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ASCO Annual Meeting Spotlight
Key news updates from the ASCO Annual Meeting
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Tuesday, July 16, 2013
ONLINE FIRST: MEK-Inhibitor Selumetinib Called First Effective Treatment for Advanced Eye Melanoma

BY PETER GOODWIN

 

CHICAGO -- The new drug selumetinib has doubled progression-free survival in patients with advanced uveal melanoma, a condition that has been virtually unresponsive to any previous therapy.

 In a presentation here at the American Society of Clinical Oncology Annual Meeting, Richard Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, reported a Phase II trial from 16 centers in the United States and Canada of 98 previously untreated patients randomized to receive temozolomide or selumetinib, an oral inhibitor of the MEK (mitogen-activated protein kinase enzymes K1 and K2) protein (Abstract CRA9003).

 

The disease is rare, “an orphan disease, with no effective treatment,” diagnosed in about 2,500 people in the U.S. annually, he said.

 

Patients receiving selumetinib had an increase in median progression free survival (PFS) from seven to almost 16 weeks, which melanoma expert Lynn Schuchter, MD, Professor and Chief of Hematology-Oncology at Abramson Cancer Center of the University of Pennsylvania, called “remarkable” --“This was an important step forward: there has been nothing for these patients,” she said.

 

Carvajal reported a 50 percent incidence of disease regression in the patients receiving selumetinib, compared with just 11 percent of those receiving temozolomide and a response rate, using RECIST criteria, of 15 percent: compared with zero on temozolomide. The hazard ratio was 0.46 -- equivalent to a 54 percent reduction of the risk of progression or death. Four out of five patients taking temozolomide crossed over to selumetinib after having radiographic evidence of disease progression, and the findings in favor of selumetinib were similar in this group too, he said.

 

Gene Variants Targeted

Carvajal explained that since the discovery in 2008 that the GNAQ and GNA 11 mutations alter mitogen-activated protein (MAP) kinase growth pathways (regulating proliferation in uveal melanoma), blocking this pathway has been a logical treatment approach. One of these genes is mutated in more than three quarters of patients with uveal melanoma, and MAP kinase pathways are known to be inhibited by selumetinib.

 

“This follows the new biology and is a rational development, paving the way to develop new treatments,” Schuchter said.

 

Randomization to selumetinib was one-to-one, with crossover permitted so that patients initially randomized to temozolomide could later receive the investigational drug. The primary endpoint of the trial was progression free survival, and the researchers also looked at response rate and overall survival.

 

The MEK inhibitor more than doubled progression free survival, and there was also a trend towards improved overall survival that was detected despite the 80 percent crossover rate, he said in an interview. He said the 15 percent response rate, though modest, is excellent compared with prior trials. There was clear superiority over temozolomide, which brings new hope for this disease, which will be the basis for future studies: “We’re going to continue to pursue the efficacy of MEK inhibition -- either alone or in combinations -- based on more pre-clinical data showing that we can improve efficacy: so there will be a new generation of clinical trials for patients,” he added.

 

The one clinically available drug that blocks MEK -- trametinib -- has been approved for melanomas harboring V-600 BRAF mutations, but those are not involved with uveal melanoma, he noted. “At this point we need to steer patients with uveal melanoma toward clinical trials that afford them access to MEK inhibitors either alone or in combination.

 

“This represents really the first proven effective therapy for these patients, and right now until a MEK inhibitor is approved for uveal melanoma patients, clinical trial participation is very important.”

 

The moderator of an ASCO news briefing that included the study, Gregory A. Masters, MD, Director of the Medical Oncology Fellowship Program at Helen F. Graham Cancer Center in Delaware, called the study results “exciting” and “a breakthrough.” Target-specific therapies are emerging from the expanding science knowledge base about the way tumors grow and spread, and this is one of many studies that support that, he said.