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Selumetinib shows promise for patients with recurrent low-grade ovarian cancer
Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States.
Low-grade serous carcinoma accounts for approximately 10% of all ovarian serous carcinomas. It is recognized as a distinct entity from other ovarian cancers based on its unique histologic, molecular and clinical characteristics.
Although low-grade serous carcinoma is more indolent and carries a favorable prognosis compared with high-grade serous carcinoma, it is more resistant to conventional systemic therapies.
Figure 1. MAPK and PI3K/AKT pathways in ovarian low-grade serous carcinoma.
Source: Adapted from Britten CD. Cancer Chemother Pharmacol. 2013;71:1395-1409.
In the recurrent setting, only 3.7% of patients respond to chemotherapy. Low-grade serous carcinomas also have a higher frequency of KRAS (20% to 40%) and BRAF (5% to 33%) mutations, as well as increased frequency of expression of activated mitogen-activated protein kinase (MAPK).
Selumetinib (AZD6244, AstraZeneca) is an oral investigational agent that has demonstrated improved response and PFS among patients with recurrent low-grade ovarian cancer.
Mechanism of action
Selumetinib is a potent, selective, small-molecule inhibitor of the MAPK MEK 1/2.
The MAPK signaling pathway plays an important role in regulating the proliferation, differentiation and survival of cancer cells. Genetic mutations in KRAS,BRAF or NRAS lead to constitutive activation of the MAPK pathway. In preclinical studies, activation of KRAS, BRAF or NRAS mutations correlated with sensitivity to MEK inhibitors.
Due to a significantly higher expression of MAPK in ovarian low-grade serous carcinoma (81%) compared with high-grade serous carcinoma (41%), MEK inhibitors represent an attractive novel treatment option for low-grade ovarian cancer. Figure 1 depicts selumetinib’s action in the MAPK pathway.
Little has been characterized about selumetinib’s pharmacokinetic and pharmacodynamic properties because the drug is still in clinical trials.
Selumetinib is given orally twice daily, with a mean half-life of approximately 5 to 8 hours. Preliminary data suggest that selumetinib should be administered on an empty stomach, due to decreased absorption when given with food. Relevant drug interactions remain unknown.
Efficacy
Treatment options for recurrent low-grade serous carcinoma are limited and include primarily chemotherapy and hormonal therapy.
Response rates for systemic therapies are fairly dismal; however, rates of stable disease range from 60% to 62%. PFS is similar for both chemotherapy and hormonal therapy at 7 to 7.5 months.
Table 1 summarizes the efficacy data for chemotherapy, hormonal therapy and selumetinib for low-grade ovarian cancer in the recurrent setting.
There currently are no FDA-approved targeted therapies for the treatment of ovarian cancer.
Farley and colleagues conducted an open-label, single-arm, phase 2 study to evaluate the efficacy of selumetinib for the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum.
Fifty-two patients (median age, 51 years) received selumetinib 50 mg orally twice daily in 4-week cycles until disease progression. The median number of cycles given per patient was 4.5, with 33% of patients receiving at least 12 cycles.
Patients were heavily pretreated; 58% had received three or more previous chemotherapy regimens.
The results, published in The Lancet Oncology in 2013, showed the overall response rate (complete response plus partial response) was 15%. Sixty-five percent of patients achieved stable disease. Of those who responded, the median time to response was 4.8 months and the median duration of response was 10.5 months.
Median PFS was 11 months. Median OS has not yet been reached.
Selumetinib was associated with a higher overall response rate and longer PFS than historical results for chemotherapy and hormonal therapy, although the regimens were not compared directly. Rates of stable disease were similar. These results are encouraging, particularly for patients with disease refractory to several lines of chemotherapy.
Farley and colleagues also analyzed patients’ tissue samples for BRAF and KRAS mutations. Thirty-four patients had sufficient DNA for mutation analysis; of them, 6% were positive for BRAF mutations and 41% were positive for KRAS mutations. Samples were not analyzed for NRAS mutations.
Differences in rate of response for any mutation were not significant, suggesting that selumetinib’s efficacy may not be solely due to BRAF or KRAS mutational activation. Other mutations also may play a role in MAPK activation and response to MEK inhibition.
To our knowledge, this was the first prospective trial dedicated to patients with ovarian low-grade serous carcinoma.
Toxicity
Selumetinib is fairly well tolerated.
Banerji and colleagues conducted a phase 1, first-in-human study in which 30 patients with advanced cancers received selumetinib at escalating doses.
Dose-limiting toxicities included grade 3 acneiform rash and grade 3 pleural effusion in the 100 mg twice daily cohort. At the maximum tolerated dose of 75 mg twice daily, the most common adverse effects were fatigue, acneiform rash, nausea, diarrhea and peripheral edema.
No treatment-related deaths occurred during the phase 2 clinical trial of selumetinib. Forty-two percent of patients required dose reductions and 25% came off study because of toxicity. Table 2 summarizes selumetinib-related toxicities during the phase 2 study.
Adverse effects of any grade occurring in more than 50% of patients included gastrointestinal, constitutional, metabolic and dermatologic events, fatigue and pain.
Grade 4 toxicities occurred in three patients (one each for cardiac, pain and pulmonary events). The most frequent grade 3 toxicities were gastrointestinal, dermatologic and metabolic events, as well as fatigue. Grade 3 gastrointestinal and dermatologic toxicities were tolerable and manageable.
Future directions
Although the results of the phase 2 clinical trial show great promise for selumetinib for the treatment of ovarian low-grade serous carcinoma, a phase 3 head-to-head study to compare the efficacy of selumetinib with conventional therapies is warranted.
There are no active phase 3 studies for selumetinib in patients with low-grade ovarian cancer. However, there is a phase 3 trial designed to compare a MEK 1/2 inhibitor, MEK162 (Novartis) to chemotherapy of the physician’s choice. The results of this study are highly anticipated.
Recent evidence has demonstrated that the addition of a PI3K inhibitor to a MEK inhibitor may have a synergistic effect on tumor cells due to interaction between the MAPK and PI3K/AKT pathways. This combination is under investigation in phase 1 and phase 2 studies in selected advanced solid tumor patients with BRAF and KRAS mutations.
The role of the PI3K/AKT pathway in ovarian cancer remains unclear.
Conclusion
It was not until the past decade that it became evident that low-grade serous carcinoma is associated with unique histologic, molecular and clinical characteristics compared with the more common high-grade serous carcinoma. This discovery has led to the development of targeted therapies that show promise in an otherwise chemoresistant disease.
Selumetinib is a well tolerated, oral MEK 1/2 inhibitor that has demonstrated substantial activity in low-grade serous carcinoma of the ovary.
Selumetinib represents an exciting new direction for the treatment of ovarian cancer and personalized medicine. Phase 3 studies will further elucidate the role of MAPK inhibition and other targeted therapies for the treatment of low-grade ovarian cancer.
References:
Banerji U. Clin Cancer Res. 2010;16:1613-1623.
Britten CD. Cancer Chemother Pharmacol. 2013;71:1395-1409.
Farley J. Lancet Oncol. 2013;14:134-140.
Gershenson DM. Am Soc Oncol Educ Book. 2013:195-199.
Gershenson DM. Gynecol Oncol. 2009;114:48-52.
Gershenson DM. Gynecol Oncol. 2012;125:661-666.
Leijen S. Cancer Chemother Pharmacol. 2011;68:1619-1628.
Schmeler KM. Curr Oncol Rep. 2008;10:519-523.
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Disclosure: Dickens, Walls and Tran report no relevant financial disclosures.