Plexxikon today announced publication of key data in this week's edition of Nature demonstrating that the high degree of selectivity of PLX4032 (RG7204) enables substantial RAF/MEK/ERK pathway inhibition, which may be necessary to achieve significant tumor shrinkage and clinical response in patients with BRAF mutant melanoma. The paper details the structure-guided discovery of PLX4032, a novel, investigational, targeted agent, selective for the oncogenic BRAF mutation prevalent in melanoma and other cancers. The findings support recently published data from the New England Journal of Medicine showing that nearly all mutation-positive patients in a Phase 1 clinical trial of PLX4032 experienced some tumor shrinkage.
“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”
Following the initial identification of mutant BRAF in melanomas and other cancers in 2002, Plexxikon leveraged its structure-guided discovery approach to identify and optimize a number of inhibitors selective for mutant BRAF, including PLX4032.
Preclinical studies showed that PLX4032 selectively blocks the RAF/MEK/ERK pathway in BRAF mutant cells and causes regression of tumors in BRAF mutant xenograft models. Toxicology studies confirmed a high therapeutic index consistent with a high degree of selectivity.
Tumor regression in cancer patients requires significant pathway inhibition
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."
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