MEK Inhibitor Therapy Research Articles

COLUMBUS-AD: phase III study of adjuvant encorafenib+binimetinib in resected stage IIB/IIC BRAF V600-mutated melanoma.

Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib+binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.

Adverse cutaneous reactions associated with MEK inhibitor therapy in a pediatric population

Adverse cutaneous reactions associated with MEK inhibitor therapy in a pediatric population

A chance to cut is a chance to cure: complete resection of an atypical neurofibroma prevents further progression to malignancy.

Plexiform neurofibromas are the hallmark of neurofibromatosis type 1 (NF1) and significantly contribute to the overall burden of disease. While surgical excision has long been the only available therapy, the MEK inhibitor (MEKi) selumetinib has been approved as a non-surgical treatment option for these tumors in 2020 (USA) and 2021 (Europe), respectively. However, selumetinib will result in tumor shrinkage only after several months of therapy and might not prevent malignant transformation of a plexiform neurofibroma that occurs with a frequency of 10-15%. Here, we demonstrate that surgical excision might be the therapy of choice in some plexiform neurofibromas despite the availability of MEKi therapy.

LGG-14. TREATMENT OF TWO PEDIATRIC FGFR-ALTERED LOW-GRADE GLIONEURONAL TUMORS WITH MEK INHIBITION

Abstract Somatic alterations in the fibroblast growth factor receptor (FGFR) gene family (FGFR1/2/3) have been implicated in tumorigenesis across pediatric low-grade glioneuronal neoplasms and represent a potential therapeutic target. FGFR rearrangements and internal tandem duplication (ITD) cause constitutive receptor tyrosine kinase activation, thereby promoting tumor cell growth, differentiation, and survival through complex downstream signaling, including via the mitogen activated protein kinase (MAPK) pathway. With increasing safety and efficacy data in pediatric neuro-oncology, MEK inhibitors may be considered to target MAPK pathway activation in FGFR-altered low-grade glioneuronal tumors, although clinical evidence within this specific molecular subgroup is lacking. Herein, we describe two cases of pediatric low-grade glioneuronal tumors harboring FGFR aberrations with encouraging clinical and radiographic response to MEK inhibition. The first patient has a multiply recurrent left parietal dysembryoplastic neuroepithelial tumor (DNET) with an FGFR1 ITD, diagnosed at eight years of age after presenting with seizures. Despite two surgical resections (with identical pathology), his disease slowly progressed. Oral MEK inhibitor therapy with trametinib was initiated, which he has remained on for the past 9+ months, with stable residual tumor without continued radiographic progression. The second patient was diagnosed at three years of age with focal epilepsy, prompting imaging demonstrating an infiltrative T2/FLAIR-hyperintense right temporal mass. Subtotal resection was performed, with pathology consistent with pediatric-type diffuse low-grade glioma. Molecular profiling identified an FGFR3-TACC3 fusion, with suspected enrichment for MAPK-pathway activation by preliminary RNA-sequencing analyses. Adjuvant therapy with trametinib was started, with small reduction in residual disease burden observed radiographically three months into treatment. Both patients continue on MEK inhibitor therapy with minimal toxicity and adequate control of underlying seizures. Though further research in larger, prospective cohorts with comprehensive biology data is necessary, oral MEK inhibitors represent a feasible and rational treatment consideration for pediatric FGFR-altered low-grade glioneuronal tumors.

Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) with Direct Cystic Infiltration of the Optic Chiasm and Tracts (P1-9.003)

<h3>Objective:</h3> N/A <h3>Background:</h3> Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare pediatric neoplasm categorized by the WHO in 2016. It is characterized by communicating hydrocephalus, slow tumor growth, CSF with absence of tumor cells, and MRI showing diffuse leptomeningeal enhancement and cystic changes. Here we present, to our knowledge, the first case in which direct cystic tumor infiltration of the optic apparatus was the initial manifestation. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 3-year-old boy developed emesis, altered mental status, bilateral leg weakness, and decreased visual acuity to 20/125 OD and 20/160 OS. MRI showed hydrocephalus and diffuse leptomeningeal enhancement of the brain and spine. Lumbar puncture showed pleocytosis, elevated protein, positive enterovirus PCR, and opening pressure of 55 cm H2O. VP shunt was placed for presumed enterovirus meningitis. Symptoms of hydrocephalus resolved but vision did not improve. Exam showed optic disc pallor bilaterally and no papilledema. OCT demonstrated retinal nerve fiber layer thinning bilaterally. Visual decline progressed despite normalization of ICP. Repeat MRI brain/orbits showed multiple new subpial cysts along the optic tracts and optic chiasm. Filum biopsy showed rare inflammatory cell. Review of the pathology and radiological findings led to a consensus of DLGNT with cysts compressing and infiltrating optic chiasm and nerves. The patient was started on the MEK inhibitor trametinib, with stabilization of MRI findings and vision, but unfortunately without visual improvement. <h3>Conclusions:</h3> Pathologic confirmation of DLGNT can be difficult as safely obtained biopsy samples are typically small. In this case, bilateral optic neuropathy developed due to infiltration of the optic nerves, chiasm and tracts, while papilledema was never seen. MEK inhibitor therapy was initiated with Trametinib leading to stabilization in disease burden. This diagnosis should be considered in pediatric patients with communicating hydrocephalus, diffuse leptomeningeal enhancement, and elevated CSF protein with otherwise normal profile including absence of tumor cells. <b>Disclosure:</b> Dr. Paddock has nothing to disclose. Dr. Dinkin has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for WILSON ELSER MOSKOWITZ EDELMAN &amp; DICKER LLP. Dr. Dinkin has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Rehabilitation Alternative Services, Inc.. Dr. Dinkin has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for AMFS / Medical Experts Nationwide. Dr. Dinkin has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Bekman, Marder, Hopper, Malarkey &amp; Perlin, L.L.C.. Dr. Dinkin has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Northwestern Mutual. Dr. Dinkin has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Young Conaway Stargatt &amp; Taylor.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3+3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N=12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150mg twice daily, oral trametinib 2mg once daily, and intravenous AT13387 260mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Abstract 2: Vertical MAPK pathway targeting in novel genetically engineered mouse and cell line models of NF1-altered melanoma: the mSK-Mel murine cohort

Abstract Large scale clinical genomic sequencing efforts have revealed inactivating mutations in the RAS-GTPase Neurofibromin 1 (NF1) in a significant subset of melanomas. To date, immunotherapy and MAPK pathway-directed targeted therapies have been largely inactive in this molecularly defined cohort and immunogenic models that reflect the distinct co-mutation patterns found in NF1-mutant melanoma patients are lacking. Leveraging a population-scale tumor genomic profiling initiative, we identified TP53 as a gene significantly co-altered with NF1 in melanoma. We thus generated and molecularly characterized a cohort of genetically engineered mice with targeted deletion of NF1 in melanocytes. Melanocyte-specific, homozygous knockout of NF1 induced hyperpigmentation yet was insufficient for tumorigenesis. Addition of TP53 knockout and/or conditional activating mutation in BRAF (BRAFVE), resulted in melanoma formation with variable and high penetrance, respectively, along with histologic features consistent with human melanomas. Tumor latency and overall survival in NF1/TP53 double knockout mice was similar to NF1/BRAFVE double mutants. NF1 knockout did not shorten the latency to tumor formation in the setting of BRAFVE/TP53 mutation but did intensify melanocytic hyperpigmentation in all genetic backgrounds tested. To facilitate preclinical and functional studies, we derived 22 congenic cell lines from harvested mouse tumors from NF1 knockout mice, with and without BRAFVE mutation, and tested their sensitivity to targeted agents. As expected, loss of NF1 conditioned the response to BRAF inhibition, while NF1-mutant cells retained sensitivity to MEK inhibition. To abrogate the effects of adaptive RAS reactivation after MEK inhibitor therapy, combined MEK/SHP inhibition in NF1/TP53 knockout cells and BRAF/SHP inhibition in NF1/TP53/BRAFVE mutant cells strongly blunted ERK phosphorylation and cell proliferation better than single agent therapy. However, this response to the addition of SHP inhibition was transient and ERK rebound was driven by continued MEK activation and dependance. In syngeneic xenograft models of NF1/TP53/BRAFVE mutation, MEK inhibition alone, or in combination with RAF and/or SHP inhibition, induced tumor regression and delayed the onset of resistance and progression as compared to doublet RAF/SHP inhibitor therapy. Overall, we demonstrated the efficacy and feasibility of vertical MAPK pathway targeting in a novel cohort of genetically relevant mouse and cell line models of NF1-mutant melanoma and provide justification for future studies of vertical MAPK pathway targeting to achieve maximal ERK pathway inhibition in this molecularly defined patient cohort. Citation Format: Alexis M. Jones, Aphrothiti J. Hanrahan, Moriah H. Nissan, Sebastien Monette, Ziyu Chen, Wenhuo Hu, Sandra Misale, Isabell Schulze, Naresh Vasani, Cailian Liu, Xia Yang, Mohsen Abu-Akeel, Elisa de Stanchina, Nikolaus Schultz, Michael F. Berger, Neal Rosen, Taha Merghoub, David B. Solit. Vertical MAPK pathway targeting in novel genetically engineered mouse and cell line models of NF1-altered melanoma: the mSK-Mel murine cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2.

Abstract 3935: CRISPR/Cas9 screens to identify proliferation and resistance mechanisms in uveal melanoma

Abstract Purpose: Uveal (ocular) melanoma (UM) is a highly aggressive and frequently fatal cancer of the eye. While only 2-4% of patients have metastases at diagnosis, up to 50% of develop metastatic disease, overwhelmingly to the liver. Almost all UM harbor an initiating mutation in the Gαq signaling pathway, most commonly in GNAQ. Most UM also contain secondary mutations that drive tumor progression, the most common being BAP1 loss. Targeted therapies such as MEK inhibitors have been utilized in UM, but tumors rapidly become refractory. The aims of this study were to identify novel mechanisms specifically activated in UM cells that drive proliferation and escape from MEK inhibitor therapy. Procedures: We performed CRISPR-Cas9 mediated gene disruption screening of UM cell lines 92.1, Mel202 and Mel270 using the Brunello sgRNA library targeting the whole genome. Cells were transduced at 0.3 MOI and 500X coverage then split into two groups to compare treatment with the MEK inhibitor (MEKi) trametinib (6nM) vs. untreated control cells. Cell pellets were collected at day 2 (baseline) and after every 3 cell divisions for 21 cell divisions (treated and control). In addition, we generated 92.1 and Mel270 cell lines stably expressing Cas9 and transduced cells at 1000x coverage with a sgRNA library targeting either 192 epigenetic regulators or 482 kinases. At least two replicates for each screen were performed. sgRNA representation between samples was compared using MAGeCK. Genes specifically essential in UM cell lines were distinguished from commonly essential genes using the Broad institute dependency map (DepMap). These hits were validated by individual sgRNAs and pharmacological inhibition. Results: Whole genome screens revealed a set of 84 genetic dependencies unique for UM cells that were required for proliferation. Among these genes were those required for the lipoic acid biosynthesis pathway: MCAT, MECR, LIPT2, LIAS as well as genes encoding the MITF-SOX10-TFAP2 transcription factors, the H3K9 methyltransferase SETDB1, and members of the MLL3/4 complex. Screening of UM cell lines with a focused guide RNA library targeting epigenetic regulators revealed that BRD2, TRIM28, KMT2D, SETD1B and HDAC1 were specifically required for UM survival. Screens with a sgRNA library targeting the kinome revealed CDK2, CDK4 and TRRAP were required for UM survival. After 1 week of treatment with MEKi trametinib, we identified 112 genes whose disruption increased the anti-proliferative effects of trametinib in Mel202 and Mel270 cells and 10 of these genes were essential only in UM. These genes included metabolic enzymes critical for fatty and lipoic acid synthesis such as MECR, MCAT and TAZ. By contrast disruption of TP53, NF1, or PTEN led to MEKi resistance. Conclusions: These results identify novel mechanisms of proliferation and therapy resistance specifically required in GNAQ mutant UM cells that may represent new therapeutic targets. Citation Format: Richard L. Bennett, Darby Monagle, Katelyn R. Raburn Smith, Amin Sobh, Keiran S. Smalley, J William Harbour, Jonathan D. Licht. CRISPR/Cas9 screens to identify proliferation and resistance mechanisms in uveal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3935.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma.

Purpose/Objectives Combination BRAF(vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited.We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis.DF was defined as any new intracranial lesions.Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of thediameters of thefive largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308,p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients withBRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

Rosai Dorfman's Disease with MAP2K1 Mutation Refractory to Chemotherapy with Complete Response to MEK Inhibitor Therapy: A Case Report

Background: Rosai Dorfman's Disease (DRD) is a rare primary histiocytosis, usually benign and self-limited, characterized by significant cervical lymphadenopathy. In 23 to 43% of cases it presents extra-lymph node symptoms. Symptomatic patients are often treated with prednisone and chemotherapy, with varying success rates. Although classically considered non-clonal inflammatory pathologies, NRAS, KRAS and MAP2K1 mutations are described in a fraction of patients with histiocytic disorders. This report will discuss a case of a patient with DRD with MAP2K1 mutation, who responded dramatically to targeted therapy with cobimetinib, after failure in several lines of treatment. Case presentation: A 41-year-old woman was evaluated for massive bilateral cervical adenopathy with 2 months of evolution, associated with fatigue, weight loss (7% in 2 months), chest pain and arthralgias of large joints. Cervical lymph node biopsy was performed, with a diagnosis of Rosai-Dorfman disease. Pet-Scan showed bilateral cervical, supraclavicular and mediastinal lymph node enlargement, with a marked increase in metabolism. She was initially submitted to corticosteroid therapy for up to 8 months, with partial response, but with recrudescence of adenopathies and symptoms in the attempts to reduce prednisone to less than 20 mg/day. She was then sequentially submitted to chemotherapy combinations containing Vinblastine, Methotrexate, 6-Mercaptopurine, Cyclophosphamide and Prednisone, presenting a progressive disease characterized by involvement of the nasopharynx. There was also a failure in response with the use of Lenalidomide. After 19 months of diagnosis, she was treated with 6 cycles of Cladribrine, obtaining a partial response, lost 5 months after completion. Investigation with NGS Panel Target One Pan Cancer (52 Genes) detected MAP2K1 c.607G> mutation. The patient started treatment with the MEK inhibitor Cobimetinib (Cotellic ®) with complete response. The medication was used for 12 months, with a dose reduction between the 7th and 12th month due to cutaneous adverse events. A complete response is maintained one month after cobimetinib discontinuation. Discussion: Due to the disease being rare there is still no well-defined protocol for DRD treatment. As it has mostly benign and self-limited evolution, observation is indicated in oligosymptomatic cases and corticosteroid therapy is the first line of treatment when necessary. Cases that are refractory to traditional therapies, such as the one presented in the report, can be treated with targeted therapies when actionable mutations are identified. The present report supports the idea that genomic analysis can be an important tool in the management of cases of refractory or aggressive DRD.

Response to MEK Inhibitor Therapy in MAP2K1 (MEK1) K57N Non-Small-Cell Lung Cancer and Genomic Landscape of MAP2K1 Mutations in Non-Small-Cell Lung Cancer.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00382 JCO Precision Oncology no. 6 (2022) e2200382. Published online December 1, 2022. PMID: 36455195 Response to MEK Inhibitor Therapy in MAP2K1 (MEK1) K57N Non–Small-Cell Lung Cancer and Genomic Landscape of MAP2K1 Mutations in Non–Small-Cell Lung Cancer Michael L. Cheng , MD1,2,3xMichael L. ChengSearch for articles by this author; Jessica K. Lee , MS4xJessica K. LeeSearch for articles by this author; Rachit Kumar, MD5xRachit KumarSearch for articles by this author; Harry Klein , PhD6xHarry KleinSearch for articles by this author; Kira Raskina , MD4xKira RaskinaSearch for articles by this author; Alexa B. Schrock , PhD4xAlexa B. SchrockSearch for articles by this author; Kesi S. Michael , BS1,7xKesi S. MichaelSearch for articles by this author; Tali Mazor , PhD6xTali MazorSearch for articles by this author; Ethan Cerami, PhD6xEthan CeramiSearch for articles by this author; Geoffrey R. Oxnard , MD4xGeoffrey R. OxnardSearch for articles by this author; David Liu , MD, MPH, MS2xDavid LiuSearch for articles by this author; Himisha Beltran , MD2xHimisha BeltranSearch for articles by this author; Lynette M. Sholl , MD8xLynette M. ShollSearch for articles by this author; Mizuki Nishino , MD, MPH9,10xMizuki NishinoSearch for articles by this author; and Pasi A. Jänne , MD, PhD1,2,11xPasi A. JänneSearch for articles by this author Show More 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA2Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA3Present address: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA4Foundation Medicine, Cambridge, MA5Harold Alfond Center for Cancer Care, MaineHealth, Augusta, MA6Department of Data Science, Dana-Farber Cancer Institute, Boston, MA7Present address: Foundation Medicine, Cambridge, MA8Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA9Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA10Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA11Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA https://doi.org/10.1200/PO.22.00382 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologySUPPORTM.L.C. was supported by a Conquer Cancer Foundation—American Society of Clinical Oncology Career Development Award.AUTHOR CONTRIBUTIONSConception and design: Michael L. Cheng, Mizuki Nishino, Pasi A. JänneProvision of study materials or patients: Rachit KumarCollection and assembly of data: Michael L. Cheng, Rachit Kumar, Kesi S Michael, Tali Mazor, Ethan Cerami, Lynette M. Sholl, Mizuki NishinoData analysis and interpretation: Michael L. Cheng, Jessica K. Lee, Harry Klein, Kira Raskina, Alexa B. Schrock, Ethan Cerami, Geoffrey R. Oxnard, David Liu, Himisha Beltran, Lynette M. Sholl, Mizuki NishinoManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Michael L. ChengHonoraria: Lynx Group, WebMD, Potomac Center for Medical EducationConsulting or Advisory Role: AstraZeneca, Inivata, Boehringer Ingelheim, Mirati TherapeuticsResearch Funding: Palleon Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Daiichi Sankyo, AstraZeneca, GenzymeJessica K. LeeEmployment: Foundation MedicineStock and Other Ownership Interests: RocheKira RaskinaEmployment: Foundation MedicineStock and Other Ownership Interests: RocheResearch Funding: Foundation MedicineAlexa B. SchrockEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, RocheKesi S. MichaelEmployment: Foundation MedicineStock and Other Ownership Interests: Roche/GenentechEthan CeramiConsulting or Advisory Role: Third Rock VenturesGeoffrey R. OxnardEmployment: Foundation MedicineStock and Other Ownership Interests: RocheHimisha BeltranConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Pfizer, Blue Earth Diagnostics, Foundation Medicine, Amgen, Loxo/LillyResearch Funding: Janssen (Inst), AbbVie/Stemcentrx (Inst), Bristol Myers Squibb Foundation (Inst)Travel, Accommodations, Expenses: Janssen OncologyLynette M. ShollStock and Other Ownership Interests: Moderna TherapeuticsConsulting or Advisory Role: Genentech (Inst), Lilly (Inst)Research Funding: Roche/Genentech (Inst)Mizuki NishinoConsulting or Advisory Role: Daiichi Sankyo, AstraZenecaResearch Funding: Toshiba (Inst), AstraZeneca (Inst), Daiichi Sankyo (Inst)Pasi A. JänneStock and Other Ownership Interests: Gatekeeper Pharmaceuticals, LoxoConsulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, TranscentaResearch Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution MedicinesPatents, Royalties, Other Intellectual Property: I am a coinventor on a DFCI-owned patent on EGFR mutations licensed to Lab Corp. I receive postmarketing royalties from this inventionNo other potential conflicts of interest were reported.

Endocrine effects of MEK and BRAF inhibitor therapy in paediatric patients: a tertiary centre experience

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma.

Combination dabrafenib (D) and trametinib (T) is an FDA approved adjuvant therapy for patients with resected stage III BRAF-mutant melanoma. We describe treatment-related toxicities with adjuvant D+T in a real-world population through a retrospective case series. The primary endpoint was development of toxicities.ResultsEighteen of the 20 patients (90%) required at least one treatment interruption due to adverse events (AEs), 11 patients (55%) required a dose reduction and 13 (65%) permanently discontinued therapy due to an AE. The nine patients who did not require dose reduction had been initiated on a lower starting dose of dabrafenib. The most common treatment-limiting AEs were recurrent pyrexia and chills (85%) and liver laboratory abnormalities (50%). The median total time on therapy was 148.5 days (range 19-383), 40.7% (range 5.2-100%) of the intended one-year duration.ConclusionAdjuvant treatment of melanoma with combination D+T is associated with treatment-limiting toxicities in the majority of this patient group. Patients should be carefully monitored throughout therapy.

Raptinal Induces Gasdermin E-Dependent Pyroptosis in Naïve and Therapy-Resistant Melanoma.

Raptinal can rapidly induce pyroptosis in naïve and BRAFi plus MEKi-resistant melanoma, which may be beneficial for patients who have developed acquired resistance to targeted therapies.

OTHR-09. The prevalence and complex management of MEK inhibitor induced cutaneous side effects

BACKGROUND: Cutaneous side effects commonly occur with MEK inhibitor (MEKi) therapy and can be challenging to manage. METHODS: A retrospective chart review was performed on sixteen pediatric patients treated with MEKi therapy for at least three months. These patients were diagnosed with either a brain tumor, plexiform neurofibroma, Langerhans Cell Histiocytosis, or Parkes Weber Syndrome (PWS). OBJECTIVES: To describe cutaneous side effects from MEKi therapy, compare the side effect profiles of patients treated for different diagnoses, and compare the side effect profiles between different MEKi agents. RESULTS: The most prevalent cutaneous toxicities for all eligible patients were acneiform rash (81%, most common), paronychia (50%, second most common), hair changes and xerosis. Mean number of cutaneous skin toxicities were 3.2 (trametinib group: 3.4, selumetinib group: 2.8). Only one patient, treated with trametinib for PWS, did not experience a cutaneous side effect. The average number of interventions (new medication or over-the-counter product) recommended to prevent or treat cutaneous-related toxicities was 6.8 per person, the majority of those were for acne and paronychia. Over 75% of the interventions were topical. Of those who experienced an acneiform rash, the average number of recommended interventions were 3.1. Sixty two percent of these patients developed acne within the first cycle; average time to development was 2.6 months into therapy. Most exhibited improvement overtime following intervention. Those patients who experienced paronychia were treated with a mean of 3.1 interventions – 37.5% developed paronychia within the first cycle of therapy; average time to development was 3.9 months into therapy. CONCLUSIONS: Cutaneous side effects are common, occur early in therapy, and require multiple interventions. The number and complexity of these interventions may further complicate the overall management of cutaneous side effects given that the responsibility of the administration falls on the patient. This differs from traditional chemotherapy regimens.

LGG-02. Cardiac toxicity in patients receiving single-agent MEK inhibition

BACKGROUND: MEK inhibitor therapy is increasingly being utilized for the treatment of pediatric tumors, including low-grade glioma, plexiform neurofibroma and Langerhans cell histiocytosis. These drugs are well-tolerated but do have risk of toxicity, including cardiac toxicity. The purpose of this study is to better characterize MEK inhibitor-induced cardiac toxicity in pediatric patients. METHODS: Retrospective review of all patients who underwent MEK inhibitor mono-therapy for at least 3 months, 2015- 2021, age 25 years or less, at St. Louis Children’s hospital and Cardinal Glennon Children's hospital. RESULTS: We evaluated 31 patients, 19 (61%) with brain tumors and 12 (39%) without. Of the thirty-one, fifteen (48%) had NF1, 1 had Tuberous sclerosis. Cardiac toxicity consisted of asymptomatic sinus tachycardia, bradycardia, or decreased ejection fraction (EF). Thirteen patients (42%) experienced an asymptomatic decrease in left-ventricular ejection fraction (EF), Grade I-III. Time on therapy before decreased EF was 5 days to 21 months, median 2.8 months. Decreased EF developed in 5 of 13 patients receiving selumetinib and 8 of 18 receiving trametinib. Of the patients who developed decreased EF, 11 (85%) had brain tumors, 6 (46%) had NF1, and 89% had received prior systemic therapy. Out of the patients who had received no prior systemic therapy (6), 2 (33%) had decreased EF, while 11/25 (44%) of those who had received prior systemic therapy did. Drug was held temporarily for 6 patients, with dose limiting toxicity for 5 patients. Drug was discontinued for 1 patient after EF continued to decline despite dose reduction. Patients showed improvement in EF as early as 2 weeks after holding therapy. CONCLUSIONS: Cardiac toxicity in our patients was limited to asymptomatic reduction in ejection fraction, sinus bradycardia and tachycardia, reinforcing the need for appropriate monitoring via echocardiography. Prior systemic therapy was associated with decreased EF.

NURS-01. Development and Implementation of a MEK Inhibitor Targeted Therapy Standardized Educational Curriculum for Pediatric Oncology Patients, Caregivers, and Clinical Staff

Abstract Molecular targeted therapies have become a fundamental treatment regimen within pediatric oncology practice, yet these medications are not without side effects, which often require interruption, dose reduction, or early discontinuation of treatment. Existing chemotherapy education curriculums focus on the side effect profile of traditional chemotherapy regimens and do not include standardized instruction on toxicities related to targeted therapies, resulting in a knowledge gap for caregivers and the clinical team. The purpose of this project was to development and implement a standardized teaching curriculum to educate patients, caregivers and clinical staff on common toxicities related to MEK inhibitors including anticipated side effects, symptom management, and toxicity surveillance. The education was presented to patients and families by a neuro-oncology nurse or nurse practitioner at the initiation of MEK inhibitor therapy. The cohort consisted of 11 patients over a 12-month period with a diagnosis of plexiform neurofibromas and neurofibromatosis type 1. Additionally, the education curriculum was presented to clinical staff during an in-service and included a pre-post intervention survey to assess effectiveness of the education curriculum. The results demonstrated that increasing patient and family knowledge at initiation of MEK inhibitor therapy likely leads to fewer dose reductions, drug interruptions, and early therapy discontinuations. Greater than 90% of the patient cohort were able to complete the treatment regimen without early termination due to toxicity, with only 18% requiring dose reduction and 9% requiring interruption of therapy. Surveys evaluating the effectiveness of the staff educational curriculum demonstrated an increased knowledge in the identification and treatment of MEK inhibitor side effects with a 26% improvement in survey results post-intervention. This project is a feasible educational approach for preventing and treating toxicities associated with MEK inhibitors and can be initiated at pediatric oncology practices to standardize MEK inhibitor education to clinicians, patients, and caregivers.

EPCT-01. Pediatric Brain Tumor Consortium (PBTC)-055: A phase I study of trametinib and hydroxychloroquine (HCQ) for BRAF-fusion or Neurofibromatosis type-1 (NF1)-associated pediatric gliomas

Abstract INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients &amp;lt; 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination.

Toxicity and outcomes of BRAF and MEK inhibitor “ramp-up” dosing strategies for patients with melanoma: A real-world institutional experience.

e21600 Background: Combination BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy is a widely accepted treatment option for patients (pts) with BRAF-V600E mutant melanoma. Although effective, these combinations exhibit high rates of adverse events (AEs), with 44% - 66% requiring dose modification or interruption and up to 26% discontinuing due to AEs in the adjuvant setting. Enhanced tolerance to BRAFi/MEKi is expected to improve pts quality of life and potentially enhance clinical outcomes. Clinicians at Roswell Park Comprehensive Cancer Center (RPCCC) have implemented a dose escalation regimen upon initiation of BRAFi/MEKi in efforts to enhance the tolerance of these combinations for pts with BRAF-V600E mutant melanoma in the adjuvant and advanced setting. Here we present a retrospective analysis of the toxicity profiles and outcomes associated with this “ramp-up” approach. Methods: Pts presenting to RPCCC in Buffalo, NY for management of stage III or IV melanoma harboring BRAF-V600E mutations were retrospectively observed from 1/2012 to 12/2020. Pts starting BRAFi/MEKi combinations, regardless of prior lines of therapy, were included unless concurrently receiving immune checkpoint inhibition. The “ramp-up” regimen involves a 25% dose of BRAFi and 50% dose of MEKi, which is gradually increased over 4 weekly intervals until full dose is achieved. Pts started on full-dose BRAFi/MEKi were included as a comparison arm. Observations included 1) demographics, 2) treatment regimens and disruptions, 3) rate and severity of AEs, 4) outcomes including best overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). Results: A total of 88 pts were analyzed (21 and 35 receiving “ramp-up” BRAFi/MEKi in the adjuvant and advanced (unresectable stage III or stage IV) setting, respectively, and 32 received full-dose (non-ramp-up) BRAFi/MEKi in the advanced setting). Demographics were similar except pts in the “ramp-up” cohorts were higher in average age (62.0 vs 56.0, p = 0.032) than pts starting at full-dose. Pts receiving adjuvant BRAFi/MEKi at “ramp-up” dosing exhibited a 4.8% (n = 1) rate of grade 3 or higher (Gr3+) AEs and 33.3% (n = 7) AE-related discontinuation rate (9.9 month average time to discontinuation). In the advanced setting, “ramp-up” vs full-dose treated pts exhibited Gr3+ AE rates of 25.7% (n = 9) vs 43.8% (n = 14; p = 0.197) and AE-related discontinuation rates of 34.4% (n = 12) vs 40.6% (n = 13; p = 0.592), respectively. Trends in overall AEs, ORR, PFS, and OS were similar to historical observations across all groups. Conclusions: This real-world analysis suggests that “ramp-up” incremental dosing of BRAFi/MEKi for pts with melanoma in the adjuvant and advanced setting may improve the tolerance and toxicity profiles of these agents without compromising their clinical efficacy, and may be of particular utility in pts with advanced age.