Thursday, December 3, 20207:00 pm-8:30 pm EST

PROGRAM DESCRIPTION

Designed and developed to provide an exhaustive overview of novel and emerging data, as well as establish a foundational context of NF1 disease state complexity, this activity will begin by identifying keystone diagnostic signs, symptoms, and clinical hallmarks in pediatric patients, and describe the genetic etiologies and multi-system pathophysiologies that have historically made NF1-associated plexiform neurofibromas so difficult to treat. Attendees will then gain insights from expert faculty regarding the pivotal shortcomings of traditional treatment approaches and the new horizons that have accompanied the burgeoning emergence of novel pharmacologic therapies, most notably MEK inhibitors. Finally, top-level clinical experts will guide attendees through a case-based section that explores the vital role of the neuro-oncology clinician and researcher in the evolving NF1 management paradigm, and provides activity participants an opportunity to design evidence-based treatment regimens for symptomatic, inoperable NF1-related tumors.

TARGET AUDIENCE

This educational initiative is targeted to neuro-oncologists, pediatric neuro-oncologists, neurosurgeons, neuroradiol-ogists, medical oncologists, neurologists, neuro-oncology researchers, and other members of the neuro-oncology team who care for patients with neurofibromatosis type 1 (NF1).

AGENDA

7:00 pm-7:10 pm Welcome and Introductions/Pre-test Jaishri Blakeley, MD

7:10 pm-7:25 pm Embracing Complexity: The Etiology, Pathophysiology, and Clinical Manifestations of Neurofibromatosis Type 1

Bruce R. Korf, MD, PhD (Activity Chair)

7:25 pm–7:50 pm Navigating Novelty in Plexiform Neurofibroma Management: An Exploration of Emerging Data and Adaptive Strategies

Andrea M. Gross, MD

7:50 pm-8:20 pm Bridging Chasms in NF1: The Pivotal Placement of the Neuro-Oncology Team in the New Paradigm

Jaishri Blakeley, MD

8:20 pm-8:30 pm Conversation with the Experts: Audience Q&A/Post-test

Faculty Panel Moderated by Dr. Korf

LIVE WEBINAR

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ACCREDITATIONIn support of improving patient care, Creative Educational Concepts is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American

Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medicine (ACCME)

CEC designates this live educational activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Upon completion of a post-test and evaluation, statements of credit for physicians will be issued within 30 business days.

Supported through an independent educational grant from AstraZeneca.

Presented by Creative Educational Concepts, Inc.

LEARNING OBJECTIVES

At the conclusion of this live internet activity, participants will gain the skills and/or knowl-edge to:

• Identify the keystone diagnostic symptom-atology and clinical hallmarks of neurofi-bromatosis type 1 (NF1), especially in the pediatric patient population.

• Describe the genetic origins and the complex, multi-system pathophysiology of NF1, with an emphasis on the clinical gravity and historical intractability of plexiform neurofibromas.

• Review traditional approaches for treating plexiform neurofibromas in patients with NF1, including surgery, radiation, and surveillance, and highlight the crucial clinical chasms that remain.

• Examine emerging pharmacologic therapies for managing symptomatic, inoperable plexiform neurofibromas, including an appraisal of completed and ongoing clinical trials and recent FDA approvals, with a focus on MEK inhibition.

• Evaluate the role of the neuro-oncology clinician and researcher in developing and delivering novel, cutting-edge NF1 therapeutic approaches and galvanizing ongoing renewal of the treatment calculus.

• Using a case-based format, design evidence-based management strategies for clinically significant, non-surgical, NF1-associated plexiform neurofibromas and low-grade gliomas.

PLANNER AND FACULTY DISCLOSURES

Any person who may contribute to the content of this continuing education activity must disclose relevant relationships (and any known relationships of their spouse/partner) with commercial interests whose products or services are discussed in educational presentations. A commercial interest is defined as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Relevant relationships include receiving from a commercial interest research grants, consultant fees, travel, other benefits, or having a self-managed equity interest in a company.

Disclosure of a relationship is not intended to suggest or condone any bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

Planners:Bruce R. Korf, MD, PhD—has disclosed that he is a consultant for SpringWorks Therapeutics. He also receives grant/research support from AstraZeneca.

Bryan Taylor, PharmD—has no relevant financial relationships to disclose in relation to the content of this activity.

Authors/Presenters:Jaishri Blakeley, MD—has disclosed that she is a consultant for Astellas, AstraZeneca, Children’s Tumor Foundation, and SpringWorks Therapeutics. She also receives grant/research support from GlaxoSmithKline, Lilly, NCI, and Sanofi.

Andrea M. Gross, MD—has no relevant financial relationships to disclose in relation to the content of this activity.

Bruce R. Korf, MD, PhD—has disclosed that he is a consultant for SpringWorks Therapeutics. He also receives grant/research support from AstraZeneca.

Content Reviewer:Miriam Bornhorst, MD—has disclosed that she is a consultant for AstraZeneca. 2

FACULTY BIOGRAPHICAL SKETCHES

Bruce R. Korf, MD, PhDActivity ChairAssociate Dean for Genomic MedicineSchool of MedicineWayne H. and Sara Crews Finley Endowed Chair in Medical GeneticsUniversity of Alabama at Birmingham (UAB)Chief Genomics Officer, UAB MedicineBirmingham, AL

Dr. Korf is the Associate Dean for Genomic Medicine, School of Medicine; Chief Genomics Officer, UAB Medicine; Wayne H. and Sara Crews Finley Endowed Chair in Medical Genetics, Professor of Genetics, Co-Director of the UAB-HudsonAlpha Center for Genomic Medicine, Associate Director for Rare Diseases, Hugh Kaul Personalized Medicine Institute and Editor-in-chief of the American Journal of Human Genetics. He is a Medical Geneticist, Pediatrician, and Child Neurologist, certified by the American Board of Medical Genetics and Genomics (clinical genetics, clinical cytogenetics, and clinical molecular genetics), American Board of Pediatrics, and American Board of Psychiatry and Neurology (child neurology). Dr. Korf is past president of the Association of Professors of Human and Medical Genetics, past president of the American College of Medical Genetics and Genomics, and current President of the ACMG Foundation for Genetic and Genomic Medicine. He has served on the Board of Scientific Counselors of the National Cancer Institute and the National Human Genome Research Institute at the NIH. His major research interests are molecular diagnosis of genetic disorders and the natural history, genetics, and treatment of neurofibromatosis. He serves as principal investigator of the Department of Defense funded Neurofibromatosis Clinical Trials Consortium, the Alabama Genomic Health Initiative, and the Southern All of Us Network. Dr. Korf is co-author of Human Genetics and Genomics (medical student textbook, now in fourth edition), Medical Genetics at a Glance (medical student textbook, now in third edition), Emery and Rimoin’s Principles and Practice of Medical Genetics (now in 6th edition), and Current Protocols in Human Genetics.

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Jaishri Blakeley, MDDirectorThe Johns Hopkins Comprehensive Neurofibromatosis CenterMarjorie Bloomberg Tiven Professor of Neurofibromatosis in Neurology, Neurosurgery, and Oncology The Johns Hopkins University Baltimore, MD

Andrea M. Gross, MDAssistant Research Physician, Pediatric Oncology BranchNational Institutes of Health, Center for Cancer ResearchBethesda, MD

Dr. Blakeley is the Marjorie Bloomberg Tiven Professor of Neurofibromatosis in Neurology, Oncology and Neurosurgery, Director of the Johns Hopkins Com-prehensive Neurofibromatosis Center, and the Neurofibromatosis Therapeutic Acceleration Program (NTAP). NTAP was founded in 2012 with the goal of dramatically shifting the landscape of clinical care for people with Neurofibro-matosis Type 1 associated plexiform and cutaneous neurofibromas via the core tenants of focus on therapeutics, foster collaboration, facilitate open and timely sharing of results, and streamline the research process. Dr. Blakeley’s research expertise is in the development of clinical trials for nervous system tumors and specifically, clinical-translational studies including tumor pharmacokinetic and pharmacodynamic investigations, imaging biomarkers and incorporation of pa-tient focused, functional endpoints. Her research, mentorship and programmat-ic efforts are all in the service of improving outcomes for the patients for whom she is honored to provide care for as an active clinician in neuro-oncology.

Dr. Gross is a Board-Certified Pediatrician and Pediatric Oncologist who earned her Medical Degree at the University of Connecticut and completed pediatric residen-cy and a chief resident year at Cincinnati Children’s Hospital Medical Center. She completed a Pediatric Hematology/oncology fellowship at Children’s National Medi-cal Center and is currently an Assistant Research Physician working in the Pediatric Oncology Branch at the National Cancer Institute in the lab of Dr. Brigitte Wide-mann. Dr. Gross has been the lead associate investigator on the phase 2 trial of selumetinib for patients with neurofibromatosis type 1 (NF1) and inoperable plexi-form neurofibromas since 2015, which led to the first FDA approved medication for NF1 in 2020. Her research focuses on clinical trials for tumor predisposition syn-dromes.  Her areas of interest include developing and utilizing functional outcome measures for tumor predisposition syndromes, working with rare disease patient advocates to increase patient engagement in clinical trial design and dealing with the challenge of medication adherence in the NF1 population.

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Disclaimer

• Identify the keystone diagnostic symptomatology and clinical hallmarks of neurofibromatosis type 1 (NF1), especially in the pediatric patient population.

• Describe the genetic origins and the complex, multi-system pathophysiology of NF1, with an emphasis on the clinical gravity and historical intractability of plexiform neurofibromas.

• Review traditional approaches for treating plexiform neurofibromas in patients with NF1, including surgery, radiation, and surveillance, and highlight the crucial clinical chasms that remain.

• Examine emerging pharmacologic therapies for managing symptomatic, inoperable plexiform neurofibromas, including an appraisal of completed and ongoing clinical trials and recent FDA approvals, with a focus on MEK inhibition.

• Evaluate the role of the neuro-oncology clinician and researcher in developing and delivering novel, cutting-edge NF1 therapeutic approaches and galvanizing renewal of the treatment calculus.

• Using a case-based format, design evidence-based management strategies for clinically-significant, non-surgical, NF1-associated plexiform neurofibromas and low-grade gliomas.

Learning Objectives

Expert Faculty

Activity ChairBruce Korf, MD, PhD

Endowed Chair in Medical GeneticsUniversity of Alabama at Birmingham

Expert PanelistAndrea Gross, MD

Pediatric OncologistNational Cancer Institute

Expert PanelistJaishri Blakeley, MD

Director, The Johns Hopkins Comprehensive Neurofibromatosis

Center

Bruce Korf, MD, PhDWayne H. and Sara Crews Finley Endowed Chair in Medical GeneticsAssociate Dean for Genomic MedicineChief Genomics OfficerUniversity of Alabama at Birmingham

Embracing Complexity The Etiology, Pathophysiology, and Clinical Manifestations of Neurofibromatosis Type 1 (NF1)

Outline

• Classification• Diagnosis• Natural history• Genetics• Pathophysiology

The Neurofibromatoses

NF1 NF2 Schwannomatosis

Inheritance Autosomal dominant, complete penetranceAutosomal dominant, complete penetrance

Autosomal dominant, incomplete penetrance

Frequency 1:3,000 1:30,000 unknown

Features

Neurofibromas, café-au-lait macules, learning disabilities, skeletal dysplasia, optic gliomas, malignant peripheral nerve sheath tumors (MPNSTs)

Bilateral vestibular schwannomas, other schwannomas, meningiomas, ependymomas, posterior subcapsular cataracts

Multiple schwannomas, pain

Gene/protein NF1—chromosome 17neurofibrominNF2—chromosome 22merlin (aka schwannomin)

SMARCB1—chromosome 22LZTR1—chromosome 22

Korf BR, Bebin EM. Pediatr Rev. 2017; Korf BR. Handb Clin Neurol. 2013.

NF1 Diagnostic CriteriaFeature (≥2 is diagnostic) Comment

Café-au-lait spots 6 or more >5 mm pre-pubertal, 15 mm post-pubertal

Skin-fold freckles Axillary, inguinal, neck base

Neurofibromas >2 solitary; 1 plexiform

Lisch nodules 2 or more; require slit lamp to visualize

Optic glioma Orbital and/or chiasmatic

Skeletal dysplasia Long bone, especially tibia, or sphenoid wing

Affected first-degree relative Autosomal dominant inheritance

Korf BR. Handb Clin Neurol. 2013; Gutmann DH, et al. JAMA. 1997.

• >6 larger than 5 mm prepuberty• Flat, pigmented lesions with sharp

edges• Often appear in early months of life• Usually fully developed by 2 years

of age• No relationship with neurofibromas

Café-au-lait Spots

Korf BR. Pediatrics. 1992; DeBella K, et al. Pediatrics. 2000.

• Appear by 3–5 years of age• Axillary and inguinal regions• Base of neck• Under breasts in women

Skin-fold Freckles

Korf BR. Pediatrics. 1992; DeBella K, et al. Pediatrics. 2000.

• May be present in young children but commonly appear around or after puberty

• May present as papular or pedunculated lesions, or may be under the skin

• Often increase in size and/or number during pregnancy

• Not a source of malignancy• Do not transform into MPNSTs

Cutaneous Neurofibromas

Ortonne N, et al. Neurology. 2018.

• Arise during development of larger nerves

• Overlying cutaneous hyperpigmentation

• Most rapid growth in childhood/early teens

• May have nodular component• Symptoms due to mass effect and

disfigurement• Risk of malignant transformation

(MPNSTs)

Plexiform Neurofibroma

Klesse LJ, et al. Oncologist. 2020; Korf BR. In: Advances in Neurofibromatosis Research. 2012.

• Arise from nerve roots• May grow through neural foramen

and compress the spinal cord• Some individuals have primary

spinal involvement at all levels with heavy internal tumor burden (“spinal NF”)

• Spinal NF associated with distinctive NF1 gene mutations, especially some missense or splicing variants

Spinal Neurofibromas

Ruggieri M, et al. Clin Genet. 2015.

• Melanocytic hamartomas• Appear in childhood• >95% in adults• No effect on vision

Lisch Nodules

Korf BR. Handb Clin Neurol. 2013; Korf BR. Pediatrics. 1992; DeBella K, et al. Pediatrics. 2000.

• May involve orbital optic nerve and/or chiasm

• Present in early childhood• May be clinically indolent or may

progress• If symptomatic, present with

• Proptosis• Decreased visual acuity• Impaired visual fields• Precocious puberty

Optic Glioma

Packer RJ, et al. Neuro-Oncol. 2020; Korf BR. Handb Clin Neurol. 2013.

Skeletal Dysplasia

• Long bone, especially tibia

• Presents in first year of life

• Anterolateral bowing• Cortical thinning• Risk of fracture• Sphenoid dysplasia/

orbital neurofibromaStevenson DA, et al. J Pediatr Orthop. 2013; Korf BR. Handb Clin Neurol. 2013.

Vascular Dysplasia

• Vascular dysplasia• Renal artery—hypertension• Cerebral—moyamoya• Dissection and hemorrhage

Friedman JM, et al. Genet Med. 2002.

MPNST

• Arise from plexiform or nodular neurofibromas• Morbidity: ~8%–13% of NF1 patients will develop

MPNST in early-adulthood• Mortality: highly-aggressive, 5-year survival rates

very low• Pain, growth, change in texture• FDG-PET may help distinguish from non-

malignant tumor(s)

Prudner B, et al. Neurooncol Adv. 2019.

• Verbal and non-verbal learning disabilities in at least 50%

• ADHD• Intellectual disability in some• Autism spectrum disorder• Areas of enhanced T2 signal

in basal ganglia, cerebellum, brainstem in childhood

Neurocognitive Features

Payne JM, et al. J Atten Disord. 2019; North K, et al. Neurology. 1994.

• Juvenile xanthogranuloma• Glomus tumors• Scoliosis• Pulmonary• Pheochromocytoma

Other Features

Stewart DR, et al. Genet Med. 2018; Miller DT, et al. Pediatrics. 2019.

• Shift to left in life expectancy• Median: 59 years vs 74 years in NF1

patients vs non-NF1• Most common NF-related causes of

death• MPNST or other malignancy• Vascular events

• Wide range of life expectancy

Life Expectancy

Rasmussen SA, et al. Am J Hum Genet. 2001.

• Autosomal dominant• Complete penetrance• Variable expression• 50% new mutation• Mosaicism may present with

segmental features

Genetics

Carey JC, et al. Ann NY Acad Sci. 1986; Korf BR. Handb Clin Neurol. 2013.

Mutation Spectrum

• Upwards of 3,000 distinct pathogenic variants

• Most lead to loss of function• Genetic testing available

• Resolve diagnosis• Genetic counseling

• Limited genotype-phenotype correlations

Misssense18%

Nonsense21%

Frameshift26%

Intragenic CNV2%

Splice27%

Whole gene deletion5%

Complex1%

Messiaen LM, et al. Hum Mutat. 2000.

Genotype-Phenotype Correlations in NF1Genetic Variant Phenotype Reference(s)

1.4–1.5 Mb deletion of entire NF1 gene

Large number of cutaneous neurofibromas,intellectual disability, facial dysmorphism, tall stature, increased risk of MPNST

Kayes LM, et al. Am J Hum Genet. 1994.

p.Arg1809 missense Noonan-like features, pulmonic stenosis, short stature Rojnueangnit K, et al. Hum Mutat. 2015.

Codons 844-848 missense in CSRD

Plexiform neurofibromas, optic gliomas, spinal neurofibromas, malignancy Koczkowska M, et al. Am J Hum Genet. 2018.

c.2970_2972del; p.Met992del Lack of neurofibromas or gliomas, LD present Koczkowska M, et al. Genet Med. 2019.

p.Met1149, p.Arg1276, or p.Lys1423

Noonan-like features, CV in p.Arg1276 and p.Lys1423, spinal neurofibromas in p.Arg1276 Koczkowska M, et al. Hum Mutat. 2020.

Mutations near 5’ end of geneMutations in CSRD domain

Increased risk of autism spectrum disorder and glioma

Morris SM, Gutmann DH. Neurology. 2018. Anastasaki C, et al. Front Genet. 2019. Anastasaki C, et al. Neurol Genet. 2017. Xu M, et al. Front Genet. 2018.

• MPNST• Breast cancer• High-grade glioma

• Learning deficits• ADHD or ASD• Motor and/or speech delays

Optic pathway glioma

Scoliosis

• Dermal neurofibroma• Paraspinal neurofibroma

Brainstem glioma

• Skinfold freckling• Lisch nodulesCALMS

• Orbital dysplasia• Tibial dysplasia• Pseudarthrosis

Plexiform neurofibroma

What to Expect and When

Gutmann DH, et al. Nat Rev Dis Primers. 2017; Miller DT, et al. Pediatrics. 2019.

Birth Infancy Early childhood Adolescence Adulthood

Pigmentary lesionsNeurofibromasSkeletal abnormalitiesLearning, cognitive, and social deficitsMalignanciesLow-grade tumors

Follow-up for Child with NF1

History

• Change in tumors• Headache• Pain/weakness• Behavior/

development• School

performance

Physical Exam

• Cutaneous and plexiform neurofibromas

• Growth/head size• Blood pressure• Neurological exam• Sexual maturation• Scoliosis• Skeletal deformity

Referrals

• Ophthalmology• Development• Miscellaneous

Testing

• As indicated• Vitamin D

Miller DT, et al. Pediatrics. 2019.

NF1 Gene

• 300 kb, 2818 amino acids• Encodes neurofibromin• Tumor suppressor gene• Stimulates Ras-GTPase—

GTPase-activating protein• Loss of function leads to

increased Ras signaling

Gutmann DH, et al. Nat Rev Dis Primers. 2017; Messiaen LM, et al. Hum Mutat. 2000.

Schwann cell

Neurofibroma

MPNST

NF1-/- NF1-/-Other changes

NF1 +/-

Tumor Suppressor Function

Maertens O, et al. Hum Mutat. 2006.

Navigating Novelty in Plexiform Neurofibroma ManagementAn Exploration of Emerging Data and Adaptive Strategies

Pediatric Oncology Branch, National Cancer InstituteBethesda, Maryland

Andrea M. Gross, MD

Learning Objectives

• Review traditional approaches for treating plexiform neurofibromas in patients with NF1, including surgery, radiation, and surveillance, and highlight the crucial clinical chasms that remain.

• Examine emerging pharmacologic therapies for managing symptomatic, inoperable plexiform neurofibromas, including an appraisal of completed and ongoing clinical trials and recent FDA approvals, with a focus on MEK inhibition.

Plexiform Neurofibromas (PN)

• Histologically benign• Involve multiple nerve fascicles/branches• Schwann cells, fibroblasts, mast cells,

highly vascular• Young age, slow growth, large size,

complex shape• Disfigurement, pain, functional

impairment, life-threatening • Transformation to malignant peripheral

nerve sheath tumor (MPNST) (10%–15%) • Medical treatment may reduce morbidity

and prevent MPNST

3 years 5 years

3 years 5 years

Klesse LJ, et al. Oncologist. 2020; Kim A, et al. Sarcoma. 2017; Korf BR. In: Advances in Neurofibromatosis Research. 2012.

• Volumetric MRI is the standard methodology for measuring PN on clinical trials (REiNS)

• Short T1-inversion recovery (STIR) images

• Response criteria• Partial response (PR): ≥20%

decrease in tumor volume• Progressive disease (PD):

≥20% increase in tumor volume from best response

Volumetric MRI Analysis of PN

Dombi E, et al. Neurology. 2007; Solomon J, et al. Comput Med Imaging Graph. 2004; Gross AM, et al. N Engl J Med. 2020.

STIR Sequence Region of Interest

Tumor Border Identified

Volume 91 ml

Natural History of Plexiform Neurofibroma Growth

• NCI NF1 natural history study• PN growth rate: volumetric MRI analysis

• PN grow most rapidly in young children• No spontaneous PN shrinkage >20% per

year• PN-related morbidity

• Most PN cause some degree of morbidity at time of first assessment

• Once PN-related morbidity develops in growing PN, it is very unlikely to resolve spontaneously, thereby reinforcing the need for early intervention

Akshintala S, et al. Neuro Oncol. 2020; Gross AM, et al. Neuro Oncol. 2018.

Plexiform Neurofibromas(N=70)

Surgery and Radiation Therapy for PN

• Surgical resection of PN can be a morbid procedure with risk for significant blood loss

• Younger patients and incomplete resection associated with increased risk of tumor regrowth

• Small retrospective case studies have shown radiotherapy can shrink tumors; however, it leads to significant increases in risk of malignant transformation and, therefore, generally NOT recommended Needle MN, et al. J Pediatr. 1997; Canavese F, et al. J Pediatr Orthop. 2011;

Wentworth S, et al. Int J Radiat Oncol Biol Phys. 2009; Grill J, et al. Int J Radiat Oncol Biol Phys. 2009; Chopra R, et al. Am J Clin Oncol. 2005.

Treatment Targets in NF1 Growth factor

Neurofibromin(GTPase-Activating Protein)

GTP GDP

Farnesylated RAS

Cytoskeleton

Rac

Rho

Raf

MEK

ERK

Proliferation

PI3K

AKT

Survival

Tipifarnib

SorafenibCediranib

Peg-Interferon Alpha 2b

ImatinibCabozantinib

BinimetinibMirdametinibSelumetinib

Sirolimus

C-kit, Mast cells

Angiogenesis

mTOR

Gutmann DH, et al. Nat Rev Dis Primers. 2017; Asati V, et al. Eur J Med Chem. 2016.

Pre-Clinical Models of Plexiform Neurofibromas• Genetically engineered mouse models

of NF1 neurofibroma predict for activity

• MEKi is first active therapyMouse Neurofibromas

DhhCre;Nf1fl/fl

Wu J, et al. Cancer Cell. 2008; Yang FC, et al. Cell. 2008; Jessen WJ, et al. J Clin Invest. 2013.M

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Phase II Studies for Progressive PN

Only 2 of 175 patients with confirmed partial response (both on PEG-Intron study)

Weiss BS, et al. Neuro Oncol. 2015; Widemann BC, et al. Neurol Oncol. 2014; Jakacki RI, et al. Neuro Oncol. 2017; Widemann BC, et al. Pediatr Blood Cancer. 2014.

• MEK inhibitor, taken twice daily on a continuous dosing schedule• Primary objective: define the maximum tolerated dose (MTD) of

selumetinib for pediatric patients with inoperable PN• First treatment to show shrinkage of plexiform neurofibromas in NF1

• Partial response in 17/24 patients

Phase I Trial of Selumetinib

Baseline Cycle 5 Cycle 10Responses at ~60% of adult recommended dose

Dombi E, et al. N Engl J Med. 2016.

• Anecdotal clinical benefit but no prospective functional measures in this study

• Primary objective: overall response rate• Key secondary objectives: functional and patient

reported outcomes• Results

• Confirmed partial response 34/50 (68%) patients• Clinical benefit with improvement in pain and function

Phase 2 TrialSelumetinib in Children with NF1 PN

Baseline Pre-Cycle 13 Pre-Cycle 37

86% improvement 72% improvementGross AM, et al. Neuro Oncol. 2018; Gross AM, et al. N Engl J Med. 2020.

NRS-11 Self-report of Tumor Pain Intensity

• Includes 5 patients’ ratings of 0 (no pain) at baseline• Excludes 2 patients with only baseline ratings

n=31 n=31

p=0.0017 p=0.0003 p

SPRINT External Control NF1 Natural History Study

3-year follow-up: 84% PFS in selumetinib arm vs 15% in natural history arm

Gross AM, et al. N Engl J Med. 2020.

Age matched control: NCI Natural history and selumetinib

Median PFS Natural History 1.3 years

Progressive PN SPRINT versus Phase II Tipifarnib Placebo Control

Tipifarnib placebo/SPRINT progressive PN

Selumetinib (N=21) TTP N/APlacebo (N=29) TTP 10.6 Months

Gross AM, et al. N Engl J Med. 2020; Weiss BS, et al. Neuro Oncol. 2015; Widemann BC, et al. Neurol Oncol. 2014; Jakacki RI, et al. Neuro Oncol. 2017; Widemann BC, et al. Pediatr Blood Cancer. 2014.

Prior studies/SPRINT progressive PN

FDA Approval of Selumetinib

April 10, 2020“The Food and Drug Administration (FDA) approved selumetinib for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).”

FDA Prescribing Information; FDA Press Release, 4/10/20.

• Eligibility: ≥16 years old with NF1 PN• Dosing: 2 mg/m2/dose (max 4 mg) PO BID, 4-week

courses (3 weeks on / 1 week off)• Response: 8/19 PR (42%)• Toxicity

• No ophthalmologic toxicity• Most common DLT = acneiform rash (2/19)• One patient (5.2%) had grade 3 pain related to drug

NF1-106: Phase II Study of PD-0325901Study Chair: Brian Weiss (ISPNO 2018)

Phase I/IIa study of trametinibGeoffrey McCowage (ASCO 2018)

• 26 children (1–16 years)• 12 of 26 patients (46%) had a partial response (PN volume reduction ≥20%)• 12% D/C to adverse events

• Paronychia and rash most common

Other MEK Inhibitors Have Activity in NF1 PN

Slide courtesy of Dr. Michael Fisher; Weiss BS, et al. Neuro Oncol. 2018; McCowage GB, et al. J Clin Oncol. 2018.

Phase II NF1 105: Study Chair: Chie-Schin ShihMultiple RTK inhibitor: MET, VEGFR2, c-KIT, RET

• Eligibility: ≥16 years old with NF1 PN• Dosing: 60 mg PO once daily (40 mg QD for 1st 2 cycles)• Dose reductions for: Palmar-plantar erythrodysesthesia (7)

Weight loss (2), skin infection (1)

NF PN mouse model Clapp Lab

Decreased tumor number and size PR 8/19 (42%)

Protocol has been amended to include pediatric cohort: ages 3–15 years

Cabozantinib Has Activity in NF1 PN

Slide courtesy of Dr. Michael Fisher; Shih CS, et al. AACR 2019. Abstract CT233; Shih CS, et al. ISPNO 2018. Abstract NFM-01.

Future PN Treatment/Trial Considerations

• When is the optimal time to start treatment?• Can treatment prevent the development of PN-related symptoms?

• What is the optimal duration of treatment? • What is the best treatment dose and schedule for targeted therapies?

• Could a different treatment schedule limit toxicities and optimize benefit?• What is the long-term safety and tolerability of

PN-targeted therapies? • What impact do PN targeted therapies have on

other NF1 manifestations?• Cutaneous neurofibromas, low-grade gliomas,

cognitive function, etc.

Bridging Chasms in NF1The Pivotal Placement of the Neuro-Oncology Team in the New Paradigm

Jaishri Blakeley, MDDirector, The Johns Hopkins Comprehensive Neurofibromatosis Center

NF1: The Scope of the Problem

• Skin: Café-au-lait spots, freckling, neurofibromas (cutaneous and diffuse infiltrating)

• Visual impairment/ blindness

• Optic pathway glioma/low-grade glioma

• Lisch nodules

• Seizures• Headache• Brain tumors• Vascular anomalies• Learning disabilities• Macrocephaly

• Secondary hypertension

• Dysmotility • GIST• Intraluminal

neurofibromas

• Bone deformities• Scoliosis• Pseudarthrosis • Dysplasias

• Plexiform neurofibroma (often multiple, precursors for more aggressive tumors)

• Increased risk of breast cancer

NF1—The Big Oncology Picture…

Modified from Neurofibromatosis Mid-Atlantic, Inc; Stewart DR, et al. Genet Med. 2018.

• Risk for six distinct malignancies• Juvenile myelomonocytic leukemia

(JMML)• Astrocytomas (low and high grade)• Neurofibrosarcoma/MPNST• Increased risk of breast cancer,

especially

Multiple oncologic and non-oncologic manifestations:• What is the most pressing need in a person with NF1?• What is the level of evidence for treatment of each tumor-type?

Peripheral Nerve Sheath Tumors

Range of NF1 Nerve Sheath TumorsCutaneous (dermal) neurofibromas

≥95%Plexiform (PN)

25%–50%Atypical (ANF)

Unknown ?MPNST 15.8%

Disfigurement, pruritus, pain Appearance, pain, function loss Malignant transformation

Loss of NF1 + CDKN2A + PRC2, P53, others

Kim A, et al. Sarcoma. 2017.

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwj2qN6gy5bNAhWMSyYKHVraATcQjRwIBw&url=http://www.healthline.com/health/neurofibromatosis-1&bvm=bv.124088155,d.cWw&psig=AFQjCNF5pVVFLisIPjJ-mritykPo263KXw&ust=1465411914884000

Plexiform Neurofibroma

1/3000 individualsRoughly 100,000 in US

• Significant disfigurement • Regional invasion = loss of function• Pain• Myelopathy and neuropathy • Airway compression • Associated with progression to potentially fatal cancer

NF1 Neurofibromatosis

type 1

pNFPlexiform

neurofibroma

MPNSTMalignant peripheral nerve sheath tumor

~40-50% of people with NF1~8-13% of pNFs transform into aggressive malignant sarcomas

ANNUBP/atypical pNF

Klesse LJ, et al. Oncologist. 2020; Prudner B, et al. Neurooncol Adv. 2019; Higham CS, et al. Neuro Oncol. 2018.

• On continuum to sarcoma, precursor to MPNST• Deletions of CDKN2A/B were found in 0/15 PN, 15/16

ANF, and 16/23 MPNST• Established CDKN2A/B deletion as first step in the

progression to MPNST

ANNUBP/Atypical Neurofibromas

Higham CS, et al. Neuro Oncol. 2018; Miettinen MM, et al. Hum Pathol. 2017; Beert E, et al. Genes Chromosomes Cancer. 2011.

Diagnosis Proposed definition

Neurofibroma (NF)

Benign Schwann cell neoplasm with thin, often wavy nuclei, wispy cell processes, and a myxoid to collagenous (shredded carrots) matrix. Immunohistochemistry includes extensive but not diffuse S100 and SOX10 positivity and a lattice-like CD34+ fibroblastic network.

Plexiform NF

NF diffusely enlarging and replacing a nerve, often involving multiple nerve fascicles, delineated by EMA+ perineurialcells

Neurofibroma with atypia(ancient neurofibroma)

NF with atypia alone, most commonly manifesting as a scattered bizarre nuclei

Cellular NF NF with hypercellularity, but retained NF architecture and 1/50 HPFs and

A B

C D

E F

18F-FDG-PET

Identifying ANNUBP/MPNST in a Sea of Plexiform Neurofibromas

• Clinical• Symptoms: new or worsening

pain• High risk profile

• MRI features: anatomic and functional

• DWI/ADC mapping

• FDG-PET features• Distinct nodular lesion (DNL)

• Well-demarcated• Encapsulated-appearance• ≥3 cm lesions• Lacking the central dot-sign

characteristic of PNs

• Present within or outside of a plexiform neurofibroma

Akshintala S, et al. Neuro Oncol. 2020; Ahlawat S, et al. Neurology. 2019; Ahlawat S, et al. Eur J Radiol. 2018.

Molecular Pathway to MPNST

The 63 patients had a total of 76 pathologically confirmed ANF; median age of study participants at diagnosis = 27.1 years

Carroll SL. Am J Pathol. 2016; Higham CS, et al. Neuro Oncol. 2018.

---- Age of first ANF---- Age of first MPNST---- Age at death

)

MPNST is a rare and aggressive sarcoma• 20%–50% of all MPNST occur in the setting of NF1; conversely, people

with NF1 have an 8%–12% lifetime risk of developing MPNST

• Most MPNST arise from transformation of a PN• MPNST is graded as low- and high-grade• Recent molecular confirmation of a premalignant tumor: ANNUBP• No effective therapies for established MPNST and no known therapies

to prevent malignant conversion• SARC006: Phase II Trial of Chemotherapy in Sporadic and

Neurofibromatosis Type 1 Associated Chemotherapy-naive Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

• 2 cycles (1 cycle = 21 days) of doxorubicin and ifosfamide (IA) followed by 2 cycles of ifosfamide and etoposide(IE)

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Higham CS, et al. Sarcoma. 2017.

Central Nervous System TumorsGliomas

• Optic pathway glioma• Pilocytic astrocytoma• Ganglioglioma

• Extra-optic pathway• Brainstem gliomas: 4%–20% of people with

NF1 • Diffusely infiltrating astrocytoma• Low-grade astrocytoma of indeterminate type• Pilocytic astrocytoma• Anaplastic astrocytoma• Glioblastoma• Ganglioglioma

NF1-Associated Gliomas

Rodriguez FJ, et al. J Neuropathol Exp Neurol. 2008; Raffel C, et al. Neurosurgery. 1989; Ullrich NJ, et al. Neurosurgery. 2007; Theeler BJ, et al. J Neurol. 2014; Varan A, et al. Clin Genet. 2016.

NF1-Associated Gliomas• NF1 mutation/loss-of-function define mesenchymal glioblastoma multiforme (GBM) –

seen in 14/38 patients (37%)• But also neural > proneural > classical

• Some pilocytic astrocytomas overexpress specific NF1 gene transcripts• One of five genes commonly mutated in GBM samples: IDH1, EGFR, PTEN, TP53, and

NF1• RB1 mutations also found in 13% of mesenchymal GBM

Verhaak RG, et al. Cancer Cell. 2010; Platten M, et al. Am J Pathol. 1996; Thiel G, et al. Anticancer Res. 1995; Sintupisut N, et al. Nucleic Acids Res. 2013.

Selumetinib in Children with Recurrent or Refractory Low-grade Glioma—PBTC-029

• Stratum 3 (of 6) was for NF1 progressive or recurrent LGG

• 25 eligible and evaluable patients– Given selumetinib 25 mg/m2 twice

daily• 10 patients (40%) achieved

sustained PR• At a median follow-up of 48.6

months, 17 patients had not progressed

Fangusaro JR, et al. Lancet Oncol. 2019.

Selumetinib in Children with Recurrent or Refractory Low-grade Glioma—PBTC-029

• Selumetinib demonstrated substantial activity in recurrent, refractory NF1-associated pediatric low-grade glioma

Fangusaro JR, et al. Lancet Oncol. 2019; Fangusaro JR, et al. ASCO. 2017. Abstract 10504; Banerjee A, et al. Neuro Oncol. 2017.

Trametinib for NF1-Associated Malignant Glioma

Pre-treatment 4 weeks post Rx 8 weeks post Rx 6 weeks off drug

Selt F, et al. J Neurooncol. 2020; Awada G, et al. Case Rep Oncol. 2020.

Pre-treatment 2 weeks post 6 weeks post

MEK Inhibitors in Development for NF1-Associated PNSTs or Gliomas

Selumetinib Trametinib Mirdametinib Binimetinib Cobimetinib

LGGPBTC-029 completed phase 2; ND, phase 3

opened

Yes, with amendment; limited No

Phase 2 pediatric study ongoing No

pNF

FDA approval in ≥2 years of age; first MEK inhibitor approved for this indication; adult

studies ongoing

Arm of phase 2 completed; 46% ORR

Initial phase 2 completedfor ≥16 years with 42% ORR; phase 2 adult and

pediatric studies ongoing

Phase 2 adult and pediatric studies

ongoingNo

Preparation Capsules only; sprinkles to be introduced TabletCapsule or dispersible

tablet Tablet Tablet

Combination In development In development No In development

With SHP2 inhibitor in solid tumors (pre-

clinical); phase 2 to initiate

Use in less than 3 years of age Yes Yes

Being studied in ≥2 years of age Yes Not determined

FDA Prescribing Information; ClinicalTrials.gov.

MEK Inhibitor ToxicityPediatrics, Adolescents, and Adults

In young patients, symptoms may be:

• Mild rash• Some paronychia• Hypotonia/muscle weakness• Retinal damage • Decreased cardiac ejection

fraction

In adolescents and adults, symptoms may be:

• Severe acne rash• Paronychia• Weight gain• Hypertension• Fatigue• Gastrointestinal problems

Klesse L, et al. Oncologist. 2020; Weiss B, et al. Neuro-Oncol. 2018; McCowage GB, et al. J Clin Oncol. 2018; Dombi E, et al. N Engl J Med. 2016; Gross AM, et al. N Engl J Med. 2020; Eroglu Z, et al. Br J Cancer. 2015; Fangusaro J, et al. Lancet Oncol. 2019.

Real-life Prescribing of MEK Inhibitorsfor NF1-Associated Tumors

Requires an interprofessional, multidisciplinary team: • Access to drug (only one currently FDA-approved,

knowledge of access programs)• Prescribing provider, w/ assistance from:

• Pharmacist• Nurse, nurse practitioner, and/or physician assistant

• Recommended use of drug:• For whom and for how long; proper dosing• Monitoring for emergence of malignancy

• Mitigation and management of toxicities• Echocardiogram (at start of Tx, at 1 mo, then q 3-6 months)• Ophthalmology (at start of Tx, at 1 mo, then q 3-6 months)• Laboratory evaluation (at start of Tx, then monthly)• Clinical assessment, physical exam, and skin toxicity monitoring (at

start of Tx, then monthly) Klesse L, et al. Oncologist. 2020; Anforth R, et al. Australas J Dermatol. 2014.

• FDA labeling for selumetinib (approved April 10, 2020) • Indicated for the treatment of pediatric patients 2 years of age and older with NF1

who have symptomatic, inoperable plexiform neurofibromas• 25 mg/m2 twice daily on empty stomach (no food 2 hours before, 1 hour after)

• Available in 10 mg and 25 mg capsules• Functional dose range is 30–100 mg/day

• Increased plasma drug concentrations with concomitant strong CYP3A4 inhibitors (and reduced concentrations with concomitant CYP3A4 inducers)

• Contains vitamin E; concomitant vitamin E supplement is not recommended• Consider financial toxicity concerns and other barriers to patient access

Real-life Prescribing of MEK Inhibitorsfor NF1-Associated Tumors

FDA Prescribing Information.

Case-based Approaches in NF1

Patient Case 1

• Diagnosed in early childhood with visible head and neck masses

• Over time, evidence of tumor growth clinically and on MRI

• No signs or symptoms of malignancy• Asymptomatic other than visible disfigurement

• Surgery attempted at 8 years old to reduce mass, but with minimal efficacy

• Now 10 years old with increasing discomfort requiring daily over-the-counter medications PRN

• On exam, decreased range of motion, but normal swallow and no symptoms/signs of respiratory distress

Patient Case 1

• Gabapentin started at last visit initially helped pain • However, continued growth of mass and pain more persistent

despite gabapentin • Estimated 30% increase in tumor volume over last 14 months• Decreased neck range of motion• Increased disfigurement evident

• Based on radiographic and symptomatic progression, the patient (now 12 years old) referred for treatment with selumetinib 25 mg twice daily

Patient Case 1

• Continues to do well on selumetinib with ongoing improved pain control

• Maintains overall response based on volumetrics and continues selumetinib, but at year two of treatment a distinct nodule is seen

Patient Case 1

• Referred for FDG-PET, which showed that the distinct nodular lesion has elevated SUVmax (SUVmax=9.8)

• Referred for biopsy, which showed malignant peripheral nerve sheath tumor (MPNST)

Nix JS, et al. J Neuropathol Exp Neurol. 2018.

Malignant Peripheral Nerve Sheath Tumor• Soft-tissue sarcoma arising from nerve and

surrounding tissue• Peak incidence in young adulthood

• >50% occur in the setting of NF1• Often arise from a large PN, no known therapies to

prevent malignant conversion• In addition to germline mutations of NF1, common

somatic alterations identified in MPNST include: • TP53 mutations• CDKN2A inactivation• Alterations to PRC2 members SUZ12 and EED

• Surgical resection with wide margins is associated with improved OS• Often only achieved with significant morbidity • Role of radiation therapy is not well-defined

Katz D, et al. Expert Rev Mol Med. 2009; Kahn J, et al. Front Oncol. 2014; Kim A, et al. Sarcoma. 2017; Higham CS, et al. Sarcoma. 2017; Akshintala S, et al. J Clin Oncol. 2019.

MEK Inhibitors under Investigation for MPNST

SARC031 (Phase 2): NCT03433183• Selumetinib + sirolimus• Remain on treatment until progression or severe toxicity • 2-stage design

• 7 patients, with no further accrual if 0 of 7 respond• If ≥1 of the 7 patients respond (CR, PR, or SD), accrue another 21 patients

• Primary objective: clinical benefit rate at 4 months (up to 6 months)• Secondary objectives

• Define and describe toxicities • Assess impact on intensity and pain interference, and correlate to changes in

clinical, imaging response, and progression• PFS and OS

ClinicalTrials.gov.

Patient Case 2

• 4-year-old female with NF1 diagnosed based on skin manifestations• Mom noticed the child had developed breast buds• Brain MRI revealed an OPG• Neuro-ophthalmology exam

• Acuity: 20/30 OD, 20/30 OS• Full fields to confrontation • No optic disc atrophy

Images courtesy of Michael Jay Fisher, MD.

Patient Case 2

The patient was observed. Why? • Is there visual dysfunction? No

• Visual acuity of 20/30 is normal at this age• Visual fields normal

• Is the tumor progressive?• We don’t know. Have one MRI. May stabilize/regress spontaneously.

• Other factors?• Location: it has progressed beyond the chiasm• Tumor is affecting hormone function (precocious puberty)

Patient Case 2

• Leuprolide was started for hormone regulation

• Over 12-month interval: visual acuity stable and MRI with decreased tumor size

• Visual acuity typically improves with age in young children

• Large tumor size or tumor growth doesn't necessarily correlate with function

• Precocious puberty or other hormone changes are not generally indications to start chemotherapy

Images courtesy of Michael Jay Fisher, MD.

Patient Case 2

But, what if…• Visual acuity in 6 months was

20/50 OD, 20/30 OS• Would start treatment • A 2-line decline in acuity (≥0.2

logMAR) is an indication to start chemotherapy independent of the MRI change

Lines on Visual Acuity Chart logMAR

20/15 6/4.5 -0.120/20 6/6 0.020/25 6/7.5 0.120/30 6/10 0.220/40 6/12 0.320/50 6/15 0.420/60 6/18 0.520/80 6/24 0.6

20/100 6/30 0.720/200 6/60 1.020/400 6/120 1.3

de Blank PM, et al. J Neuroophthalmol. 2017.

A Study of the Drugs Selumetinib versus Carboplatin/Vincristine in Patients with Neurofibromatosis and Low-grade Glioma (NCT03871257)

• Randomized controlled trial (phase 3) of standard treatment with carboplatine/vincristine versus selumetinib for people with NF1-associated low-grade glioma (LGG)

• Co-primary endpoints• Event-free survival (from randomization to first occurrence of any of the following events:

clinical or radiographic progression, recurrence, second malignant neoplasm, all-cause death)• Improvement in visual acuity

• Secondary endpoints • Radiographic response• Overall survival• Motor function• QOL• Neuro-cognitive and executive function

ClinicalTrials.gov.

SNO General Info FinalSNO Slide HandoutSlide Number 1DisclaimerLearning ObjectivesExpert FacultyBruce Korf, MD, PhDEmbracing Complexity �The Etiology, Pathophysiology, and Clinical Manifestations of Neurofibromatosis Type 1 (NF1)OutlineThe NeurofibromatosesNF1 Diagnostic CriteriaCafé-au-lait SpotsSkin-fold FrecklesCutaneous NeurofibromasPlexiform NeurofibromaSpinal NeurofibromasLisch NodulesOptic GliomaSkeletal DysplasiaVascular DysplasiaMPNSTNeurocognitive FeaturesOther FeaturesLife ExpectancyGeneticsMutation SpectrumGenotype-Phenotype Correlations in NF1What to Expect and WhenFollow-up for Child with NF1NF1 GeneTumor Suppressor FunctionNavigating Novelty �in Plexiform Neurofibroma ManagementAndrea M. Gross, MDLearning ObjectivesPlexiform Neurofibromas (PN)Volumetric MRI Analysis of PNNatural History of Plexiform Neurofibroma GrowthSurgery and Radiation Therapy for PNTreatment Targets in NF1Pre-Clinical Models of Plexiform NeurofibromasSlide Number 39Phase I Trial of SelumetinibPhase 2 Trial�Selumetinib in Children with NF1 PN Slide Number 42SPRINT External Control NF1 Natural History StudyProgressive PN �SPRINT versus Phase II Tipifarnib Placebo Control FDA Approval of SelumetinibSlide Number 46Phase II NF1 105: Study Chair: Chie-Schin Shih�Multiple RTK inhibitor: MET, VEGFR2, c-KIT, RETFuture PN Treatment/Trial ConsiderationsBridging Chasms in NF1Jaishri Blakeley, MDNF1: The Scope of the ProblemNF1—The Big Oncology Picture…Slide Number 53Peripheral Nerve Sheath TumorsRange of NF1 Nerve Sheath TumorsPlexiform NeurofibromaANNUBP/Atypical �NeurofibromasIdentifying ANNUBP/MPNST �in a Sea of Plexiform NeurofibromasMolecular Pathway to MPNSTMalignant Peripheral �Nerve Sheath Tumor (MPNST)Central Nervous System TumorsNF1-Associated GliomasNF1-Associated GliomasSelumetinib in Children with Recurrent �or Refractory Low-grade Glioma—PBTC-029Selumetinib in Children with Recurrent �or Refractory Low-grade Glioma—PBTC-029Trametinib for NF1-Associated Malignant Glioma MEK Inhibitors in Development �for NF1-Associated PNSTs or GliomasMEK Inhibitor Toxicity�Pediatrics, Adolescents, and AdultsReal-life Prescribing of MEK Inhibitors�for NF1-Associated TumorsSlide Number 70Case-based Approaches in NF1Patient Case 1Patient Case 1Patient Case 1Patient Case 1Malignant Peripheral Nerve Sheath TumorMEK Inhibitors under Investigation for MPNSTPatient Case 2Patient Case 2Patient Case 2Patient Case 2A Study of the Drugs Selumetinib versus Carboplatin/Vincristine in Patients with Neurofibromatosis and Low-grade Glioma (NCT03871257)