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Refractory Serous Ovarian/Peritoneal Cancer: Promising Results with MEK-Inhibitor Selumetinib

LAINO, CHARLENE

doi: 10.1097/01.COT.0000414904.81932.34
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CHICAGO—The oral small-molecule MEK inhibitor selumetinib was safe and effective at controlling low-grade serous ovarian and peritoneal cancer after surgery and other chemotherapy, according to the results of a 52-patient Phase II study by Gynecologic Oncology Group (GOG) researchers reported here at the American Association for Cancer Research Annual Meeting (Abstract CT-05).

John H. Farley, MD, COL (ret), Professor of Gynecologic Oncology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center in Phoenix, presented the findings of the NCI-funded study showing that selumetinib was associated with a median progression-free survival (PFS) time of 11 months, and 63% of patients had a PFS of more than six months. Eight patients had a complete or partial response, and 34 had stable disease.

The drug was generally well tolerated, although three patients had Grade 4 adverse events: one cardiac, one pain, and one pulmonary event, Farley reported. There were numerous Grade 3 adverse events, most commonly gastrointestinal and dermatologic.

A total of 58% of patients had received at least three prior chemotherapy regimens and were running out of options, he noted. "Our response rate is two to three times that seen in the literature [in this cancer]...and there was a 45% increase in survival. The main toxicities were GI and the dermatologic rash sometimes seen with molecular agents."

Patients received 100 mg of selumetinib twice daily in four-week cycles until progression or toxicity. They received a median of 4.5 cycles of selumetinib, and 33% of patients received at least 12 cycles.

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Molecular Studies

Selumetinib targets the MEK-1/2 protein kinase in the MAP kinase pathway, which is known to mutate in this form of cancer. RAS/RAF/MEK/ERK signaling was among the first MAP kinase cascades to be characterized.

JOHN H

JOHN H

Molecular studies suggest that up to 70% of patients with low-grade serous ovarian and peritoneal cancers harbor KRAS and BRAF mutations, Farley said.

As a result, he and his co-researchers had hoped that RAS/RAF mutations would identify responders, but that did not pan out. Testing in the 34 patients who had sufficient DNA for mutational analysis showed no statistically significant differences in the proportion of responses by these mutations.

Yet, pERK (protein kinase-like ER kinase) positivity was associated with response. The median progression-free survival time was 11.3 months in patients with pERK scores greater than 108 vs. 5.9 months for those with lower pERK scores, he said. "We were looking for a logical way to treat these patients, and it seemed logical that MEK would be active, and it appears we were correct, but the activity doesn't appear strictly related to the RAS/RAF mutation."

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Several MEK Inhibitors in Development

José Baselga, MD, PhD, Chief of the Division of Hematology and Oncology and Associate Director of Massachusetts General Hospital Cancer Center, who moderated a news conference at the meeting that highlighted several late-breaking clinical trials, said, "These are striking results in a disease where conventional therapy doesn't work well."

He noted that there are currently about six or seven MEK inhibitors in development. Asked which was the leader of the pack, he said, "All are in early phases. They are probably different, but what is important is they are being utilized in different indications, so it will be an evolving story."

Farley added that all the MEK inhibitors have so far been fairly equivalent in terms of tumor response, but that different drug companies chose to go forward in particular indications. "It appears GlaxoSmithKline is ahead in terms of ovarian cancer," he said, noting that a U.S./U.K. Phase III trial pitting GSK-1120212 against standard therapy in 230 patients with recurrent low-grade serous carcinoma is expected to start later this year.

A member of the audience noted that Array BioPharma Inc. reported last fall that selumetinib missed the primary endpoint in a Phase II study of 87 patients with KRAS-mutant non-small-cell lung cancer, failing to show a statistically significant improvement in survival when added to docetaxel compared with docetaxel alone. However, there was a trend toward prolonged survival compared with docetaxel alone, and several secondary endpoints were met.

© 2012 Lippincott Williams & Wilkins, Inc.
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