Merck's ERK inhibitor shows promise in combo against resistant cancers

Merck started developing ERK inhibitors in 2013 because cancer patients treated with BRAF and/or MEK inhibitors became resistant to therapy through ERK activity. (Merck)

One-fifth of patients in a phase 1 study responded to an investigational ERK inhibitor from Merck, bolstering hopes that this type of drug could be used effectively in combination with other cancer drugs. ERK is a cell signal that is believed to drive the growth of many cancers.

Merck started developing ERK inhibitors in 2013 to plug a gap in the treatment of melanomas and other cancers with BRAF mutations. Targeted treatments for these cancers are available, but patients often become resistant and their cancer returns. The candidate in question, MK-8353, targets downstream ERK signaling to suppress resistance rather than taking aim at early signals that drive hyperactive growth.

"ERK is very complex, and it's still surprisingly poorly understood, but what is very clear is that it is required for cancer growth, and that's why there are a number of inhibitors in this pathway that are either approved, or under clinical evaluation,” said Channing Der, a professor in the UNC School of Medicine Department of Pharmacology, in a statement.

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Researchers at UNC and a number of other sites tested the drug in 26 patients with advanced solid tumors. They found that of the 15 patients who could be evaluated, three patients had a partial response to MK-8353.

The low response rate—20%—is comparable to response rates observed in other treatments, such drugs that target MEK enzymes in the MAPK/ERK pathway.

Because of that low response rate, said Stergios Moschos, an associate professor in the UNC School of Medicine, "ERK inhibitors cannot be given as single agents, just like MEK inhibitors. The question is: Which combination is best?"

Other companies are going the combo route to beat melanoma. Shortly after Array Biopharma had to pull its new drug application for its MEK inhibitor, binimetinib, it picked up $31.6 million from Ono Pharma to test the drug in combination with its BRAF inhibitor, encorafenib.

And Novartis is working to expand the label for its combination of Tafinlar and Mekinist, acquired in 2015 from GlaxoSmithKline. The FDA approved the drugs separately for the treatment of melanoma in 2014, and three years later, the tandem therapy scored approval for the treatment of non-small cell lung cancer with the BRAF V600E mutation.

The UNC trial was part of a larger effort there aimed at examining the potential of ERK inhibitors in treating different cancers. Merck is currently testing MK-8353 along with its immuno-oncology drug Keytruda in a phase 1b study that's recruiting patients with advanced tumors.