Sponsorship Opportunities

Aaina Kochhar, MD¹, J.Paige Souder, MD,PhD¹,Emily Muth, MS, CGC¹,Samantha DeMarsh, DO², Molly Hemenway, PNP²  , Nicholas K. Foreman, MD^2.

¹Children’s Hospital Colorado, Department of Pediatrics, Division of Genetics and Metabolism.

²Childrens Hospital Colorado, Department of Pediatrics, Center for Cancer and Blood Disorders.

Title – Congenital bilateral plexiform neurofibromas of the cavernous sinuses presenting as buphthalmos at birth.

Purpose – We describe a term newborn presenting with congenital glaucoma, buphthalmos and poor vision, who was found to have bilateral cavernous sinus plexiform neurofibromas extending through the skull base foramina into the left, greater than right, orbits and face. Treatment with a MEK inhibitor was initiated given progressive vision impairment. 

Method – A full term newborn female infant presented with left-sided buphthalmos and congenital glaucoma. Brain MRI showed bilateral enhancing cavernous sinus masses, extending along both trigeminal nerves, and nodular enhancement of right oculomotor nerve. These lesions were initially suspected to be atypical intracranial hemangiomas or plexiform neurofibromas. The patient had multiple cafe au lait macules on exam, but did not meet clinical diagnostic criterion for Neurofibromatosis type 1 (NF1) in the newborn period.  She received medical treatment for glaucoma. Genetic testing and follow up imaging were done. 

Results - Whole exome sequencing showed a heterozygous denovo pathogenic variant in the NF1 gene c.1756-1759del, p.(Thr586ValfsTer18). Follow up MRI brain, orbits and face at 3 months of age, showed increasing size of bilateral plexiform neurofibromas expanding the cavernous sinuses and extending through skull base foramina into left greater than right orbit and face. Given the growth in size of the masses, impact on vision and potential other cranial nerve functions, therapy with the MEK inhibitor, Trametinib, was recommended.

Conclusion – We describe aggressive bilateral cavernous sinus plexiform neurofibromas with intraorbital extension and vision loss. It is an unusual clinical manifestation of NF1 and we offered treatment with a MEK inhibitor in this scenario, to stabilize/prevent further growth of the plexiform neurofibroma. 

References

1.Congenital bilateral plexiform neurofibromas of the cavernous sinuses, Pediatr Radiol (2003) 33: 272–274.

2.Congenital ectropion uvea and mechanisms of glaucoma in neurofibromatosis type 1: new insights, Ophthalmology 2012 Jul;119(7):1485-94. 

Characteristics, Cycle of First Onset, and Time to Resolution of Commonly Reported (≥15%) Treatment-Related Adverse Events (TRAEs) in the ReNeu Trial of Mirdametinib in Children and Adults With Neurofibromatosis Type 1 (NF1)-Associated Plexiform Neurofibroma (PN)

Presenting Author: Laura J. Klesse, MD, PhD

University of Texas Southwestern, Dallas, TX

Laura J. Klesse, MD, PhD¹; Christopher L. Moertel, MD²; Prakash Ambady, MD³; Stefania Maraka, MD⁴; Phioanh (Leia) Nghiemphu, MD⁵; Zsila Sadighi, MD⁶; David Schiff, MD⁷; Molly Nickerson, PhD⁸; Michael D. Weber, PharmD⁸; Armend Lokku, PhD⁸; Stacie Stapleton, MD⁹; Tobias Walbert, MD, PhD¹⁰; Julia Meade, MD¹¹; Reuben Antony, MD¹²; Kathryn Nevel, MD¹³; Timothy R. Gershon, MD, PhD¹⁴; Dusica Babovic-Vuksanovic, MD¹⁵

¹University of Texas Southwestern, Dallas, TX; 

²University of Minnesota, Minneapolis, MN; 

³Oregon Health & Science University (OHSU), Portland, OR;

⁴University of Illinois at Chicago, Chicago, IL;

⁵University of California, Los Angeles (UCLA), Los Angeles, CA; 

⁶MD Anderson Cancer Center, Houston, TX; 

⁷University of Virginia - Emily Couric Cancer Center, Charlottesville, VA;

⁸SpringWorks Therapeutics Inc., Stamford, CT; 

⁹Johns Hopkins All Children's Hospital, St. Petersburg, FL;

¹⁰Henry Ford Health, Wayne State University and Michigan State University, Detroit, MI; ¹¹University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA;

¹²University of California - Davis, Sacramento, CA; 

¹³Indiana University School of Medicine and IU Health, Indianapolis, IN;

¹⁴Children’s Center for Neurosciences Research, Emory University School of Medicine, Atlanta, GA; 

¹⁵Mayo Clinic - Rochester, Rochester, MN. 

Supported by: SpringWorks Therapeutics, Inc.

DISCLOSURES

LJK: Uncompensated relationships with Alexion Pharmaceuticals;

CLM: Employment with OX2 Therapeutics; leadership role with OX2 Therapeutics; equity interest in OX2 Therapeutics; consultancy/advisory role with Alexion Pharmaceuticals and SpringWorks Therapeutics; patents, royalties, or other intellectual property with OX2 Therapeutics; travel expenses from Alexion Pharmaceuticals;

PA: Honoraria with SpringWorks Therapeutics, SERVIER; Consulting or Advisory Role with  SpringWorks Therapeutics, SERVIER; Patents, Royalties, Other Intellectual Property for Morpholino oligonucleotides useful in cancer treatment; Patent number: 11679121; Abstract: Disclosed are morpholino oligonucleotides that can be used to silence expression of MGMT, pharmaceutical compositions that include said morpholino oligonucleotides, and methods of using said morpholino oligonucleotides in the treatment of cancer, particularly methods that involve the use of radiation to deliver said morpholino oligonucleotides. Type: Grant Filed: December 7, 2020; Date of Patent: June 20, 2023;

SM: Consulting or advisory role with SpringWorks Therapeutics;

PN: Honoraria with Alexion Pharmaceuticals; Consulting or Advisory Role with SpringWorks Therapeutics; Research Funding with Chimerix (Inst), Recursion Pharmaceuticals (Inst), NCCN (Inst), SpringWorks Therapeutics (Inst), Millennium (Inst), Erasca, Inc (Inst), Global Coalition for Adaptive Research (Inst), Children's Tumor Foundation (Inst);

ZS: Employment with Adjuvant Behavioral Health; Leadership with Adjuvant Behavioral Health; Speakers' Bureau with Alexion Pharmaceuticals;

DS: Consultancy/advisory role with Orbus Therapeutics, PRA, Anheart Therapeutics, Servier (I), SymBio Pharmaceuticals; royalties for submissions to UpToDate;

MN, MDW, AL: employment with SpringWorks Therapeutics, Inc; equity interest in SpringWorks Therapeutics, Inc;

SS: No relevant disclosures;

TW: Consulting or Advisory Role with Novocure, Alexion Pharmaceuticals, SpringWorks Therapeutics, SERVIER, Anheart Therapeutics; Travel, Accommodations, Expenses with SERVIER;

JM: Consultancy/advisory role with Alexion Pharmaceuticals; travel expenses from Alexion Pharmaceuticals;

RA: Consultancy/advisory role with Alexion Pharmaceuticals; honoraria from Alexion Pharmaceuticals;

KN: Consultancy/advisory role with Servier Pharmaceuticals, royalties for editorial role with Oxford University Press;

TRG: Research funding from SpringWorks Therapeutics, Inc;

DBV: Honoraria from Alexion Pharmaceuticals and SpringWorks Therapeutics, Inc; consultancy/advisory role with AstraZeneca; research funding from SpringWorks Therapeutics, Inc; employment with Mayo Clinic; consultancy/advisory role with Alexion Pharmaceuticals; research funding from Alexion Pharmaceuticals, Recursion, and SpringWorks Therapeutics, Inc.

ABSTRACT 

Background: Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2y) with symptomatic NF1-PN not amenable to complete resection. This analysis evaluated cycle of first onset and time to resolution of commonly reported TRAEs in the pivotal ReNeu trial, where patient- and parent proxy-reported outcome improvements and PN volume reductions were demonstrated.

Methods: Safety results are reported as of the data cutoff (September 20, 2023). Median cycle (1-cycle=28 days) of first onset and time to resolution (days) for common TRAEs (≥15%) were evaluated for prepubescents (2 to <12y, n=32), postpubescents (12 to <18y, n=24), young adults (18 to ≤50y, n=48), and older adults (>50y, n=10). Time to resolution was calculated from the start of the first event to the end of the last event. The protocol provided strategies for AE supportive care, but no AE prophylaxis was mandated at treatment initiation.

Results: The most frequent cycle of onset for TRAEs was Cycle 1 (81%). Common TRAEs were mostly grades 1 to 2 (83%, Table 1) and did not occur with greater frequency or severity over time. Median cycle of onset (Table 2) and time to resolution (Figure) for common TRAEs are reported. In prepubescents, median cycle of onset was Cycle 1 for vomiting; Cycle 3 for dermatitis acneiform; and Cycle 5 for paronychia, diarrhea, and nausea. For postpubescents, median cycle of onset was Cycle 1 for dermatitis acneiform, diarrhea, nausea, and vomiting; and Cycle 4 for paronychia. In young adults, median cycle of onset was Cycle 1 for dermatitis acneiform, diarrhea, and nausea; and Cycle 2 for vomiting. For older adults, median cycle of onset was Cycle 1 for dermatitis acneiform, diarrhea, nausea, and vomiting. Time to resolution was variable between TRAEs and among patients in all age groups. Eighteen patients had a TRAE of asymptomatic ejection fraction (EF) decrease, median (range) time to onset was 127 (41, 1361) days, and all except one prepubescent patient experienced resolution. No patients experienced a symptomatic EF decrease.

Conclusions: In ReNeu, symptomatic improvements and PN volume reductions were observed at the earliest measured timepoint (Cycles 3 and 5, respectively) and were sustained over time. In all age groups, common TRAEs were detected earlier than treatment benefits and were generally resoluble. It is important to manage patients’ expectations and proactively manage TRAEs to improve treatment experience and adherence.

Figures/Tables: 

Table 1. TRAEs (Incidence of ≥15%) in the ReNeu Trial

TRAEs, treatment-related adverse events.

TRAEs have been reported in order of decreasing incidence.

Table 2. Median (Range) Cycle of TRAE (Incidence of ≥15%) First Onset in the ReNeu Trial

TRAEs, treatment-related adverse events.

TRAEs have been reported in order of decreasing incidence.

Figure. Median (Range) Time to TRAE (Incidence of ≥15%) Resolution in the ReNeu Trial

NE, not evaluable; TRAEs, treatment-related adverse events.

^aIndicates no event of paronychia for older adults 

Time to resolution was calculated as the start date of the first event of the preferred term to the end date of the last event of the preferred term. If the last event of the preferred term was ongoing, then the event was considered unresolved and was not

included in the summary statistics.

Mission Moment: A moderated panel discussion featuring NF patients . Patient Panel: NF1: Katie Holt; NF2: Jake Lipe; SWN: Michele Holbrook
Location: Salons D-G

Location: Salons A-C

Location: Salons D-G