Selumetinib promising for refractory low-grade serous ovarian cancer

By Fran Lowry

NEW YORK (Reuters Health) – Low-grade serous ovarian cancer, an indolent cancer that does not respond well to traditional cytotoxic chemotherapy, appears to respond to selumetinib (AZD-6244), a small-molecule mitogen-activated protein kinase (MEK) inhibitor, researchers said Saturday at the annual meeting of the American Association for Cancer Research.

In a phase II Gynecologic Oncology Group (GOG) study of 52 women, selumetinib controlled low-grade serous ovarian or peritoneal cancer in 81% of the patients, reported Dr. John Farley, from St. Joseph’s Hospital and Medical Center, Phoenix, Arizona.

“This particular type of tumor is very chemo-resistant, and with the therapies we currently have, particularly in the recurrent setting, patients only have a 1% to 2% response rate to traditional chemotherapeutic regimens, which target fast-growing cells,” Dr. Farley told Reuters Health.

“Because this disease usually involves the abdominal cavity and patients tend to have problems with their bowels and eating, it can be very debilitating,” he said.

Selumetinib targets the MEK-1/2 protein kinase in the MAPK pathway, which is known to mutate in this form of cancer.

Women with recurrent low-grade serous ovarian or peritoneal cancer enrolled in the study between December 2007 and November 2009. They received selumetinib 100 mg orally twice a day in four-week cycles until disease progression or toxicity limited treatment. Fifty-eight percent of the women in the trial had already been treated with at least three chemotherapy regimens.

The median number of cycles received was 4.5, and 33% of the patients received at least 12 cycles of selumetinib.

By RECIST criteria, one patient had a complete response, seven had partial responses, and 34 (65%) had stable disease. The median for progression-free survival was 11.0 months, and 63% of patients (33/52) had a PFS greater than six months.

Selumetinib was well tolerated, according to Dr. Farley. Grade 4 toxicities were cardiac in one patient, pulmonary in one patient, and pain in one patient. The most common grade 3 toxicities were gastrointestinal (occurring in 13 patients) and dermatologic (in nine patients).

The researchers also explored associations between rat sarcoma/rapidly accelerated fibrosarcoma (RAS/RAF) family mutations and clinical outcomes. Thirty-four patients had sufficient tumor DNA for mutational analysis. Six percent had BRAF, 41% had KRAS, 15% had NRAS mutations, and 38% had none.

Additionally, 39% of patients had positive expression of phosphorylated-extracellular signal regulated kinases (p-ERK.) The median PFS in those patients was 11.3 months, versus 5.9 months in p-ERK negative patients.

“Initially, we did the study hoping that the mutations would make the tumors more responsive,” Dr. Farley said. “Interestingly, it seems there are other pathways outside of the RAS/RAF mutational pathway which causes over-expression of p-ERK because there were patients who had elevated p-ERK levels but who did not have the RAS/RAF mutation, and 100% of those patients had either stable disease or response to therapy. So it seems there might be another mutation outside of the RAS/RAF mutations which is activating the MAP kinase pathway that we are targeting with this medication. However, we haven’t identified that mutation.”

Dr. Michael Seiden, President and CEO of Fox Chase Cancer Center, in Philadelphia, told Reuters Health that selumetinib is the first “interesting” drug for low-grade serous ovarian or peritoneal cancer to come along “in decades and perhaps ever.”

But he cautioned: “There are still a few things that still need to be worked out. We were hoping the study would detect a molecular marker that would define who would benefit, and it hasn’t done that yet. The other thing is that the tumors are so slow growing that even broccoli would give you stable disease, so you have to be a little careful about how you evaluate stable disease in these very slow-growing tumors.”

Still, the fact that eight patients had a complete or partial response to treatment is important, said Dr. Seiden, who was not on the study team. “One of them had their tumor disappear, which is really unusual, and many of the patients are still on the drug for more than a year. This is now clearly the most active drug we’ve seen in this rare subtype of ovarian cancer and it should be pushed forward.”

This will likely take an international collaborative effort since the tumor subtype is so rare, he added. “There are a lot of people around the world who are anxious to get a new drug for this disease and I do think that actually would be pretty feasible.”

Selumetinib was developed by Array BioPharma Inc and has been licensed to AstraZeneca. The companies are also testing it in combination with dacarbazine as first-line treatment for BRAF-mutant melanoma, and in combination with docetaxel as second-line therapy for KRAS-mutant advanced non-small cell lung cancer.