Neurofibroma / Nerve Sheath Tumor

Dermal

≥ 95%

Plexiform (PN)

25-40%

Atypical (ANF)

Unknown ?

MPNST

15.8%

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

Loss of NF1 + CDKN2A/B + PRC2, P53, others

Whole Body MRI: Identification of Distinct Nodular Lesions

Age 2 Age 9 Age 12

• Round/oval, well demarcated, ≥ 3 cm, within or outside PN

• Lack the central dot sign characteristic of PN

• FDG avid in comparison to the surrounding PN

• Growth rate exceeds PN growth rate.

Development of Atypical Neurofibroma in Plexiform Neurofibroma

Girl with NF1 and Neck/Chest PN

ANFNeurofibroma

Encapsulated lesion resected, no recurrence

Relationship of Growth Rate and Age

• Nodular lesions grow independently of age.

• Nodular lesions are not observed in very young children.

• Nodular lesions may have different biology: Atypical neurofibromas (CDKN2A/B deletion)

• PN grow most rapidly in young patients.

• PN growth ≥20% per year is rare in ≥ 15 year-old patients.

Srivandana

Akshintala

Acknowledgements Imaging:

• Eva Dombi

• Jeffrey Solomon

Research nurse / NP / PCC / MD:

• Trish Whitcomb, Marielle Holmblad

• Anne Goodwin

• Amanda Carbonell

• Andrea Baldwin, Joanne Derdak

• Kara Heisey

• Andrea Gross, Diana Bradford

• Christine Higham

Participating sites/collaborators

• Brian Weiss

• Michael Fisher

• AeRang Kim

• Doug Stewart

• Karlyne Reilly

• Eric Legius

• Ros Ferner

CTEP:

• John Wright, Austin Doyle

FDA

AstraZeneca

REiNS:

Scott Plotkin

Preclinical Trials

• Nancy Ratner

• Wade Clapp

SARC

DoD NF Clinical Trials Consortium

Funding:

• DoD, CTF

• NTAP: Jaishri Blakeley

Statistical support:

• Seth Steinberg

Patient and families

Phase II Trial of Imatinib Eligibility: NF1 3-65 y/o with clinically significant PN

Treatment: Imatinib 220 mg BID for children, 400 mg BID for adults

Primary endpoint: Volumetric response (≥20% decrease in PN volume)

Results:

• Response rate:

• 6 of 36 pts had OR (17%)

• 6 of 23 pts (26%) treated ≥ 6 months had OR

• Most common AEs: Rash (6), edema (6) neutropenia (2) AST (1)

K. Robertson…D. Wade Clapp. Lancet Oncology 2012

Appearance Improvement

10 y/o with right neck plexiform

neurofibroma

Baseline Pre cycle 5 Pre cycle 10 Pre cycle 15

Management of Atypical Neurofibromas

10 year-old boy with asymptomatic, newly diagnosed PN

Germline NF1 Splicing c.288+2T>G

Somatic Frameshift p.I1402fs

CDKN2A/B Het. loss

9pter-p13.3

Het. loss

9pter p-21.3

Inguinal Paraspinal

Pathology ANF NF

Malignant Peripheral Nerve SheathTumor (MPNST)

Aggressive soft tissue sarcoma (STS), 50% in neurofibromatosis type 1 (NF1)

Complete surgical resection is required for cure

No effective medical therapy, no improvement in outcome

Presented by:

MPNST State of the Science: Outlining a Research Agenda for the Future - Oct 5-7, 2016

Histopathologic Evaluation of ANF and their Transformation into MPNST

Expert Pathology Consensus Review

Diagnosis Proposed Definition

Neurofibroma with atypia

(“Ancient NF”)

NF with atypia alone, most commonly manifesting as

scattered bizarre nuclei

Cellular NF NF with hypercellularity, but retained NF architecture and

<1 mf/50 HPF

Atypical neurofibromatous

neoplasms of uncertain

biologic potential (ANNUBP)

Schwann cell neoplasm with at least 2 of 4 features:

cytologic atypia, loss of neurofibroma architecture,

hypercellularity, mitotic index >1/50 HPF and <3/10 HPF

MPNST, low grade Features of ANNUBP, but with mitotic index of 3-9/10 HPF

and no necrosis

MPNST, high grade MPNST with at least 10 mf/10 HPF or 3-9 mf/10 HPF

combined with necrosis

M. Miettinen, C. Antonescu, C. Fletcher, A. Lazar, M. Quezado, A. Stemmer-Rachamimov, Arie Perry

NCI/CTF: MPNST State of the Science Conference 2016

Miettinen M…Perry A., Human Pathology 2017

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Aggressive soft tissue sarcoma (STS)

4% of all STS, 50% in neurofibromatosis type 1 (NF1)

Lifetime incidence of MPNST in NF1 15.8%

Risk factors:

• Whole gene deletion, prior radiation therapy, ANF, large PN tumor burden

Development in preexisting PN and ANF in NF1

• LOF somatic alterations in PRC2 core components: EED and SUZ12

• 92% of Sporadic MPNSTs

• 70% NF1-associated MPNSTs

• 90% Radiotherapy-associated MPNSTs

Clinical signs and symptoms of PN and MPNST overlap

Complete surgical resection with negative margins required for cure

No effective medical therapy

No improvement in outcome

Role of Chemotherapy in MPNSTResponse to “standard sarcoma” chemotherapy in sporadic and NF1 MPNST

Variable N 5-Year OS

(%)

Chemotherapy

Response (%)

Reference

NF1 29 32 18Carli, 2005

JCONo NF1 138 55 55

NF1 27 11 8Ferrari, 2011

European J

of CancerNo NF1 44 45 60

NF1 3 - 33Hirbe, 2017

SarcomaNo NF1 2 - 100

NF1 28 - 18Higham, 2017

SarcomaNo NF1 9 - 44

Phase II Trial of Chemotherapy for MPNST

Eight chemotherapy cycles total:

• Doxorubicin: 37.5 mg/m2 days 1 and 2 (cumulative 300 mg/m2)

• Ifosfamide: 1,800 mg/m2 days 1-5 (cumulative 72,000 mg/m2)

• Etoposide: 100 mg/m2 days 1-5 (cumulative 2,000 mg/m2)

MPNSTResponse

Evaluation

Local

ControlChemotherapy

8 cycles total

NF1 IE x 2IA x 2

Sporadic IA x 2 IE x 2

PET

3D MRI

Surgery

XRTMRI

PET

3D MRI

I - Ifosfamide

A - Adriamycin

E - Etoposide

NCI, SARC, NF1 Centers

SARC006: Response Evaluation

Characteristics NF1 Sporadic

Evaluable post cycle 4 28 9

Complete Response - -

Partial Response 5 4

Stable Disease 20 4

Progressive Diasease 3 1

CR/PR rate (%) 17.9 44.4

Response after 4 Cycles (2 IA, 2IE) and 2 Cycles (IA)

-80

-60

-40

-20

0

20

40

60

% C

han

ge f

rom

Ba

se

lin

e

★★

-80

-60

-40

-20

0

20

40

60

% C

han

ge f

rom

Ba

se

lin

e

★★

NF1 MPNSTSporadic MPNST

-80

-60

-40

-20

0

20

40

60

% C

han

ge f

rom

Ba

se

lin

e

-80

-60

-40

-20

0

20

40

60

% C

han

ge f

rom

Ba

se

lin

e

✖

Higham C…Widemann B. Sarcoma, 2017

Phase II Trials with Targeted Agents for Refractory MPNST

Target Agent Patients (N) Age (yr) Outcome

Erlotinib EGFR 20 (10 NF1) ≥18 No PR, 18/20 PD after 2 cycles

SorafenibRaf, VEGFR,

PDGFR, C-KIT12 ≥18 No PR, PFS 1.7 mo, SD n= 3

ImatinibC-KIT, PDGFR

VEGFR7 ≥10 No PR or SD

Dasatinib C-KIT, SRC14 ≥13

No PR, no SD at 4 cycles

Bevacizumab,

Everolimus

Angiogenesis

mTOR25 (17 NF1) ≥18 No PR, 3 pts. SD at cycle 4

MLN8237

(Alisertib)Aurora Kinase A 10 ≥18 No PR, 12 week PFS 60%

Ganetespib

Sirolimus

HSP90

mTOR10 (5 NF1) ≥16 No PR, 1 SD at cycle 4 (RECIST)

Clinical benefit in MPNST: Complete response, partial response, stable disease at 4 cycles

Slow Spontaneous Volume Decrease in 10 of 112 PN

20% volume decrease over 4 yearsPt # Decrease

from max.

vol. (%)

Follow-up

Duration

(years)

Decrease

/ year

(%)

Age at

max. vol.

(years)

24 34 4 9 20

26 21 10 2 8

85 21 3 8 19

5 21 5 4 31

7 21 4 5 11

66 17 3 5 27

10 17 7 3 18

6 13 7 2 10

17 12 4 3 19

36 11 3 3 20

Median 19 4 4 19

Range 11-34 3-10 2-9 8-31

2002: 674 mL 2007: 1420 mL2010: 1347 mL 2012: Not measurable

Progression Free Survival Phase A

Log-rank p-value one-sided: 0.129

PF

S (

%)

TTP (months)

: 10.6 months

: 19.2 months

Progression Free Survival Phase B

Log-rank p-value one-sided: 0.15

PF

S (

%)

From start of treatment on phase B

: 14.5 months

: 13.3 months

TTP (months)