Selumetinib is first drug to help patients with recurrent low-grade ovarian cancer
Article | 11 February 2013 Print This ShareThis
In the first-targeted therapy clinical trial for low-grade serous ovarian cancer, eight of 52 (15%) patients had a complete or objective partial response (tumor shrinkage) and 34 (65%) had no disease progression during the two-year course of the study. Results of the Phase II clinical trial, in which the drug selumetinib was evaluated by the National Cancer Institute's Gynecological Oncology Group, appear in the February edition of The Lancet Oncology.
"These are remarkably encouraging results for what can ultimately be a devastating disease," said David Gershenson, professor in The University of Texas MD Anderson Cancer Center Department of Gynecological Oncology and Reproductive Medicine, and the paper's senior author.
These patients have a median overall survival of 80 months, about twice as long as those with high-grade disease, who are typically in their 60s when diagnosed and comprise 90% of ovarian cancer patients. The average age of women with low-grade cancer falls in the early 40s, Gershenson said, and it's not uncommon to see women in their 20s, 30s and 40s and the occasional teenager with the disease.
Drug under development at Array BioPharma
Encouraging Phase II trial results with selumetinib, a small-molecule MEK inhibitor developed by USA-based Array BioPharma (Nasdaq: ARRY), in women with recurrent low-grade serous ovarian or peritoneal cancer, were presented last year by the Gynecologic Oncology Group at the American Association for Cancer Research Annual Meeting 2012 (The Pharma Letter April 5, 2012).
High-grade serous ovarian cancer is susceptible to chemotherapy upon relapse or recurrence. Cancer-causing genetic mutations in BRAF and KRAS genes occur more frequently in low-grade ovarian cancer, so the researchers chose a drug that targets the molecular network that includes those genes. Selumetinib inhibits MEK1/2, a critical molecule in what's known as the MAPK pathway, which includes BRAF and KRAS. All 52 patients had received at least one previous therapy, with 30 having had three or more. Clinical trial results with selumetinib include:
• Median progression-free survival of 11 months and 34 patients (65%) went at least six months without their disease worsening.
• Two-year overall survival of 55%.
• Median overall survival had not been reached, because more than half of patients (61%) remained alive at the time of data cut-off for the study.
• No treatment-related deaths.
Side effects ranged from cardio and gastrointestinal toxicity to pain, fatigue, anemia and dermatological effects. Of the 52 patients, 22 had their doses reduced and 13 ultimately left the study due to side effects.
Dr Gershenson said researchers will further explore the question of matching drug to mutation during a larger Phase II/III clinical trial that he will lead with investigators from the NCI Gynecological Oncology Group and the UK. The study will enroll 250 patients and is likely to begin later this summer.
A step toward personalized therapy for ovarian cancer
In an accompanying commentary, Sven Mahner and Jacobus Pfisterer, German oncologists who did not participate in the research, note that the study is a step toward individualized treatment for ovarian cancer that reflects important molecular differences between low-grade and high-grade disease.
The response rate and disease stabilization rate are "particularly promising in a setting of heavily pre-treated recurrent disease," they said. "A strength of the study is mandatory reference pathology of recurrent disease to ensure exclusion of patients with progression to high-grade disease, who are likely to benefit from chemotherapy, and recurrent borderline ovarian tumors that have excellent prognosis with salvage surgery alone," Drs Mahner and Pfisterer wrote.