By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: Selumetinib, a selective MEK1/2 inhibitor, achieved objective responses in 15% of patients with recurrent low-grade serous ovarian cancer (LGSOC). The data are relevant as this uncommon tumor type is associated with general chemoresistance, frequent aberration in the MAPK pathway, and prolonged overall survival compared with its more common high-grade variant. Phase 3 trials are planned.
Source: Farley J, 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;14:134-140.
Low-grade serous carcinoma of the ovary (LGSOC) is a distinct histological variant characterized by chemoresistance, frequent mutations in the MAPK pathway, and prolonged overall survival. Based on its molecular characterization, a Phase 2, open-label, single-arm trial was conducted by the Gynecologic Oncology Group using selumetinib, an oral, selective inhibitor of MEK1/2. This gene is a downstream target of many growth factors for which the ras and raf oncogenes serve as important substrates. In this trial, women (aged ≥ 18 years) with recurrent low-grade serous ovarian or peritoneal carcinoma were given selumetinib (oral 50 mg twice daily) until progression. The primary endpoint was the proportion of patients who had an objective tumor response. Secondary endpoints were progression-free survival (PFS), duration of response, overall survival (OS), toxicity and tolerance of therapy, and an exploratory analysis of K-ras and B-raf mutation was made to response. In all, 52 patients were enrolled in this flexible, two-stage Phase 2 trial over a 2-year period. All patients were eligible for analyses. Eight (15%) patients had an objective response to treatment — one patient had a complete response and seven had partial responses. The median time to response was 4.8 months and the median duration of response was 10.5 months. Thirty-four (65%) patients had stable disease. The median PFS was 11 months and the median OS has not been reached. Thirty-three (63%) patients had non-progressive disease at 6 months. There were no treatment-related deaths. Grade 4 toxicities were cardiac (1), pain (1), and pulmonary events (1). Grade 3 toxicities that occurred in more than one patient were gastrointestinal (13), dermatological (9), metabolic (7), fatigue (6), anemia (4), pain (4), constitutional (3), and cardiac events (2). No correlation to response based on K-ras/B-raf mutation was seen among the 34 patients who had enough genomic DNA for this analysis. The authors concluded that selumetinib is well tolerated and is active in the treatment of recurrent LGSOC; further investigation is warranted in these patients.
LGSOC is a distinct subset of serous ovarian cancer characterized morphologically by low-grade nuclear atypia and infrequent mitotic counts.1 Unlike other histologies classified by the World Health Organization, serous cancer is now considered in two tiers: low grade and high grade. These categories do not strictly follow Grade 1 vs Grade 2/3; in fact, a retrospective review of serous histology in a large Phase 3 chemotherapy adjuvant trial demonstrated that 8 of 21 (38%) low-grade ovarian tumors were initially classified as FIGO grade 2/3.2 This grading scheme has shown strong intra- and inter-pathological validity and was a strength of the current study, as all pathology was reviewed and confirmed on potential participants before registration.3 Genomically, LGSOC is more closely aligned with serous tumors of low malignant potential (borderline tumors) than to high-grade serous ovarian cancer, despite the two histology types demonstrating invasion and metastatic and recurrence potential.4 And, like platinum-resistant high-grade serous cancer, LGSOC is dramatically chemoresistant, demonstrating 4% or less objective response to a number of commonly used, FDA-approved cytotoxic agents for ovarian cancer management.5 Further, it was the identification of mutations in the MAPK pathway (rare in high-grade serous ovarian cancer) that provided the rationale for using a MEK inhibitor in this disease.6 MEK is a downstream target of a series of growth factor activation (e.g., IGF1-R, EGFR, VEGFR, etc.) that govern important cellular characteristics such as growth, proliferation, and metastases. As was observed in the trial, mutations in the immediate substrates such as ras and raf are frequent and can lead to MEK activation. The observed response rate of 15% is impressive in the patient population given the low likelihood of objective response based on historical data with chemotherapy and hormonal therapy. Although it was disappointing to not see a direct relationship between mutation in these upstream effectors and objective response, there are several caveats to consider: 1) the test samples were from initial diagnosis in most cases (the median number of chemotherapy regimens before trial entry was 3), 2) only the most common K-ras and B-raf mutations were studied, 3) only a proportion of the original population was tested, and 4) there is likely tumor heterogeneity between the primary and metastatic sites. The trial is important because it provides a clear path to potential registration in randomized trials. In these efforts, physician’s choice of therapy can be used as a control arm and toxicity profiles can be extremely relevant, even if there are no response or survival differences. Currently, two randomized trials of a MEK inhibitor vs physician’s choice are set to begin this year. It is a unique opportunity to demonstrate targeted therapy in a subset of ovarian cancer patients where effective options, other than more surgery, are limited.
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3. Malpica A, et al. Am J Surg Pathol 2007;31:1168-1174.
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5. Gershenson DM, et al. Gynecol Oncol 2009;114:48-52.
6. Nakayama N, et al. Br J Cancer 2008;99:2020-2028.