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Background: GSK2118436 is a potent inhibitor of B-Raf, a signal transduction kinase in the MAPK pathway that can be mutated to become an oncogenic driver in several human cancers, including melanomas (70%). GSK2118436 inhibits in a dose dependant manner phoshorylation of ERK (pERK) in cell lines encoding B-RafV600E mutation leading to inhibition of cell proliferation and tumor regression. Purpose: To predict clinical relevant doses based on exposure-response relationship from preclinical pERK inhibition tumor xenograft data and exposure observed in first-time-in-human (FTIH) study. Methods: Tumor pERK and tumor volume measurements from nude mouse xenograft models, including colon carcinoma and melanoma encoding B-RafV600E mutation, were pooled for the analysis. GSK2118436 was administered using a wide range of oral (0.1 to 300 mg/kg QD, 5 to 300 mg/kg BID) and continuous IV (3 to 100 mg/kg/day) doses. Tumor pERK inhibition was characterized as a function of GSK2118436 concentration using an inhibitory Emax model. For tumor regression, tumor volume was described using a linear growth model with tumor death rate expressed as a function of GSK2118436 concentration. The analyses were conducted using nonlinear mixed effects modeling. To extrapolate to clinical exposure, GSK2118436 concentrations in mouse were corrected for blood:plasma ratio. Results: The relationship between preclinical tumor pERK inhibition and exposure was described using a mean (90% CI) plasma IC50 of 18.5 (4.3-32.4) ng/mL (35.5nM). In preclinical models, tumor regression was observed at 30mg/kg QD orally and 3mg/kg IV and was dependent on dosing regimen. Based on exposure observed in IV studies, tumor regression was associated with >70% pERK inhibition. Tumor growth was characterized with a mean rate of 1.04 mm3/hr and was inhibited by GSK2118436 with a mean (90% CI) plasma IC50 of 28 (5.9-50.4) ng/mL (53.8nM) for tumor death rate. The model was successful in describing data observed with different modes of administration. In the FTIH study, inhibition of tumor pERK was exposure-related with >80% inhibition predicted at doses ≥100 mg BID. Consistent with target inhibition, administration of the recommended Phase 2 dose of 150 mg BID resulted in clinical activity in subjects with B-Raf-mutant melanoma. Mean exposure at trough exceeded 100 ng/mL (192nM), which is >3-fold the target exposure for tumor growth inhibition (53.8nM) based on the preclinical model. Conclusions: The exposure-response models developed using preclinical tumor pERK inhibition and mouse xenograft data translated well to the clinical biomarker and efficacy data observed with GSK2118436 and support 150 mg BID as a clinically effective dose. 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 5035. doi:10.1158/1538-7445.AM2011-5035

Activation of the Ras-Raf-MEK-ERK pathway has been implicated in a large range of human cancers. Growth factor receptor stimulation by extracellular ligands activates Ras, which then sets in motion a signal transduction cascade through the Raf, MEK and ERK serine/threonine kinases. Mutation of the B-Raf kinase constitutively activates MAPK signalling, thus bypassing the need for upstream stimuli. This has been genetically associated with several human cancers, especially occurrence of the B-RafV600E mutant and its high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. The ability to selectively and potently inhibit B-Raf should provide a potential therapy for patients with mutant B-Raf tumors, for which addictive dependency on this pathway is observed. We have identified a novel, potent, and selective Raf kinase inhibitor that is capable of inhibiting the kinase activity of wild-type B-Raf, B-RafV600E and c-Raf with IC50 values of 3.2, 0.8, and 5.0 nM, respectively. Kinase panel screening for over 270 kinases has indicated that this inhibitor is selective for Raf kinase, with ∼400 fold selectivity towards B-Raf over 91% of the other kinases tested. Specific cellular inhibition of B-RafV600E kinase by this inhibitor leads to decreased ERK phosphorylation and inhibition of cell proliferation by an initial arrest in the G1 phase of the cell cycle, followed by cell death. This inhibition is selective for cancer cells that specifically encode the mutation for B-RafV600E. Oral compound administration inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts, growing subcutaneously in immuno-compromised mice. This cell-specific B-RafV600E inhibitor is currently being evaluated in a human Phase I clinical trial. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B88.