Abstract 1042: Maintenance or switch maintenance therapy with selumetinib or cediranib after chemoradiation prolongs survival in an orthotopic human lung cancer model.
Authors: Takahashi Osamu , Komaki Ritsuko U. , Jürgensmeier Juliane M. , Smith Paul D. , Wistuba Ignacio I. , Tailor Ramesh C. , Jacoby Joerg J. , Korshunova Maria V. , Kim Yong Bae , Erez Baruch , Herbst Roy S. , O'Reilly Michael S. 
Published: August 2014

Abstract
Background The outcome of lung cancer is poor and new therapies are needed. Selumetinib (AZD6244, ARRY-142886) and cediranib are potent MEK 1/2 and VEGFR tyrosine kinase inhibitors, respectively. In the current study, we evaluated the therapeutic efficacy of each with chemoradiation followed by maintenance therapy in a KRAS mutant orthotopic human non-small cell lung cancer model.
Methods NCI-H460 lung cancer cells were injected into the lungs of mice. Mice were randomized (32/group) to therapy with radiation (20 Gy in 5 fractions) + paclitaxel (200 μg/week), radiation, paclitaxel, and selumetinib (25 mg/kg/day) or cediranib (3 mg/kg/day), or vehicle control (n=8). When controls became moribund, 8 mice from each group were sacrificed and assessed for tumor burden. The remaining mice were re-randomized to switch or continuation maintenance with selumetinib or cediranib or vehicle (8/group). Mice were sacrificed when they became moribund and tumor tissues were subjected to immunohistologic analyses.
Results After the initiation phase, chemoradiation reduced tumor volume by 78% (p = 0.0002 vs control) with modest effects on regional metastases. The anti-tumor and anti-metastatic effects of chemoradiation were markedly enhanced by selumetinib or cediranib with a reduced total tumor volume of 96% and 99% (p = 0.002 or 0.0002) and primary lung tumor volume of 88% or 98% (p = 0.002 and 0.0002) compared to control. Trimodality therapy inhibited angiogenesis and tumor proliferation and increased tumor and endothelial cell apoptosis. In the maintenance phase, selumetinib or cediranib after chemoradiation prolonged survival compared to vehicle with a median survival of 41 or 43 vs 33 days (p = 0.008 or 0.005, respectively). Maintenance selumetinib or cediranib after chemoradiation + selumetinib resulted in a median survival of 46.5 or 53 vs 36.5 days for control (p = 0.001 or 0.0004, respectively). Maintenance selumetinib or cediranib after chemoradiation + cediranib improved survival by 52 or 67 vs 39 days for control (p = 0.0002). There was no significant survival difference for switch or continuation maintenance. The longest survival (105 days) was observed for selumetinib maintenance after chemoradiation + cediranib. Failure patterns with maintenance therapy included regional and distant metastases with brain, bone, and adrenal metastases observed.
Conclusions Selumetinib or cediranib substantially enhanced the effects of chemoradiation in an orthotopic human lung cancer model. Maintenance therapy with selumetinib or cediranib after trimodality therapy significantly prolonged survival. Mice developed regional and distant metastatic disease in patterns similar to those observed clinically. These data provide a basis for clinical trials and our model allows for the study of failure and resistance patterns with maintenance therapy in lung cancer.
Citation Format: Osamu Takahashi, Ritsuko U. Komaki, Juliane M. Jürgensmeier, Paul D. Smith, Ignacio I. Wistuba, Ramesh C. Tailor, Joerg J. Jacoby, Maria V. Korshunova, Yong Bae Kim, Baruch Erez, Roy S. Herbst, Michael S. O'Reilly. Maintenance or switch maintenance therapy with selumetinib or cediranib after chemoradiation prolongs survival in an orthotopic human lung cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1042. doi:10.1158/1538-7445.AM2013-1042