Selumetinib Is Active, Well-Tolerated Treatment in Low-Grade Serous Ovarian Cancer

David Gershenson, MD

A phase II study found that the novel small-molecule inhibitor selumetinib is well tolerated and achieved an objective response in patients with low-grade serous carcinoma of the ovary or peritoneum. The results of the study were published in The Lancet Oncology.¹

Although women diagnosed with low-grade serous ovarian cancer tend to live longer than women with highgrade serous carcinoma, their disease also tends to be chemoresistant to first-line therapies, as well as therapies for recurrent disease. Because of this, researchers have been exploring ways to utilize targeted therapies to treat the disease.

“After surgery, with or without presurgical chemotherapy, when low-grade serous ovarian cancer persists or returns, chemotherapy and hormonal therapy are relatively ineffective,” said David Gershenson, MD, professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston and senior author of the study, in a statement.

Selumetinib is a selective inhibitor of the MEK1 and MEK2 kinases found as part of the MAPK pathway. Alterations of this pathway are frequently associated with lowgrade serous ovarian cancers.

In this open-label, single-arm phase II study, 52 patients with recurrent low-grade serous ovarian or peritoneal carcinoma received 50 mg of oral selumetinib twice daily until their disease progressed. The primary endpoint was the proportion of patients who had an objective tumor response according to RECIST. Additionally, the researchers looked at whether there was any correlation between BRAF or KRAS mutational status and response to selumetinib.

The study found that eight patients (15%) had an objective response to treatment, with one patient achieving a complete response and seven patients achieving partial responses. A total of 34 patients (65%) had stable disease. No treatment-related deaths were observed.

“These are remarkably encouraging results for what can ultimately be a devastating disease,” Gershenson said.

Grade 4 toxicities observed in the study included one cardiac event, one pain event, and one pulmonary event. Grade 3 toxicities that occurred in more than one patient included gastrointestinal (13), dermatological (9), metabolic (7), fatigue (6), anemia (4), pain (4), constitutional (3), and cardiac events (2). In this study population, 42% of patients had dose reductions and 25% of patients discontinued selumetinib due to toxicity.

The mutational status analysis found that some patients had mutations of KRAS and BRAF, but the authors noted that the differences in the percentage of patients with an objective response for any mutation were not significant.

In an accompanying editorial, Sven Mahner and Jacobus Pfisterer, of the Department of Gynecology and Gynecologic Oncology at the University Medical Center Hamburg-Eppendorf in Germany, wrote that sufficient paraffin-embedded tissue needed to study the biological markers associated with these tumors was only available for 65% of the patients in this study, which may have contributed to a lack of correlation between mutation status and response and outcome. However, they also wrote that the encouraging results of this trial warrant further investigation, including the determination of the optimum dosage of the drug so as to avoid dose reductions and drug-related toxicities.²

References

1. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134-140.
2. Mahner S, Pfisterer J. Towards individualised treatment in ovarian cancer. Lancet Oncol. 2013:14(2):101-102.