Abstract LB-412: Combining bexarotene with erlotinib in window of opportunity and phase II trials causes lung cancer responses independent of KRAS mutations
Authors: Dragnev Konstantin H. , Ma Tian , Cyrus Jobin , Galimberti Fabrizio , Memoli Vincent , Busch Alexander M. , Tsongalis Gregory J. , Seltzer Marc A. , Johnstone David , Erkmen Cherie P. , Nugent William , Rigas James R. , Liu Xi , Freemantle Sarah J. , Kurie Jonathan M. , Waxman Samuel , Dmitrovsky Ethan 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related mortality in the United States. Improved ways to treat and prevent lung cancer are needed. Increased epidermal growth factor receptor (EGFR) expression frequently occurs in lung carcinogenesis. Treatment with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib prolongs survival, especially in patients whose lung cancers harbor activating EGFR mutations. However, patients with non-small cell lung cancers (NSCLCs) that harbor KRAS mutations can be less responsive. Therefore, there is a need for improved NSCLC treatments irrespective of KRAS or EGFR mutation status. Previous studies showed that the rexinoid bexarotene causes cyclin D1 proteasomal degradation. The EGFR-TKI erlotinib also represses cyclin D1, but via different mechanisms. The combination of bexarotene with erlotinib was explored. Initial effects of this combination on tumor growth and cyclin D1 expression were examined in murine transgenic lung cancer cell models with or without KRAS/p53 mutations. Findings were translated into both early stage window of opportunity (14 patients enrolled) and advanced stage (42 patients enrolled) phase II NSCLC trials. In the window of opportunity trial, cyclin D1 was measured in pre-versus post-treatment NSCLC biopsies and in buccal swabs. EGFR and phospho-EGFR immunohistochemical expression was assessed in the paired tumor biopsies. KRAS and EGFR mutations were also examined. A phase II trial in heavily pre-treated stage IV NSCLC cases was performed with early PET responses evaluated. Findings reveal significant repression of cyclin D1 expression and lung cancer cell growth. Intriguingly, cyclin D1, EGFR and phospho-EGFR immunohistochemical expression profiles were reduced while necrosis and inflammatory cellular responses were induced in the window of opportunity trial independent of the presence of KRAS or EGFR mutations. Cyclin D1 was repressed in post-treatment buccal swabs. The refractory NSCLC trial (2 median relapses, 21% with prior EGFR-inhibitor therapies) had 3 major clinical responses (2 had KRAS or EGFR mutations) with prolonged survival (583, 665, and 1460+ days). Median survival was 22 weeks (16 weeks for controls). Hypertriglyceridemia or rash significantly increased median overall survival to 24 weeks. Early PET response did not reliably predict clinical response.
In summary, combining bexarotene with erlotinib can repress cyclin D1 and confer in vitro and clinical anti-tumor responses (including induced tumor necrosis and inflammatory changes) independent of EGFR or KRAS mutations present in the lung cancers. Notably, survival increased in the treated stage IV NSCLC patients when hypertriglyceridemia or rash developed. Clinical activity of this regimen is encouraging and warrants further study for lung cancer therapy or chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-412. doi:10.1158/1538-7445.AM2011-LB-412