Selumetinib Controlled Recurrent Low-Grade Serous Ovarian Cancer

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Newswise — CHICAGO — Selumetinib, a small-molecule MEK inhibitor, demonstrated the ability to control low-grade serous ovarian or peritoneal cancer, according to phase II study results presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

The first line of defense against low-grade serous ovarian cancer is surgery, followed by cytotoxic chemotherapy. However, this is a slow-growing cancer and does not respond well to traditional chemotherapies, which target fast-growing cells.

Seeking a more rational treatment approach, Gynecologic Oncology Group (GOG) researchers led by John Farley, M.D., a professor at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Omaha, Neb., used selumetinib to target the MEK-1/2 protein kinase in the MAPK pathway, which is known to mutate in this form of cancer.

GOG researchers assigned 52 women to 100-mg doses of selumetinib orally twice daily in four-week cycles; 33 percent underwent 12 or more cycles. Prior to the study, 58 percent of patients had received three or more rounds of chemotherapy.

Selumetinib controlled the disease in 81 percent of patients. Specifically, eight patients had complete or partial responses to treatment, and 34 had stable disease. The median survival rate without cancer progression was 11 months, and 63 percent of patients had progression-free survival longer than six months. In addition, selumetinib was well tolerated, with three patients experiencing grade 4 adverse events.

“The results were striking,” said Farley. “Many of the patients in the study had received multiple rounds of chemotherapy and were running out of options. By using these tumors’ historical inherent molecular aberrations to select patients for a treatment that in theory could exploit these abnormalities, we took an important step toward individualized cancer therapies.”

In addition to studying the impact of selumetinib on this type of ovarian cancer, investigators were also interested in how patients with RAS/RAF mutations responded to the drug. The team analyzed the tumor DNA from 34 patients, 62 percent of whom had some form of RAS/RAF mutation. Ultimately, they found that RAS/RAF mutations had no impact on patient response.

The study was funded by the National Cancer Institute.

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Presenter: John Farley, M.D.

Abstract Number: CT-05

Title: A phase II trial of selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum

Author Block: John H. Farley1, William E. Brady2, Michael J. Birrer3, Heather Lankes2, Robert Coleman4, Mark Morgan5, Robert Mannel6, Diane Yamada7, David Mutch8, William H. Rodgers9, David M. Gershenson4. 1St. Joseph's Hospital and Medical Center, a member of Catholic Healthcare West, Phoenix, AZ; 2Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3Massachusetts General Hospital, Boston, MA; 4Dept. of Gynecologic Oncology; University of Texas; MD Anderson Cancer Center, Houston, TX; 5Fox Chase Cancer Center, Philadelphia, PA; 6University of Oklahoma Health Sciences Center, Oklahoma City, OK; 7University of Chicago Section of Gynecologic Oncology, Chicago, IL; 8Washington University School of Medicine Department of OB/GYN, St Louis, MO; 9Lenox Hill Hospital Department of Pathology, New York, NY

Background: This study evaluated selumetinib (AZD6244, ARRY-142866) , an inhibitor of MEK-1/2, and explored associations between RAS/RAF mutations with clinical outcome.Methods: Women with recurrent low-grade serous ovarian or peritoneal carcinoma were eligible and received selumetinib at 100 mg orally BID until progression or toxicity. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST v 1.0. BRAF, KRAS, and NRAS mutational analysis was performed.Results: Between December 2007 and November 2009, 52 patients were enrolled. Fifty-eight percent of patients had received at least 3 prior chemotherapy regimens. Eight patients (15.4%) had complete (1) or partial (7) responses, and 34 (65%) had stable disease. The median PFS was 11.0 months. The median number of cycles received was 4.5, and 33% of patients received at least 12 cycles of selumetinib. Sixty-three percent of patients (33/52) had PFS> 6 months. Grade 4 toxicities included cardiac (1 patient), pulmonary (1), and pain (1). The most common grade 3 toxicities were gastrointestinal (13), and dermatologic (9). Thirty-four patients had sufficient DNA for mutational analysis: 6% BRAF, 41% KRAS, 15% NRAS mutations were found, and 38% had no detectable mutation. There were no statistically significant differences in the proportion of responses by any mutation.Conclusions: Selumetinib is well tolerated and is active in the treatment of recurrent low-grade serous carcinoma. In exploratory analyses, response to selumetinib did not appear to be related to RAS/RAF mutational status, however the sample size was small. The 81% disease control rate is encouraging and worthy of further evaluation of MEK inhibitors in this population.