess3, Christel Bastida4, and Razelle Kurzrock5
1 Drug Development Program, Sarah Cannon Research Institute, Denver, CO 80218
2 Department of Investigational Cancer Therapeutics (Phase I Program), U.T. MD Anderson Cancer Center, Houston, TX
3 Department of Biostatistics, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX
4 Department of Symptom Research, U.T. MD Anderson Cancer Center, Houston, TX
5 Moores Cancer Center, University of California San Diego, La Jolla, CA
Correspondence:
Gerald Falchook, email:
Keywords: Erolotinib, Cetuximab, Bevacizumab, EGFR, VEGF
Received: February 20, 2014 Accepted: August 6, 2014 Published: August 7, 2014
Abstract
Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer.
