In a phase II trial of the experimental MEK inhibitor selumetinib (AZD6244), women who had failed 3 or more rounds of chemotherapy had 81% disease control and a median progression-free survival of 11.3 months.
Treatment with selumetinib benefits women with tumors overexpressing p-ERK
Low-grade serous ovarian cancer is notoriously resistant to cytotoxic chemotherapy; fewer than 15% of women respond initially. But in a phase II trial of the experimental MAP–ERK kinase (MEK) inhibitor selumetinib (AZD6244), women who had failed 3 or more rounds of chemotherapy had 81% disease control and a median progression-free survival (PFS) of 11.3 months.
Unexpectedly, benefit correlated more closely with the protein p-ERK than with mutation of BRAF, the protein that selumetinib targets.
About 60% of low-grade ovarian tumors have RAS/RAF activation of the MAPK pathway. However, for this trial, the researchers did not have exhaustive mutational analysis prior to selecting the 52 participants.
“In this era of individualized medicine, we still enrolled participants regardless of tumor genotype, and we're glad we did,” says John Farley, MD, a professor at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center in Omaha, NE. Farley is scheduled to present the results at the American Association of Cancer Research Annual Meeting 2012 in Chicago at a press conference on March 31 and a session on April 3.
“We found that many patients without the BRAF mutation targeted by selumetinib still had an overexpression of p-ERK, and if they did, they benefited,” says Farley. “That indicates there is another mechanism for activation in the MAPK pathway that we could take advantage of.”
Over the 2-year trial, 8 patients (15.4%) responded to the therapy, 34 (65%) had stable disease, and 33 (63%) had PFS of greater than 6 months. “These results are significantly better than anything reported to date,” Farley says. All of the 39% of participants with p-ERK overexpression either responded or had stable disease. The drug was well tolerated.
Of the 34 patients who had sufficient DNA for mutational analysis, 6% had mutations in BRAF, 41% in KRAS, and 15% in NRAS, which was identified for the first time in this cancer, whereas 38% had mutations in none of these genes.
The researchers plan to launch a phase III trial comparing a MEK inhibitor to cytotoxic chemotherapy in recurrent low-grade serous ovarian cancer.