EORTC 2014: Screening of Champions Predictive TumorGraft Platform Guides the Clinical Development of the Selective Dual BRAF-EGFR Inhibitor CEP-32496
Screening of Champions Predictive TumorGraft Platform Guides the Clinical Development of the Selective Dual BRAF-EGFR Inhibitor CEP-32496
Bruce Ruggeri2, Michele Wabler1, Elizabeth Bruckheimer1, Brandy Wilkinson1, Bruce Dorsey2, Steve Trusko2, Jay Friedman1
Champions Oncology, Inc.1, Teva Pharmaceuticals Inc. (Discovery Research)2
Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60-70% of melanomas and 4–16% colorectal cancers. CEP-32496 (Teva Pharmaceuticals) is an orally active dual inhibitor of wild type and V600E-mutant BRAF kinase and EGFR, as well as other oncogenic protein kinases, including BCR/ABL and RET. Champions Oncology has developed a predictive platform that utilizes the implantation of patient derived xenografts (PDX) in immune-deficient mice that preserves the biological properties of the original human tumor and provides an accelerated and focused translational path into clinical trials. A screening study using a panel of Champions TumorGraft® models of human colorectal cancer and melanoma possessing either the BRAF mutant or BRAF wild type genotype was conducted to compare the therapeutic activity of CEP-32496 versus a clinically approved BRAF inhibitor, vemurafenib, as well as two standard of care agents (irinotecan or temozolomide). This screening study demonstrated an overall comparable or superior response (p<0.05) of CEP-32496 compared to vemurafenib in 13 out of 15 tumorgraft models of melanoma. Notably, CEP-32496 displayed robust therapeutic activity (p<0.05) over vemurafenib in 7 tumorgraft models of BRAF-mutated colorectal cancer. Given these initial results in colorectal cancer, we further explored the anti-tumor activity of CEP-32496 and several standard of care agents for colorectal cancer (irinotecan, oxaliplatin, 5-FU, and cetuximab) given as monotherapy or in combination in two tumorgraft models of BRAF-mutated colorectal cancer. In both colorectal tumorgraft models, the combinations of sub-optimal oral doses of CEP-32496 and optimal doses of each standard of care agent achieved significantly improved anti-tumor activity (p<0.05) relative to standard of care agents and in many cases vehicle-treated animals. The combination treatment regimens were generally well tolerated exhibiting no body weight loss or mortality. Based on this dataset, CEP-32496 is currently in clinical trials in cancer patients.