Enzyme inhibitor produces stable disease in patients with advanced solid cell cancers

Phase II trials initiated

Prague, Czech Republic: Preliminary trials of a MEK enzyme inhibitor have shown that it is capable of producing long-lasting stable disease in patients with advanced solid cancers. Tests showed that the drug inhibited key targets in the patients' tumours, and now it is being tested in phase II clinical trials.

Professor Alex Adjei told the EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Wednesday 8 November) that the drug AZD6244 (ARRY-142886) [2] inhibited MEK1/2 - an enzyme that plays an important role in the Ras/Raf/MEK/ERK cell signalling pathway, which regulates cell proliferation and survival. Activation of this pathway has been implicated in a number of cancers, including lung, pancreatic, colon, melanoma and thyroid cancer.

"Laboratory studies have shown that AZD6244 has an effect on human tumours at nanomolar concentrations, and the first part of the phase I clinical trial has determined the maximum tolerated dose and the safety of the compound. Results from this second part of the trial demonstrate that a dose of 100mg of AZD6244 is well tolerated, produces a high incidence of long-lasting stable disease, and is associated with a profound inhibition of the cell signalling protein pERK and a reduction in cell proliferation - which indicates that the drug is working against the tumours," said Prof Adjei, who was professor of oncology at the Mayo Clinic, Rochester, USA, before moving in October to be the senior vice-president for clinical research and chair of the Department of Medicine at the Roswell Park Cancer Institute, Buffalo, USA.

Prof Adjei and his colleagues at the Mayo Clinic, University of Colorado Health Sciences Center and Fox Chase Cancer Center recruited into the second part of the trial 34 patients with advanced cancers, including melanoma, breast, lung and colorectal cancers. Approximately 40% of the patients had melanoma. The researchers were particularly interested in this tumour type because a large proportion harbour B-Raf mutations, and tumours with these mutations may be highly sensitive to MEK inhibitors.

The patients were randomised to receive 100 or 200mg doses, twice a day for 28-day cycles. The larger dose proved to be too high for continuous dosing due to adverse side effects, but the smaller dose was well tolerated over a prolonged period.

The researchers tested biopsy tissue taken from the patients both before and after dosing. They found that the pERK protein was reduced by 77%. They also looked at another protein, Ki-67, which is used as a marker for cell proliferation. After dosing, there was a reduction in Ki-67 in nine out of 20 patients, and in five of those nine patients the reduction was at least 50% or more.

"We found that after 15 days of dosing, AZD6244 continued to inhibit pERK at times when concentrations of the drug in the blood were at their lowest levels between doses. At the lowest concentration, 400 nanograms of the compound per microlitre of plasma still corresponded to a 35-44% inhibition of pERK," said Prof Adjei.