Editor

Cancer drug developers watched closely as Array BioPharma Inc. and partner AstraZeneca plc released top-line results from the first randomized Phase II combination trial with a MEK inhibitor.

The study didn't achieve statistical significance on its primary endpoint of overall survival – a fact that sent Array's stock down about 14 percent over the next two days. But as with the results of initial single-agent Phase II trials in 2007, headlines touting a failure didn't tell the whole story, and the detailed data showed plenty of reasons for optimism about MEK inhibitors as a class.

MEK is a kinase that is frequently activated in cancer, particularly in tumors with RAS or RAF mutations. Interest in MEK inhibitors has led to several big-dollar deals: Array and AstraZeneca's $95 million deal in 2003 was the first, but it was followed by Exelixis Inc.'s $40 million-plus deal with Genentech Inc., Ardea Biosciences Inc.'s $407 million deal with Bayer AG and a separate $467 million Array deal with Novartis AG. (See BioWorld Today, Dec. 19, 2003, Jan. 4, 2007, April 29, 2009, and April 21, 2010.)

Yet Array and AstraZeneca's initial data from single-agent trials with MEK inhibitor AZD6244 didn't provide glowing validation for the field, at least at first glance. A Phase II melanoma trial showed no difference in efficacy between AZD6244 and chemotherapy drug Temodar (temozolomide, Schering Plough Corp.), and signal searching studies in pancreatic, colorectal and non-small-cell lung cancer also failed to outperform the standard of care. Array's stock fell 28 percent. (See BioWorld Today, Dec. 21, 2007.)

From the minute the data were released, however, analysts complained that the trial design was the only failure, and that a targeted drug that could match chemo's efficacy without the side effects was a win. Array CEO Robert Conway also explained that the initial trials were conducted with an early formulation, and AstraZeneca is now advancing a new formulation that doubles the exposure at the maximum tolerated dose.

More learnings would follow: A subset analysis of the Phase II trial showed patients with uveal melanoma achieved progression-free survival for 114 days on AZD6244 vs. 50 days on chemotherapy. "I think that's become the theme with cancer drug development – finding the appropriate population," said Array Chief Scientific Officer Kevin Koch.

Some thought MEK inhibitors might also work better as combinations rather than monotherapies. That strategy gained credibility as Phase Ib data combining the new AZD6244 formulation with chemotherapy in a targeted population – melanoma patients with BRAF mutations – showed a 56 percent response rate.

Clearly those in the know were far from deterred by the initial data, as MEK inhibitor deal-making continued apace. But all watched closely as Array and AstraZeneca unveiled data from the first randomized Phase II study of the new AZD6244 formulation plus chemotherapy in the targeted population of KRAS-mutant non-small-cell lung cancer.

The trial did not meet its primary endpoint of significantly increasing overall survival, as Array announced in late September. But as in 2007, there was more to that outcome than the headlines revealed.

Conway explained that the trial was designed and powered for progression-free survival (PFS) as the primary endpoint, but AstraZeneca switched to overall survival. Yet AZD6244 (now dubbed selumetinib) plus chemo significantly beat chemo alone for PFS as well as secondary endpoints of objective response rate and alive and progression-free at six months.

"We were very encouraged by the results," Conway told BioWorld Insight, adding that they are "highly important for MEK inhibition as an oncology therapeutic."

More information about the potential of MEK inhibitors and the best strategies for moving them forward should come soon. AstraZeneca is testing selumetinib in a bevy of trials, including a Phase II study in uveal melanoma, a Phase II chemo-combination trial in BRAF-mutant melanoma, and many others.

Other trials are testing ARRY-162, Array's second-generation MEK inhibitor partnered with Novartis, in various combinations.

Conway noted that he sees opportunity for MEK inhibitors both as monotherapies in targeted populations and as combination therapies – with targeted agents or with chemo – in potentially broader indications.

Others are testing those strategies as well. Bayer and Ardea recently started a Phase II trial of their MEK inhibitor plus Nexavar (sorafenib, Onyx Pharmaceuticals Inc. and Bayer AG) in hepatocellular carcinoma, and Roche AG is testing recently-approved melanoma drug Zelboraf (vemurafenib) with a MEK inhibitor.