binimetinib and Ovarian-Neoplasms

Low-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.. This 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.. A 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. Although 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

Topics: Adult; Aged; Benzimidazoles; Cystadenocarcinoma, Serous; Doxorubicin; Fallopian Tube Neoplasms; Female; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Polyethylene Glycols; Progression-Free Survival; Protein Kinase Inhibitors; Topotecan; Young Adult

Topics: Benzimidazoles; Cystadenocarcinoma, Serous; Fallopian Tubes; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Ovarian Neoplasms; Peritoneum; Physicians

More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

Topics: Antineoplastic Agents; Benzimidazoles; Bevacizumab; CA-125 Antigen; Carbamates; Carboplatin; Cystadenocarcinoma, Serous; Disease Progression; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; MAP Kinase Kinase 1; Medroxyprogesterone; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Oximes; Paclitaxel; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Sulfonamides; Tamoxifen; Treatment Outcome; Young Adult

Low-grade serous ovarian cancer (LGSOC) is relatively chemoresistant, and no precision therapy is approved for this indication. Despite promising results in phase II trials, MEK inhibitors have failed to show improved progression-free survival in a phase III trial when compared to physician's choice chemotherapy. We report for the first time temporal changes in the tumor genome assessed in sequential tumor samples of a 48-yr-old patient with a

Topics: Benzimidazoles; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Mutation; Ovarian Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); ras Proteins; Receptor, ErbB-3; Signal Transduction

Advanced ovarian cancer is very responsive to first line platinum therapy, however almost invariably it relapses with a resistant disease. We have reported that patient derived ovarian xenografts (PDXs), independently from the degree of the initial response to cisplatin (DDP), show a significantly lower response to a second DDP cycle. We here report the effect of new combination regimens containing a MEK inhibitor (MEK), bevacizumab (BEV) and paclitaxel (PTX) as second line therapy in platinum-relapsing PDXs.We selected three DDP-relapsing PDX models based on the presence of activation of the RAS/RAF/MEK/ERK axis, mutated p53, lack of PTEN expression and activation of the PI3K pathway. In all the selected xenograft models, the antitumor efficacy of the doublets can be summarized as PTX/BEV > BEV/MEK > PTX/MEK and the antitumor activity of the triple combination was higher than any double combination. All the different combinations were well tolerated. The present data corroborate the activity of bevacizumab in combination with chemotherapy for the treatment of relapsing ovarian tumors and suggest that the addition of another targeted agents (MEK inhibitor) can further increase the antitumor activity without any increase in toxicity. PDX models represent a useful model to test second line therapy after failure of DDP first line.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bevacizumab; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Humans; Mice; Mutation; Ovarian Neoplasms; Paclitaxel; Platinum; Recurrence; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

MEK inhibitor chemotherapy, used in various malignancies, has been reported to be associated with serous retinal detachments. This study reports serial multimodal imaging focused primarily on infrared reflectance and spectral-domain optical coherence tomography (SD-OCT) in the monitoring of MEK inhibitor retinal toxicity. The benefit of OCT angiography in understanding the pathophysiology of MEK inhibitor toxicity is also shown.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Female; Fluorescein Angiography; Follow-Up Studies; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Multimodal Imaging; Optical Imaging; Ovarian Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Retina; Retinal Detachment; Thiazoles; Tomography, Optical Coherence

Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK. Here we demonstrate that an additional MAP3K, MAP3K8 (TPL-2/COT), accumulates in high-grade serous ovarian carcinomas (HGSCs) and is a potential prognostic marker for these tumours. By combining analyses on HGSC patient cohorts, ovarian cancer cells and patient-derived xenografts, we demonstrate that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. In addition, we show that the MEK pathway is the main pathway involved in mediating MAP3K8 function, and that MAP3K8 exhibits a reliable predictive value for the effectiveness of MEK inhibitor treatment. Our data highlight key roles for MAP3K8 in HGSC and indicate that MEK inhibitors could be a useful treatment strategy, in combination with conventional chemotherapy, for this disease.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; Cystadenocarcinoma, Serous; Female; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Ovarian Neoplasms; Prognosis; Proto-Oncogene Proteins; Ribosomal Protein S6 Kinases, 90-kDa; Xenograft Model Antitumor Assays