Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60-70% of melanomas, 23-83% of papillary thyroid carcinomas, 4-16% colorectal cancers, and a lesser extent in serous ovarian and non-small-cell lung cancers. The V600E mutation is found in the vast majority of these cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor that demonstrates selective anti-tumor activity against BRAFV600E mutated cancer cells both in vitro and in vivo. CEP-32496 is orally bioavailable and demonstrates in vivo pharmacodynamic inhibition of pMEK and pERK signaling and tumor stasis and regressions in BRaf V600E cell line tumor xenograft models. In the current study Champions primary human TumorGraft models of melanoma and colorectal carcinoma possessing the B-Raf V600E genotype were utilized to determine the oral anti-tumor efficacy of CEP-32496 in more clinically relevant models in order to support the clinical development of CEP-32496. Champions Oncology has developed an innovative platform for oncology research that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor. Previous reports have demonstrated the correlation between the responses observed in Champions TumorGraft™ models and clinical responses from the patients from which the models were derived. CEP-32496 was evaluated in a panel of nine Champions TumorGraft models and compared to the recently FDA-approved B-RAF inhibitor, vemurafenib (Roche/Genentech/Daiichi) in order to determine the potential clinical activity of the compound. Mice bearing established Champions TumorGrafts were treated orally with 35 mg/kg bid of CEP-32496 or vemurafenib for 25 to 35 days and anti-tumor efficacy and tolerability were evaluated. Results demonstrated that in 5/9 (56% of the Tumorgraft models) CEP-32496 showed significantly superior in vivo efficacy compared to vemurafenib. Equivalent anti-tumor efficacy was observed in 3/9 (33%) TumorGraft models with both CEP-32496 and vemurafenib. Both inhibitors demonstrated comparable tolerability profiles. Additional TumorGraft models are currently under evaluation and retrospective bioinformatics analyses are planned to determine potential signatures of response and resistance for CEP-32496 to facilitate both its clinical development and potential differentiation from vemurafenib. Overall, these results demonstrate that CEP-32496 shows comparable to superior efficacy in this panel of Champions primary TumorGraft models when compared to vemurafenib.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3755. doi:1538-7445.AM2012-3755