binimetinib and Neoplasms

Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer.. Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.. Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).. Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Topics: Benzimidazoles; Drug Administration Schedule; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Neoplasms; Proto-Oncogene Proteins B-raf; ras Proteins; Treatment Outcome

Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.. This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients.. Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition.. Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

Topics: Adult; Aged; Antineoplastic Agents; Benzimidazoles; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Japan; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasms; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Retinal Detachment

The use of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors has become more common in the treatment of systemic cancer. These agents have been associated with a central serous-like retinopathy in some patients. Recognition of such retinal findings and the relatively benign nature of these events is important to avoid unnecessary intervention, including the cessation of a potentially life-prolonging medication.. To evaluate the presence and characteristics of subretinal fluid (SRF) associated with the use of MEK inhibitors in the treatment of systemic cancer and to correlate the presence of SRF with visual acuity and symptoms over time.. Post hoc analysis was conducted of prospectively collected data from 51 patients with locally advanced or metastatic cancer undergoing treatment with the MEK inhibitor binimetinib in 1 of 4 clinical trials. All clinical trial participants underwent complete ophthalmic examination by retina specialists at a private practice in Boston, Massachusetts, and were monitored between February 29, 2012, and January 8, 2014. The examination included Snellen-measured visual acuity, dilated fundus examination, and spectral-domain optical coherence tomography at baseline, biweekly for 2 months, then monthly for the remainder of their trial participation. Post hoc design and data analysis were performed between December 1, 2013, and June 20, 2014.. Visual symptoms, visual acuity, fundus appearance, and the presence and characteristics of SRF noted on optical coherence tomography. The characteristics of angiograms performed at the discretion of the treating physician were reviewed.. Of the 51 participants, 18 (35%) were men; the mean (SD) age was 60 (13) years (range, 32-87 years). Forty-six (90%) study participants developed SRF during the study period, with 9 (20%) experiencing symptoms at any point. The mean (SD) central retinal thickness of 39 study participants who developed SRF at the first visit increased from 280 (26) µm at baseline to 316 (43) µm at the first visit after starting binimetinib treatment (paired t test, P < .001). On examination, SRF appeared as elevated, yellow-orange pockets in the fovea and/or along the arcades. Corresponding optical coherence tomographic imaging revealed SRF beneath the interdigitation zone. The fovea was affected in 37 of 46 (80%) individuals; the location of SRF accumulation varied. Visual symptoms were mild and mainly transient, occurring in 9 participants with SRF (20%; 95% CI, 10%-33%). Only 2 participants (4%) were found to have SRF at the last study visit after discontinuation of treatment with binimetinib. Both had Snellen-measured visual acuity of 20/25 or better.. The presence of SRF was common in study participants undergoing treatment with the MEK inhibitor binimetinib. Visual symptoms were mild and mainly transient. The presence of SRF did not lead to permanent ocular sequelae. Cessation of life-extending treatment with MEK inhibitors is not indicated when SRF is present.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Central Serous Chorioretinopathy; Female; Fluorescein Angiography; Fundus Oculi; Humans; Male; MAP Kinase Kinase 1; Middle Aged; Neoplasms; Prospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Visual Acuity

To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors.. A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT).. Single-center, retrospective cohort study.. Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point.. Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation.. The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001).. The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azetidines; Benzimidazoles; Central Serous Chorioretinopathy; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Retrospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Visual Acuity; Young Adult

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers; Body Weight; Cachexia; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Morpholines; Muscle, Skeletal; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Benzimidazoles; Cachexia; Cell Line, Tumor; Enzyme Activation; Humans; Mitogen-Activated Protein Kinases; Neoplasms; Protein Kinase Inhibitors

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an impact on viability. However, inhibition of mTOR or combined inhibition of MEK and mTOR reduced cell growth in a synergistic manner. Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition. Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.

Topics: Animals; Apoptosis; Benzamides; Benzimidazoles; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Diphenylamine; Humans; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays