Mapping a New Treatment Journey in NF1: New Developments With MEKi for Pediatric and Adult Patients With NF1-Plexiform Neurofibromas

Chair, Christopher L. Moertel, MD, discusses NF1-PN in this CME/AAPA activity titled “Mapping a New Treatment Journey in NF1: New Developments With MEKi for Pediatric and Adult Patients With NF1-Plexiform Neurofibromas.” For the full presentation and complete CME/AAPA information, and to apply for credit, please visit us at https://bit.ly/4cv5aNx. CME/AAPA credit will be available until August 21, 2025.

1. Mapping a New Treatment

Journey in NF1

New Developments With MEKi for
Pediatric and Adult Patients With

NF1-Plexiform Neurofibromas

Christopher L. Moertel, MD

The University of Minnesota School of Medicine

The University of Minnesota Masonic Children's Hospital
Minneapolis, Minnesota

Go online to access full CME/AAPA information, including faculty disclosures.

2. Neurofibromatosis Type 1 and Associated Plexiform
Neurofibromas: Prevalence and Manifestations’?

Neurofibromatosis type 1 (NF1)
+ Affects >120,000 Americans and 2 million people worldwide

+ Genetic neurocutaneous disorder that predisposes individuals to
benign and malignant tumors

1. Ortonne N et al. Neurology. 2018;91:S5-S13, 2. Friedman JM. Am J Med Genet, 1999:89:1-6. 3. Landy JP el al. JAMA Netw Open. 2021:4:0210045. PeerView.com

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3. Neurofibromatosis Type 1 and Associated Plexiform
Neurofibromas: Prevalence and Manifestations’?

Plexiform neurofibromas (PN)

+ Found in 40%-60% of people with NF1

+ Composition: Schwann cells, fibroblasts, infiltrating mast cells, and
endothelial cells around nerves

+ Disfigurement & motor dysfunction due to
infiltrative nature

+ Can be deep, nodular, and not visible

+ Symptoms may include: pain, neurologic deficits, and mass effect on
surrounding structures

+ Can be life-threatening: mechanical compression of trachea, large blood
vessels, spinal cord

1. Otome N et al, Neurology. 2018:91:S5-S13, 2, Friedman JM. Am J Med Genet, 1909:80:16. 3. Landry JP eta, JAMA Notw Open. 2021:4:0210045. PeerView.com

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4. NF1-PN: General Considerations and Treatment Overview’?

« Felt to be congenital, but may not
be apparent in infancy

+ Growth most often occurs in
young childhood

+ PN can have long periods of 20
relative stability

+ Surgery is a mainstay
of treatment
+ Chemotherapy is not effective

+ Role of radiation therapy is
unclear

— 2.8-fold increased risk of
secondary malignancy Age, y

y= 1343" 6°(0.34x) RE = 0.4

8

3

Change in PN Volume por Year, %
3 8

0 5 1 16 20 25 m
Age, y

‘Tumor Size, em?

4. Tucker Teta. J Mod Genet. 2008:46:81-85, 2, Bhatia S et al. J Gin Oncol 2018;37:3050-3058, 3, Dombi E e al. Newology. 2007:68:643.647. PeerView.com

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5. Surgery for PN

Surgery plays an important management role in current guidelines;
best for small and completely removable/resectable tumors!

However, challenges related to surgery include:

+ Complication rate of 32%

+ Worsening sensory symptoms (15%)

+ New or worsening motor deficits (5%)

+ CSF leaks or pseudomeningoceles (4%)
+ Spinal deformity (2%)

+ Wound infections (5%)

In addition, prior
evidence has shown that
46% of patients had tumor
progression after surgery,
and that ~20% of patients
had repeat surgery due to
PN progression®*

1. LyK et a. Med Gin North Am 2019:103:1035-1084. 2. Safeee NM ot al. J Neurosurg Spine, 2017.26:103-111.3. Needle MN et al J Pediatr. 1997.131:678:682 |
4: Nguyen Ret al Genat Mod. 2013:15:691-697 PeerView.com

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6. Rationale for MEKi Therapy’?

ARAAARAL
+ NF1is caused by a mutation in the #4
neurofibromin 1 (NF1) gene

— NF1 is a tumor suppressor gene

— Loss of neurofibromin results in
overactivation of the growth
signaling pathways

+ Mitogen-activated protein kinase
(MEK) is a key downstream
component of the RAS signaling
cascade

Inhibition of MEK results in the
suppression of the overactive RAS
signaling pathway

1.Walace MR ell. Sconce, 1900;249:181-108.2. Yap YS el al Oncotaral. 20145:5873-1502. 3, Mister Metal. nt J Mol Sci. 2013:14:4854-4864 PeerView.com

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7. MEK Inhibitors in NF1-PN: Current Status

Age! Regulatory Status

Approved for pediatric patients aged 2-18 years with NF1 who
have symptomatic, inoperable PN

Selumetinib*

Ongoing phase 2b for pediatric and adult patients with NF1-PN;
initiated new drug application (NDA) to FDA in March 2024

Phase 2 completed; FDA approved as 1L single agent for
Trametinib* unresectable or metastatic melanoma with BRAF V600E or
V600K mutations — available off-label for NF1-PN

Binimetinib* Phase 2 adult and pediatric studies ongoing

| as enn eating ert, s/n comps, ps lw. ga rue msn roo ceros 7
indy. 3, Sadat Kae D ot al Neuro Oncol 2022241128. 4, Mueler 5 ta. Nowro-Onco! 2020 22820 421. PeerView.com

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8. Our Goals for Today

Enhance your understanding of the latest evidence supporting modern and
emerging MEKi in the treatment of NF1-PN

Strengthen your ability to develop evidence-based treatment plans that
include MEKi for pediatric and adult patients with NF1-PN

Equip you with techniques for managing practical care delivery
considerations with MEKi (including dosing, monitoring, and AE
management)

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9. Progress With MEKi in Pediatric
and Adult Patients With NF1-PN

10. SPRINT: Selumetinib in Pediatric NF1-PN!

Phase 2 trial that led to the FDA approval of selumetinib in 2020 for pediatric patients 2-18
years of age with NF1-related symptomatic, inoperable PN

Patients aged 2-18 years
with NF1 and unresectable

Selumetinib

PN, and a PN-related ts Bi ee
complication (28-d cycle)

(N = 50)
Primary endpoint: Response by 3D analysis of MRI (220% decrease in PN volume)

Secondary endpoints: Tumor-specific functional parameters, PRO, tolerability, PK,
PD, and safety

1. Gross AM etal. N Eng! J Mod. 2020,382:1490-1442 PeerView.com

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11. Longer-Term Evidence Shows Consistency of Clinical
Benefit With Selumetinib in NF1-PN!

N =74 children with NF1-PN

Up to 5 years of selumetinib
treatment

Overall cPR of 70%

Durable tumor shrinkage,
sustained improvement in pain
beyond results previously
reported at 1 year

No new safety signals
Monitoring throughout
treatment is necessary

1. Gross AM eta. Neuro Oncol 2023:25:1883-1804

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2
3
É
e
&

No. at Risk
Selumetinib
Natural history

Combined Phases 1 and 2 vs Natural History

10
08
08
“a Median PFS with
‘solumetinio was Selumetinib
approximately
à 67 y vs 1.3 y with the
previously published
Natural history " natural history cohort
o
o 2 4 & 8
Time, y
74 6 56 4 2 9 3 1 0
3 6 2 9 0 - = = =

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12. Longer-Term Response Data With Selumetinib in NF1-PN!

N = 74 children with NF1-PN ; >
Up to 5 years of selumetinib A i"
treatment E “
+ Median time to initial response: Es

8 cycles (range 4-40) E
o E Subject

+ Median time to best response:
18 cycles (range 4-94) zo.
+ Median duration of first i “
confirmed PR: 34.5 cycles H .
(min 4, max 77) A e
e

1.Gross AM eta. Neuro Oncol 2023:25.1883-1804. PeerView.com

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13. Longer-Term Data Shows No New Safety Concerns With
Selumetinib in NF1-PN!

Most Common AE (| 74) All Grades, n (%) Grade 23, n (%)
Gl
Vomiting 58 (77) 2 (3)
Diarrhea 51 (69) 9 (12)
Nausea 49 (66) 1 (1)
Skin
Rash acneiform 45 (61) 3 (4)
Paronychia 36 (48) 8(11)
Increased creatine phosphokinase 56 (76) 6 (8)

+ Dose reductions occurred in 29 participants (39%) due to selumetinib-related AE
+ 42 participants (54%) discontinued therapy
— Reasons for discontinuation: PD, n = 9; principal investigator discretion, n = 9; AE, n = 9;
other, n = 15

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1. Gross AM el al Neuro Oncol, 2025:25(10):1883-1894.

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14. Evidence With Selumetinib in Adults With NF1-PN1

Efficacy Safety
+ 27 patients enrolled as of + Most common side effects were rash,
February 2020 transaminitis, and pancreatic enzyme elevation
+ 16 patients achieved PR (69%) + 2 patients were dose reduced (1 due to rash
+ Patients reported significant and 1 due to transaminitis)
improvements in pain + 2 discontinued by choice
+ Median change in PN volume at + 2 withdrawn by Pl (best interest of patient)
best response: -22% (range -41% | |. 4 patient each removed for transaminitis,
to +5.5%) surgical resection, serious concurrent medical
illness, and noncompliance

1.OSukivan Coyne GH et al. in Oncol 202038(15. supp. PeerView.com

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15. ReNeu: Mirdametinib in Pediatric and Adult NF1-PN!

Open-Label, Pivotal Phase 2b of Mirdametinib in Adults and Children With NF1-PN

Adult
a, Mirdametiniba

(capsule or dispersible
tablet), 2 mg/m? BID
(max 4 mg BID), 3 weeks
on/1 week off, no fasting
requirement
(24 cycles,

Patients aged 22
years with
inoperable NF1-PN
causing significant
morbidity

+ Primary endpoint: Confirmed ORR (% of patients with 220% reduction in target tumor
volume by MRI on consecutive scans assessed by BICR)>

+ Key Secondary Endpoints: DOR, pain severity (NRS-11), HRQoL (PedsQL), and safety

“In LTFU, patents coninue on mirdametnib at the last dose assigned in the treatment phase. ® Per REINS crteria, Primary endpoint assessed in 24-cyle

treatment phase.
A. wweclincaltials ovistudyINCTOS962549.

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Safety follow-up
(30 days)

Optional LTFU

Safety follow-up
(30 days)

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16. ReNeu: Efficacy of Mirdametinib in Pediatric Patients’

going Phase 2b Study Evaluating Mirdametinib in Pediatric Patients

With NF1-PN (N

Efficacy
+ 29 out of 56 (52%) of pediatric patients achieved a 220% reduction in PN volume
+ Median best change in PN volume: -42% (range, -90 to 48)
+ 52% with confirmed objective response achieved a deep response
(>50% tumor volume reduction)
+ Statistically significant improvements in pain, QOL, and physical function
also reported

1. Moore Cet al, ASCO 2024, Abstract 3016. PeerView.com

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17. ReNeu: Mirdametinib Demonstrated Deep and Durable
Tumor Volume Reductions in Pediatric Patients!

Best Change in Tumor Volume for Each Target PN and Cycle During

60 Which This Was Achieved , %

40 cs

20 EC PD Lo]
ES mci
& © mov
2 20 mo
a
c= Mica
O 40 028

60 wc.

mcs
bd Mos
100 Patients

1.MoetelC el. ASCO 2024. Abstrac 3016. PeerView.com

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18. Efficacy of Mirdametinib in Adults: ReNeu!

ig Phase 2b Study Evaluating Adult Patients With

NF1-PN (N = 58)

Efficacy

+ 24 out of 58 (41%) adult patients achieved a 220% reduction in PN volume
— Two additional adults achieved confirmed PR in LTFU

+ Median best change in PN volume: -41% (range, -90 to 13)

+ 62% of adults with confirmed objective response achieved a deep response
(>50% tumor volume reduction)

+ Statistically significant improvements in pain, QOL, and physical function
also reported

1. Mowtel Ct al. ASCO 2024. Abstrac 3016. PeerView.com

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19. ReNeu: Mirdametinib Demonstrated Deep and Durable
Tumor Volume Reductions in Adults!

Best Change in Tumor Volume for Each Target PN and Cycle During
Which This Was Achieved , %

moc
mcr
mc
mc
mca
c28
"ca
cs
LE
Mos

pian tes Net ¡B

60

40 cs
20

0

Change, %

100 Patients

1.MoetelC e al. ASCO 2024. Abstract 3016. PeerView.com

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20. ReNeu: Mirdametinib Demonstrated a Manageable Safety
Profile in Pediatric and Adult Patients!

Adults (n = 58)
TRAEs in Safety Popul:
‘Any Grade | Grade 23
Any TRAE 57 (98) 9(16)
TRAEs of any grade reported in 220% of patients in either cohort
Dermatitis acneiform 45 (78) 5(9)
Diarrhea 28 (48) 0
Nausea 21 (36) 0
Vomiting 16 (28) 0
Fatigue 12 (21) 1(2)
Ejection fraction decreased 7 (12) 0
Blood creatinine phosphokinase increased 6(10) 12)
Paronychia 1(2) 0
Serious TRAES 1(2)
Interruptions due to TRAES 5(9)
Dose reductions due to TRAES 10 (17)

Discontinuations due to TRAES

1.MogrelC et al. Oral Presentation at Global NF Conference 2024.

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12 (21)

53 (95) 14 (25)

24 (43) 1(2)
21 (38) 1(2)
12(21) 0
8(14) 0
5(9) 0
11 (20) 1(2)
11 (20) 4(7)
17 (80) 0
0

8(14)

7(12)

5(9)

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21. ReNeu: Safety Comparison of Mirdametinib Capsule
and Dispersible Tablet Formulations’

Dispersible Tablet (

Capsule (n = 35)

Patient age, median (range) 6.0 (2.0-14.0) 13.0 (5.0-17.0)

AE with a 215% difference by formulation, n (%)
Cough 7 (33) 5 (14)
Rash 6 (29) 5 (14)
Alopecia 5 (24) 39)
Eczema 5 (24) 39)
Headache 5 (24) 14 (40)
Dermatitis acneiform 4 (19) 20 (57)
Otitis media 4(19) 0
Weight increased 1(5) 8 (23)

The dispersible tablet formulation is also important for adults
+ Some patients are on the autism spectrum and may exhibit difficulty swallowing capsules
+ Some patients may have difficulty swallowing capsules due to increased gag reflexes

1. Hesse LJ et al Intemational Symposium on Pediatric Neuro-Oncology 2024. Poster NFS-31. PeerView.com

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22. Trametinib Has Been Used for Adult and Pediatric
Patients With NF1-PN

Highly specific inhibitor of MEK1/2

FDA approved as single agent for treatment of BRAF-inhibitor
treatment-naive patients with unresectable or metastatic melanoma
with BRAF V600E or V600K mutations >

available off-label

Available in pill and liquid formulation

Dosing: empty stomach, once a day

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23. Preparing for Personalized Care
With MEKi Across the NF1-PN

Treatment Journey

24. The Role for MEK Inhibitors in Pediatric and Adult NF1-PN

A 4-year-old girl diagnosed with NF1 A 28-year-old male patient with NF1
at birth is brought to clinic due to a who presents with a target PN in the
symptomatic, inoperable PN neck that is causing significant pain
+ What factors inform treatment + What is the current standard of care
decisions? for adults with NF1-PN?
+ Is treatment with a MEKi the best * Whatis the experience with adults
option for this pediatric patient? on MEKi therapy?
+ How do you manage toxicities with + How will the approval of new MEKi
MEKi (ocular, Gl, skin)? impact treatment decisions and
+ How do you address challenges patient care?

such as difficulty swallowing
capsules among pediatric patients?

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25. Putting MEKi in the Context of Broader NF1-PN Treatment

Factors Indicating the Need
for Treatment

+ Size, extent, and progression of tumor
+ Patient age
+ Is there morbidity?

— Pain

— Significant disfigurement

— Functional deficit

+ Is there impending morbidity (adjacent
to or compression of structures)?

+ In most cases, stable tumors not
causing morbidity should be observed
as they may never progress or cause
symptoms

1. Ly et al. Med Cin North Am. 2019:103:1035-1054.2. Mer DT etal. Podatcs. 2018; 183:620190660. 3. Stewart DR et al. Ganot Med. 2018:20:671.82.
tion-approved crugs/da-approves-solumetiib-neuroioromatosis+ype-1-symptomaicinopera

A pe ra gow
neurofibromas. =

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+ Surgery

Treatment Considerations

+ Chemotherapy has not demonstrated efficacy in NF1-PN
+ Radiotherapy is contraindicated due to risk of inducing

MPNST (2.8-fold increased risk)

— If resectable without significant morbidity
— Surgical treatment of larger tumors is often

unsatisfactory due to nerve involvement and tendency
to grow back

+ Medical treatment/clinical trial with MEKi
— Selumetinib for pediatric pts and off-label for adults
— Trametinib available off-label for pediatric and adult pts
— Mirdametinib and other MEKi in rapid development

Depto A"
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26. Monitoring During Treatment With MEKi Therapy

Assessing Treatment Response _—_

+ Volumetric MRI: detect subtle changes in tumor volume

+ Patient-reported outcomes: use tools like PROMIS to track
changes in pain intensity and QOL

+ Long-term monitoring: sustained treatment with MEKi is
required for sustained tumor control; regular follow-ups are
essential to ensure continued efficacy

+ Safety monitoring: continuous monitoring and regular clinical
evaluations for detecting side effects and managing adverse
effects promptly

1. Dombi E etal N Engl J Med. 2016:975:2550-2580. PeerView.com

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27. Monitoring During Treatment With MEKi Therapy

Tox s to Monitor fo

+ Gastrointestinal: nausea, vomiting, abdominal pain, diarrhea, mucositis
+ Skin: rash, dry skin, paronychia, pruritus, dermatitis, hair changes

+ Ocular: monitor closely for retinal vein occlusion and retinal pigment
epithelial detachment

+ Cardiac: assess ejection fraction prior to initiating treatment and every
3 months during the first year, then every 6 months thereafter, and as
clinically indicated due to risk of cardiomyopathy

+ Musculoskeletal: myalgia; monitor for CPK elevation and rhabdomyolysis
+ General: fatigue, pyrexia, edema

+ Nervous system: headaches

+ Increased risk of bleeding due to vitamin E in capsules

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28. Considerations on the Use of MEK Inhibitors
in Pediatric and Adult NF1-PN

A 4-year-old girl diagnosed with NF1
at birth is brought to clinic due to a
symptomatic, inoperable PN

Pediatric Case
Considerations

Selumetinib is the standard of care for

pediatric NF1-PN

= Counsel family on skin, dietary, and
nausea management and other potential
side effects

+ Trametinib is also a viable off-label option

* Mirdametinib, when approved, will offer an
effective MEKi option with a lower GI toxicity
profile compared with selumetinib
= Counsel family on skin and other potential

side effects

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A 28-year-old male patient with NF1
presents with a target PN in the neck
that is causing significant pain

Adult Case
Considerations

Selumetinib and trametinib are viable
off-label options
+ Mirdametinib may soon become the first
approved, evidence-based MEKi in adults with
NF1-PN
+ Regularly monitor for spinal cord and
neck safety
+ Employ appropriate anticipatory management
of potential GI, skin, and other MEKi-related
toxicities to optimize efficacy

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29. Take-Homes

Selumetinib remains the only FDA-approved MEKi in
pediatric patients with NF1-PN

Mirdametinib will likely be approved soon (NDA submitted
in March 2024)

Differences in toxicity profiles may help inform the choice
between selumetinib or mirdametinib (eg, potentially less
Gl side effects with mirdametinib)

Safety management is key to positive long-term outcomes

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