Inhibitor Binimetinib Research Articles

Refining Radiation for the Next Century.

![][1] Wilhelm Roentgen's report more than a century ago describing X-ray imaging fostered in the application of ionizing radiation (IR) for cancer therapy. Today, about half of all the patients with cancer are treated with radiotherapy and it remains one of our most effective

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma.

Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.Experimental Design and Results: BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic, and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP, and NUPR1 and the proapoptotic protein PUMA. MEKi such as binimetinib induced the expression of the proapoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process.Conclusions: The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. Clin Cancer Res; 23(20); 6203-14. ©2017 AACR.

Binimetinib for the treatment of NRAS-mutant melanoma

ABSTRACTIntroduction: Activating NRAS mutations occur in approximately 15–20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients.Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy.Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy.

MEKi‐related retinopathy

SummaryPatients that are being treated for different types of malignancies may develop eye problems, which may be due to their treatment. We studied patients that received treatment with the MEK inhibitor binimetinib prospectively: 23% of 30 patients with metastatic cutaneous melanoma and 5 patients with metastatic uveal melanoma reported visual complaints during treatment. These complaints were time‐dependent, mild, and reversible. OCT revealed serous subretinal fluid in 74% of patients. Moreover, a persistent profoundly abnormal electro‐oculogram was found, indicating a panretinal dysfunction of the retinal pigment epithelium. Since no other abnormalities could be detected on multimodal imaging, this clinical entity is referred to as MEK‐associated serous retinopathy.Ophthalmological monitoring is warranted in patients using MEK inhibitors; however, discontinuation of administration generally does not seem necessary because of the relatively low visual impact and transient nature of the associated serous retinopathy. Possible pathogenetic mechanisms of this retinopathy include anti‐RPE and anti‐retinal autoantibodies and/or direct RPE toxicity of MEK inhibitors.Ophthalmology. 2015 Sep;122(9):1907‐16. https://doi.org/10.1016/j.ophtha.2015.05.027

MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors.

The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma.

Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.Results: Sensitivity to binimetinib and ribociclib was inversely related (r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR.

Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. Array BioPharma and Novartis Pharmaceuticals Corporation.

Cooperative Epigenetic Remodeling By TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity

Epigenetic modifiers and signaling factors are frequently mutated and often co-occur in various myeloid malignancies. However, precisely how these mutations cooperate to cause myeloid leukemia is not fully understood. Here, we show that cells with concurrent Ten-eleven-translocation 2 (Tet2) loss and Nras mutation can cause lethal chronic myelomonocytic leukemia (CMML) like disease in vivo and synergistically activate Ras signaling through epigenetic silencing of Sprouty 2 (Spry2), thereby making cells with both disease alleles dependent on MAPK signaling and highly sensitive to MEK inhibition.To assess if Tet2 loss and Nras mutation cooperate in myeloid transformation, we crossed Tet2 conditional knockout mice (Mx1-Cre+Tet2f/f) and Nras mutant mice (Mx1-Cre+Nras+/G12D) to generate Mx1-Cre+Tet2f/fNras+/G12D mice (Tet2Δ/ΔNras+/G12D). These mice, compared to single mutant mice with either allele alone, had more significant monocytosis, expansion of Lineage- Sca-1+ c-Kit+ (LSK) and myeloid progenitors in both bone marrow (BM) and spleen and development of lethal CMML-like disease (median survival 264 days). Moreover, serial transplantation of splenic cells derived from leukemic Tet2Δ/ΔNras+/G12D mice caused similar CMML-like disease in recipients, which emanates from LSK-positive stem/progenitor cells as the disease propagating population.To delineate how Tet2 loss and Nras mutation synergize in leukemic transformation, we next performed western blot and phospho-flow analysis of MAPK and PI3K signaling in primary hematopoietic cells. Interestingly, pErk, pAkt and pS6 expression were significantly higher in Tet2Δ/ΔNras+/G12D cells compared to WT or single mutant cells, indicating that Tet2 loss and Nras mutation cooperates to further activate Ras signaling (Figure 1). Consistent with our murine model, TET2 silencing in NRAS mutant human leukemia cells increased MAPK output, consistent with augmentation of signaling by concurrent TET2/NRAS alterations in human leukemia cells.To unravel the molecular mechanism of Ras signaling activation, we assessed mRNA / protein expression and performed bisulfite sequencing of known regulators of MAPK signaling, including Sprouty family members. We observed significant decrease of Spry2 expression, stepwise and specific hyper-methylation of CpG islands in the Spry2 promoter region in Tet2Δ/ΔNras+/G12D cells compared to WT or single mutant cells, consistent with progressive epigenetic remodeling in these leukemia cells in vivo (Figure 2). Genome wide methylation profiling of WT, single mutant and Tet2Δ/ΔNras+/G12D LSK cells using enhanced reduced representation bisulfite sequencing demonstrated clear separation of leukemic Tet2Δ/ΔNras+/G12D LSKs from WT or single mutant LSKs. Most importantly, restoration of Spry2 expression in Tet2Δ/ΔNras+/G12D cells led to decrease in pErk / pAkt level and significantly reduced colony formation, which functionally validates Spry2 as a key epigenetic target in Tet2/Nras mutant leukemia cells.We next assessed whether the increased MAPK signaling seen in Tet2Δ/ΔNras+/G12D cells leads to differential sensitivity to MEK inhibition by performing studies with the clinical MEK inhibitor binimetinib (ARRY162). Tet2Δ/ΔNras+/G12D cells showed significantly higher sensitivity to binimetinib compared to Nras+/G12D cells in vitro (IC50, 6.948nM vs. 690.4nM). Moreover, in vivo treatment of Tet2Δ/ΔNras+/G12D leukemic recipients with binimetinib restored splenomegaly, significantly reduced disease burden in BM and spleen and improved overall survival compared to vehicle treatment (median survival 24.5 days vs. 44.5 days, p=0.0018, Figure 3). Of note, knockdown of human TET2 in NRAS mutant human leukemia cells sensitized to MEK inhibition in a similar manner demonstrating this approach may have value in leukemia patients with concurrent TET2 and NRAS mutations.These data clearly indicate that Tet2 loss and Nras mutation synergize in myeloid transformation and cooperatively remodel DNA methylation, which leads to epigenetic silencing of Spry2 and synergistic activation of MAPK signaling, which can be leveraged through therapeutic MEK inhibition. Our studies provide novel insights into how signaling and epigenetic mutations cooperate in leukemic transformation and provide a rationale for mechanism based therapy in CMML patients with these high risk genetic lesions. [Display omitted] [Display omitted] [Display omitted] DisclosuresMelnick:Janssen: Research Funding. Levine:Qiagen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

BackgroundMitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. Patients and methodsIn this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. ResultsSixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. ConclusionsBinimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients

Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.

Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2199-z) contains supplementary material, which is available to authorized users.

Abstract 666: Activity of the MEK inhibitor Binimetinib (MEK162) in combination with paclitaxel in patient-derived xenograft models of high-grade serous ovarian carcinoma

Abstract High-grade serous ovarian carcinoma (HGSOC) has the poorest prognosis amongst all gynecological cancers with a median survival of approximately 5 years. While most patients (pts) initially respond to therapy, few achieve long-term remission or cure; thus, new treatment strategies are needed. Paclitaxel (Pac), an agent commonly used in the treatment of HGSOC, induces the Ras/Raf/MEK/ERK pathway and resistance may be partially mediated through activation of MEK/ERK, suggesting a rationale for combining a MEK inhibitor with Pac. Binimetinib (MEK162) is an oral, potent, selective, allosteric small-molecule MEK1/2 inhibitor. The combination of binimetinib and Pac was studied in a panel of in vivo ovarian carcinoma xenograft models derived from either cell lines (A2780, SK-OV-3) or primary patient tumor resections pathologically confirmed to be HGSOC (OVC38B1, OVC604, OVC629, OVC104) and propagated solely in mice (pt-derived xenograft [PDX]). Three of these PDX models were from newly diagnosed pts, while 1 (OVC38B1) was from a pt who had relapsed following a prior response to a platinum/taxane regimen. All models were sequenced for cancer-specific genes by next-generation sequencing; no mutations were found in Ras, Raf, MEK or ERK. To evaluate single-agent and combination activity, tumor-bearing mice received 25 mg/kg Pac IP (days 1,5,9) and/or 30 mg/kg binimetinib PO (days 2-15). Single-agent binimetinib was modestly effective in 3/6 models (tumor growth inhibition [TGI] ≥ 50%), which is consistent with the lack of MAPK pathway mutations in these models. Single-agent Pac was highly effective in 3/6 models (TGI ≥ 90%) including OVC38B1 and 2 PDX models from newly diagnosed pts; the remaining models were taxane-resistant. This is consistent with expected high rates of response in the setting of newly diagnosed pts and/or prior responders. Binimetinib plus Pac had superior efficacy to either agent alone in 4/6 models including all taxane-resistant models. In 2 PDX models from newly diagnosed pts, combination activity was not improved, but Pac was highly effective as a single agent (72-82% regression) leaving little room for enhancement. Encouragingly, the combination induced tumor regressions in 2 taxane-resistant models in which no single-agent regressions were observed. In conclusion, in vivo drug sensitivity studies with binimetinib and Pac recapitulate the response expected in HGSOC based on stage, genetic background and clinical history. In models of taxane-resistant disease, combination with binimetinib had improved activity over taxane alone warranting further study of this approach in HGSOC. Citation Format: Shannon L. Winski, Karyn Bouhana, Susan Rhodes, LouAnn Cable, Deborah Anderson, Lance Williams, Brian Tunquest, Tiffany Logan, Guy Vigers, Patrice Lee. Activity of the MEK inhibitor Binimetinib (MEK162) in combination with paclitaxel in patient-derived xenograft models of high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 666. doi:10.1158/1538-7445.AM2015-666

Malignant head and neck melanoma: Part 2: Therapy

Resection margins of melanomas in the head and neck region often have to be adapted according anatomical circumstances. In the case of thicker primary tumors or after complete resection of locoregional lymph node metastases, adjuvant therapy with interferon-α can be performed; in some cases, adjuvant radiotherapy may also be indicated. In the case of inoperable lymph node or distant metastases, systemic treatment is required. Beside well-established mono- or polychemotherapy regimens, newer targeted therapies with BRAF inhibitors (vemurafenib, dabrafenib), mitogenic-activated protein kinase (MEK) inhibitors (trametinib, binimetinib, and cobimetinib), and kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib) are also available.

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma

To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. Prospective observational, cohort-based, cross-sectional study. Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.

Overall Survival and Biomarker Results from a Phase 2 Study of Mek1/2 Inhibitor Binimetinib (Mek162) in Patients with Advanced Nras-Mutant Melanoma

ABSTRACT Aim: No approved therapies exist that specifically target NRAS-mutant melanoma (≈ 20% of cases). In this study of BRAF V600- or NRAS-mutant melanoma, binimetinib, a potent and selective MEK1/2 inhibitor, was the first targeted therapy to show preliminary clinical activity in NRAS-advanced melanoma (Ascierto et al. Lancet Oncol, 2013). Methods: This is a phase 2 open-label single arm study of binimetinib 45 mg orally twice daily (bid) in patients with advanced/unresectable or metastatic BRAF V600- or NRAS-mutant melanoma. Updated efficacy, safety, and biomarker analyses of a larger NRAS-mutant subgroup than previously reported are presented here. Primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival (PFS) and overall survival (OS). Genomic profiling covering a panel of 293 clinically relevant cancer genes was conducted on pretreatment biopsies. Results: Patients with NRAS-mutant melanoma (n = 117) received binimetinib 45 mg bid. Median duration of exposure was 15.9 wks. ORR was 14.5% (1 CR, 16 PRs); disease control rate (≥SD) was 56%. Median PFS was 3.6 mos (95% CI, 2.6–3.8); median OS was 12.2 mos (Lower 95% CI, 7.9). The most common treatment-related adverse events (AEs) were dermatitis acneiform (54%), increased blood creatine phosphokinase (CK, 51%), and peripheral edema (42%). The most common grade 3/4 AE was increased blood CK (25%). Reduced pERK and DUSP6 expression demonstrated MAPK pathway inhibition by binimetinib; however, there was no clear association between efficacy and reduced expression, maybe due to limited data. Genetic landscape of a subset of patients (n = 78) with corresponding efficacy will be presented. CCND1 or CCND3 amplifications were exclusively seen in 5 patients with shorter PFS (≤3.6 mos), suggesting the hypothesis that constitutive CDK4/6 pathway signaling may play a role in resistance. Conclusions: Binimetinib 45mg bid is active in NRAS-mutant melanoma with an acceptable safety profile. A pivotal phase 3 study (NEMO) evaluating binimetinib in NRAS-mutant melanoma is ongoing. Understanding of the genetic landscape will be further refined from data collected in the NEMO study. Disclosure: C. van Herpen: has been on a board of directors and/or advisory board for Merck and has received research funding for Novartis and Merck; A. Hauschild: has received trial grants for Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD, Novartis, Oncosec, Roche. He has also consulted for and received honoraria from these companies and MedImmune; R. Dummer: has received research funding and consulted for Novartis; C. Berking: has consulted for Novartis, Roche, GSK, MSD, BMS, Astrazenca; received honoraria from Novartis, Roche, GSK, MSD, BMS; J.T. Beck: has received research funding from Novartis; D. Schadendorf: has been on a board of directors and/or advisory board, consulted for, and received honoraria from Novartis, GSK, Roche, BMS, Merck, Amgen; received research funding from Merck; G. Gibney: has been on a board of directors and/or advisory committee for and consulted for Genentech/Roche; P. Queirolo: has been on a board of directors and/or advisory committee for Roche, GSK, BMS; has consulted for Roche; received honoraria from GSK; P.A. Ascierto: received research funding from Novartis, Roche-Genentech, Ventana; been on a BOD or advisory committee for Novartis, Roche-Genentech, GSK, BMS; consulted for Roche-Genentech, MSD, GSK, Ventana, received honoraria from BMS, Roche-Genentech, GSK; C. Blank: has received research funding from Novartis and has been on a board of directors and/or advisory committee for Novartis, Roche, BMS, GSK, MSD; H. Nauwelaerts, F. Niazi, V. Antona and A. Zubel: is an employee of Novartis Pharma AG; R.R. Pal: is an employee of Novartis Healthcare Pvt. Ltd.; A. Reddy: is an employee of Novartis Pharmaceuticals Corporation; M.C. Heinrich: has received research funding from Novartis, Pfizer, Ariad, AROG; consulted for Novartis, Pfizer, Ariad, MolecularMD; received honoraria from Novartis, Pfizer, Ariad; owned stock in MolecularMD; provided expert testimony for Novartis. All other authors have declared no conflicts of interest.

Transient MEK inhibitor-associated retinopathy in metastatic melanoma.

Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging. Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography. Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.

Dual targeting of RAF-MEK-ERK and PI3K-AKT-mTOR pathways in RAS-mutant cancers: Preclinical insights and institutional experience from a clinical trial of binimetinib (MEK162) plus BYL719.

e13559 Background: Current development is focused on agents targeting the RAF-MEK-ERK and PI3K-AKT-mTOR pathways. Combinations of these agents may address causes of de novo resistance. Identifying patients (pts) most likely to benefit from these combinations is important. Methods: A panel of 20 cell lines (5 BRAFM, 5 KRASM, 5 PIK3CAM and 5 BRAF/PIK3CA/KRASWT) were exposed to MEK and/or AKT inhibitors and evaluated for inhibition of pathway signaling and cell growth. Inhibition of signaling output of the RAF-MEK-ERK (p-ERK) and PI3K-AKT-mTOR (p-S6) pathways was quantified by ELISA. Growth inhibition was determined using sulforhodamine B assay. Based on the results of preclinical experiments, at our center we prioritized enrolling pts with RAS mutant tumors (including ovarian cancer and non-small cell lung cancer [NSCLC]) into an ongoing phase 1b clinical trial (CMEK162X2109) evaluating the combination of MEK inhibitor binimetinib (MEK162) and the PI3K-α inhibitor BYL719 in pts with RAS and RAF mutant tumor...

Effect of the BRAF inhibitor LGX818 on endoplasmic reticulum stress and sensitivity of NRAS-mutant melanoma cells to the MEK inhibitor binimetinib.

9062 Background: The BRAF inhibitors vemurafenib and dabrafenib have demonstrated antitumor activity in patients with metastatic BRAFV600-mutant melanoma. However, patients with BRAF wild-type, in particular patients with aggressive NRAS-mutant melanoma, do not benefit. In a phase 2 trial, the MEK inhibitor binimetinib showed activity in patients with NRAS-mutant melanoma with overall response rates of >20%. In a previous study, we showed that the BRAF inhibitor vemurafenib induces apoptosis in BRAFV600-mutant melanoma cells through a mechanism involving induction of endoplasmic reticulum (ER) stress. ER stress induction appeared to be an off-target effect of vemurafenib that remarkably enhances its pro-apoptotic activity in BRAFV600-mutant melanoma. Methods: In this study, we investigated whether it is possible to take advantage of ER stress induction to establish effective combination therapies for patients with NRAS-mutant melanoma. Results: BRAF-mutant and NRAS-mutant metastatic melanoma cell lines were treated with the BRAF inhibitors vemurafenib, dabrafenib and LGX818, and the classical ER stress inducer thapsigargin, and were subjected to electron microscopy. Of note, LGX818 induced morphological features of ER stress, including a significant dilation of the ER in both BRAF-mutant and NRAS-mutant melanoma cell lines. As expected, LGX818 inhibited phosphorylation of ERK and growth and induced apoptosis in BRAF-mutant but not in NRAS-mutant melanoma cells. However, LGX818 significantly enhanced growth inhibition and apoptosis induced by the MEK inhibitor binimetinib in NRAS-mutant melanoma cells. Moreover, LGX818 in combination with binimetinib induced the expression of the ER stress-related factors p8, ATF4, ATF3, CHOP and TRB3 in NRAS-mutant melanoma cells. siRNA inhibition of ATF4 reduced melanoma cell apoptosis induced by LGX818 combined with binimetinib. Conclusions: These data suggest that the BRAF inhibitor LGX818 induces endoplasmic reticulum stress and potentiates the antitumor activity of MEK inhibitors in NRAS-mutant melanoma.