In the Phase 1 trial, paired biopsy specimens from a subset of patients, were analyzed for pathway inhibition before and after two weeks of treatment. Data showed that with increasing doses of PLX4032, more than 80% inhibition of ERK phosphorylation (a measure of RAF/MEK/ERK pathway activation) in the tumors of patients correlated with significant tumor shrinkage and clinical response. In contrast, in patients exposed to plasma levels of PLX4032 at sub-therapeutic doses (less than 240 mg BID), partial inhibition of RAF activity in the tumor tissue of a subset of patients did not result in meaningful tumor shrinkage or clinical response.

"These data provide important support for our clinical development of PLX4032, and are a direct translation of our preclinical data demonstrating that comprehensive inhibition of the ERK pathway may be necessary for significant tumor regression," said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. "Plexxikon's hallmark capability of making highly selective kinase inhibitors has enabled us to administer high doses of PLX4032 in the clinic to substantially inhibit this important pathway. The selectivity of this unique BRAF inhibitor is key to minimizing significant off-target toxicities, and is an important distinguishing feature of this first-in-class BRAF inhibitor."

Source : Plexxikon