Selumetinib is well tolerated and active in recurrent LGSC of the ovary or peritoneum.
Major finding: Selumetinib is well tolerated and active in recurrent LGSC of the ovary or peritoneum.
Concept: LGSC of the ovary exhibits MAPK activation and a high frequency of KRAS and BRAF mutations.
Impact: Further clinical studies of MAPK pathway inhibitors are warranted for patients with LGSC.
Low-grade serous carcinomas (LGSC) of the ovary and peritoneum are histologically and molecularly distinct from high-grade serous carcinomas and largely resistant to cytotoxic chemotherapeutics. Because LGSCs frequently harbor activating mutations in components of the MAPK pathway, including the KRAS and BRAF oncogenes, Farley and colleagues assessed the safety and efficacy of selumetinib, a selective small-molecule inhibitor of MAP/ERK kinase (MEK) 1 and MEK2, in patients with LGSC. In an open-label, single-arm phase II trial, 52 women with pathologically confirmed, recurrent LGSC of the ovary or peritoneum were treated with selumetinib, and the proportion of patients with an objective tumor response was determined as the primary endpoint. Although 58% of the patients had previously received several chemotherapeutic treatments, 8 patients (15%) experienced an objective response, including 1 complete response and 7 partial responses, and 65% had stable disease after selumetinib treatment. The median progression-free survival (PFS) was 11 months, with a PFS longer than 6 months in 63% of patients, and median overall survival was not yet reached. Selumetinib was well tolerated, as grade 4 toxicities only occurred in 6% of patients; the most common grade 3 toxicities were manageable with dose reductions and included gastrointestinal, dermatologic, and metabolic adverse events. Intriguingly, genomic analysis of tumor DNA samples indicated that objective response to selumetinib was not significantly associated with the presence of a mutation in KRAS or BRAF. These findings suggest MEK1/2 inhibition as a more effective and less toxic strategy for the treatment of patients with recurrent LGSC compared with cytotoxic chemotherapy and support additional investigation of agents targeting the MAPK pathway in this disease.
Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, 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 2012 Dec 21 [Epub ahead of print].
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