Drug & Device Development

Selumetinib fails in HCC trial, minimally better in biliary cancer

Last Updated: 2011-04-28 15:05:09 -0400 (Reuters Health)

By Gabriel Miller

NEW YORK (Reuters Health) - Monotherapy with selumetinib, an experimental drug that inhibits the MEK1/2 kinase enzyme, has no effect on hepatocellular (HCC) carcinoma, according to a phase II trial.

Of the 17 patients in the study who completed a full cycle, none had a partial or complete response on radiographic imaging and the progression-free survival was short. Enrollment to the trial was therefore halted at the interim analysis.

Similarly, a second study found that selumetinib produced a limited objective response rate in metastatic biliary cancer patients.

Both studies were published online April 25 in the Journal of Clinical Oncology.

"Based on our results I don't recommend further development of (selumetinib) in hepatocellular carcinoma," said Dr. Bert O'Neil, an associate professor of clinical research at the University of North Carolina and the lead author of the HCC study, in an email to Reuters Health.

However, the drug may eventually play a role in combination therapy for certain subtypes of disease.

"What we see from this study is a signal that MEK inhibition with selumetinib is interesting, but may not be sufficient on its own," Dr. Tanios Bekaii-Saab from Ohio State University, who led the biliary cancer study, told Reuters Health in an email.

"Future studies combining this agent or group of agents need to be explored rationally with other targeted agents such as EGFR and Akt inhibitors," Dr. Bekaii-Saab said.

Dr. O'Neill agrees that "the mechanism may still be important."

"We need to do further work to understand whether there is some smaller subgroup of HCCs that are dependent upon signaling of this pathway," he said.

The HCC trial assessed responses to selumetinib in 19 patients with locally advanced or metastatic disease, including 14 with Child-Pugh A cirrhosis. They were given 100mg of the drug twice daily for 21 days.

With a median six-week study time (range, 1 to 33 weeks), six of the 17 patients had stable disease.

The investigators say that although the drug did what it was intended to do -- inhibit MEK phosphorylation -- the downstream effect of the drug's action on the tumor itself was mixed and the study didn't provide any clear predictors of response.

In the biliary cancer study, 28 patients with metastatic disease took the same dose, but for an additional week, to 28 days, for a median of four cycles.

Of the 25 patients evaluable for response, three patients had an objective response, including three with confirmed partial responses, and seventeen patients (68%) had stable disease.

Similar to the HCC study, the biliary cancer study found an "absence of clear predictors" for patients' response, the investigators wrote.

Both studies found similar rates of toxicities, which included rash, xerostomia and nausea.

Three of the researchers who studied selumetinib in HCC report financial interests with Merck and/or AstraZeneca. Two of the authors of the biliary cancer trial report financial connections to AstraZeneca.

SOURCES:

http://bit.ly/mh4qay

http://bit.ly/jhvFNn

J Clin Oncol 2011.