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Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment.

ABSTRACT: Background:Management of advanced/recurrent low-grade serous ovarian carcinoma (LGOSC) is often challenging. Effective treatment options remain limited for hormone and chemotherapy-resistant LGSOC.CASE: A 65-year-old woman with recurrent widespread LGSOC harboring the KRAS-G12?V hotspot mutation experienced a dramatic clinical response to Binimetinib (MEK162), a mitogen-activated protein kinase (MEK) inhibitor, after failing multiple chemotherapy and hormonal treatments. An 81% reduction of target lesions by RECIST 1.1 over 31?months of response duration was confirmed with serial CT scans. Episodes of drug-related toxicity (pneumonitis) easily resolved without sequelae with the use of oral steroids. Conclusion:Binimetinib may present a new treatment option for hormone- and chemotherapy-resistant LGSOC harboring KRAS mutations.

SUBMITTER: Han C

PROVIDER: S-EPMC6014583 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment.

Han Chanhee C Bellone Stefania S Zammataro Luca L Schwartz Peter E PE Santin Alessandro D AD

Gynecologic oncology reports 20180524

<h4>Background</h4>Management of advanced/recurrent low-grade serous ovarian carcinoma (LGOSC) is often challenging. Effective treatment options remain limited for hormone and chemotherapy-resistant LGSOC.CASE: A 65-year-old woman with recurrent widespread LGSOC harboring the KRAS-G12 V hotspot mutation experienced a dramatic clinical response to Binimetinib (MEK162), a mitogen-activated protein kinase (MEK) inhibitor, after failing multiple chemotherapy and hormonal treatments. An 81% reduction ...[more]

PMID: 29946554

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Project description:PurposeLow-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC.MethodsThis was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety.ResultsA total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent.ConclusionAlthough the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

Project description:Ovarian tumors of low malignant potential and low-grade ovarian serous carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from high-grade ovarian serous carcinoma. We performed gene expression profiling on three normal human ovarian surface epithelia samples, and 10 low-grade and 10 high-grade ovarian serous carcinomas. Analysis of gene expression profiles of these samples has identified 80 genes upregulated and 232 genes downregulated in low-grade ovarian serous carcinomas. PAX2 was found to be one of the most upregulated genes in low-grade ovarian serous carcinoma. The upregulation of PAX2 was validated by real-time quantitative RT-PCR, western blot and immunohistochemical analyses. Real-time RT-PCR showed a statistically significant difference in PAX2 mRNA expression (expressed as fold change in comparison to normal human ovarian surface epithelia) among ovarian tumors of low malignant potential (1837.38, N=8), low-grade (183.12, N=17), and high-grade (3.72, N=23) carcinoma samples (P=0.015). Western blot analysis revealed strong PAX2 expression in ovarian tumors of low malignant potential (67%, N=3) and low-grade carcinoma samples (50%, N=10) but no PAX2 protein expression in high-grade carcinomas (0%, N=10). Using immunohistochemistry, tumors of low malignant potential (59%, N=17) and low-grade carcinoma (63%, N=16) samples expressed significantly stronger nuclear staining than high-grade ovarian carcinoma samples (9.1%, N=263). Furthermore, consistent with earlier immunohistochemical findings, PAX2 expression was expressed in the epithelial cells of fallopian tubes but not in normal ovarian surface epithelial cells. Our findings further support the two-tiered hypothesis that tumors of low malignant potential and low-grade ovarian serous carcinoma are on a continuum and are distinct from high-grade ovarian carcinomas. In addition, the absence of PAX2 expression in normal ovarian epithelia but expression in fallopian tube fimbria and ciliated epithelial inclusions would suggest the potential development of tumors of low malignant potential and of low-grade ovarian serous carcinomas from secondary Müllerian structures.

Dataset Information

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment.

Publications

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment.

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