This document provides an overview of neuroblastoma, including: - Neuroblastoma is cancer of neural crest cells that give rise to sympathetic neural ganglia and adrenal medulla. It has a diverse presentation and prognosis ranging from spontaneous regression to aggressive metastatic tumors. - Risk classification involves assessing histopathology, DNA index, MYCN amplification, and other factors to determine prognosis as favorable or unfavorable. - A clinical trial evaluated adding dinutuximab, GM-CSF, and IL-2 to standard isotretinoin therapy in patients with high-risk neuroblastoma and found common side effects included pain, hypersensitivity reactions, and capillary leak syndrome.

1. Neuroblastoma
Background
NEUROBLASTOMA
OVERVIEW

2. Section
page 2
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Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
NEUROBLASTOMA
OVERVIEW
What is Neuroblastoma?
Cancer of neural
crest cells that give
rise to sympathetic
neural ganglia and
adrenal medulla.1
Diverse pattern of
presentation and
prognosis that can
range from spontaneous
regression to aggressive
metastatic tumors.1
Endoderm
Ectoderm
Osteoblasts
Fibroblasts
Odontoblasts
Chondroblasts Cementoblasts
NEURAL
CREST
CELLS
ECTOMESYNCHYMAL
CELLS
Sympathetic
Neuron
Sensory
Neuron
Motor
Neuron
Melanoblasts Schwann Cells
NEUROBLASTS
1|
Irwin, M.S., Park, J.R. (2015). Neuroblastoma: Paradigm for precision medicine.
Pediatric Clinics of North America, 62(1), 225-­
256.

3. Section
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Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
NEUROBLASTOMA
OVERVIEW
Neuroblastoma Risk Classification: HISTOPATHOLOGY
The International
Neuroblastoma
Pathology
Classification
(INPC) system
used to designate
whether the tumor
tissue has favorable
or unfavorable
histologic features.1
Undifferentiated Differentiating Stroma-rich
Stroma-poor
Unfavorable Histology Favorable Histology
Neuroblastoma
tissue samples
1| Armideo, et al. J Adv Pract Oncol, 2017;8:44–55, https://doi.org/10.6004/jadpro.2017.8.1.4,
2| Image from Ohio State University, http://www.bmi.osu.edu/cialab/mia_nb.php

4. Section
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US/UTX/SEPT16/051
Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
NEUROBLASTOMA
OVERVIEW
Favorable
HYPERDIPLOID:
More than 46
chromosomes
DNA index 1
Unfavorable
HYPODIPLOID:
Less than 46
chromosomes
DNA index 1
Neuroblastoma Risk Classification: DNA INDEX1
1| Irwin, M. S., Park, J. R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric
Clinics of North America, 62(1), 225-256.
X 2
46

5. Section
page 11
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Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
NEUROBLASTOMA
OVERVIEW
Considered
“amplified” if
copies are
identified
Detected by using FISH
with MYCN-labeled probe
MYCN
10+
MYCN:
Oncogene on
chromosome 2
MYCN amplification is a
poor prognostic Indicator
Unfavorable
1| Irwin, M. S., Park, J. R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric
Clinics of North America, 62(1), 225-256.
Neuroblastoma Risk Classification: MYCN AMPLIFICATION1
MYCN = v-­
myc avian myelocytomatosis viral
oncogene neuroblastoma-­
derived homolog.
FISH = Fluorescence in situ hybridization

6. Section
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NEUROBLASTOMA
OVERVIEW
REFERENCES 1| Yang et al. Drugs Future. 2010;35(8)665. 2| Ward et al. CA Cancer J Clin. 2014;64(2):83-103.3| Cohn et al. J Clin Oncol. 2008;27(2):289-297. 4| American Cancer Society. Survival rates for neuroblastoma based on risk
groups. http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-survival-rates. Revised January 22, 2016. Accessed April 13, 2016. 5| Irwin, M. S., Park, J. R. (2015). Neuroblastoma: Paradigm for
precision medicine. Pediatric Clinics of North America, 62(1), 225-256.
Unituxin®
(dinutuximab)
Injection
Chimeric
anti-GD2
monoclonal
antibody
HUMAN
100% 33% 10%
MURINE
Unituxin is a chimeric anti-GD2 monoclonal antibody
The Antibody Therapy Team
consists of
“multiple parts”
part human, and
part mouse
meaning
having one clone,
man-made
MOUSE CHIMERIC HUMANIZED

7. Section
page 1
US/UTX/SEPT16/051
NEUROBLASTOMA
OVERVIEW
REFERENCES 1| Unituxin [package insert]. Research Triangle Park, NC:
United Therapeutics Corporation; 2015.
Pretreatment and Guidelines for Pain Management1
Sodium Chloride
q4-6hrs
as tolerated
q4-6hrs as needed
for fever or pain
Administer additional doses
(25-50 μg/kg) as needed§
IMMEDIATELY PRIOR
17.5 mg/m2/d
IV infusion
Antihistamine
Acetaminophen*
(50 μg/kg IV infusion;
then 20-50 μg/kg/h
continuous IV infusion)
0.5-1.0 mg/kg diphenhydramine
(50mg maximum) IV infusion
Injection, USP
(0.9%; 10 mL/kg IV infusion)
(10-15 mg/kg;
maximum dose 650 mg)
Morphine sulfate†‡
These guidelines are based on protocol
from the COG-ANBL0032 study
IV=intravenous; USP=US Pharmacopeia.
* Administer ibuprofen (5-10 mg/kg) q6h as needed for
control of persistent fever or pain.
† Consider using fentanyl or hydromorphone if morphine
sulfate is not tolerated.
‡ If pain is inadequately managed with opioids, consider use
of gabapentin or lidocaine in conjunction with IV morphine.
§ Up to once every 2 hours followed by an increase in the
morphine sulfate infusion rate in clinically stable patients.
1hr
before
20min
before
10-20hrs
Unituxin treatment
2hrs
After
TIMELINE
For 1hr
Please see continued Important Safety Information for Unituxin on slides 4-10.

8. Section
page 2
US/UTX/SEPT16/051
NEUROBLASTOMA
OVERVIEW
REFERENCES
Cycles
1 2 3 4 5 6
The Unituxin
antibody therapy
regimen is
1| Unituxin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2015.
2| Yu et al. N Engl J Med. 2010;363(14):1324-1334.
Antibody Therapy Treatment Overview:1,2
~1
month
Unituxin
GM-CSF
RA
Unituxin
GM-CSF
RA
Unituxin
GM-CSF
RA
Unituxin
IL-2
RA
Unituxin
IL-2
RA
RA
6
cycles in length
GM-CSF = granulocyte-macrophage
colony-stimulating factor;
IL-2 = interleukin 2;
RA = 13-cis-retinoic acid.
Adapted from Yu et al.1

9. CLINICAL
TRIALS DATA
Please see continued Important Safety Information for Unituxin on slides 4-10.
Side Effects
Reported from ANBL0032

10. Section
page 2
US/UTX/SEPT16/051
Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
CLINICAL
TRIALS DATA
1| Yu et al. N Engl J Med. 2010;363(14):1324-1334.
2| Data on file. United Therapeutics Corporation. Research Triangle Park, NC 27709. March 2014.
Overview:
Randomized, open-
label, multicenter trial
to determine whether
adding dinutuximab,
GM-CSF, and IL-2 to
standard isotretinoin
therapy after intensive
multimodal therapy
improves outcomes in
patients with high-risk
neuroblastoma
Randomization ITT
1:1
RA
Efficacy End Points:
Primary, event-free
survival;
Secondary, overall
survival
GM-CSF = granulocyte-
macrophage colony-
stimulating factor;
IL-2 = interleukin 2;
RA = 13-cis-retinoic acid.
n=113
n=226
n=113
X5 X6
X1
Ch14.18
GM-CSF
or IL-2
RA
RA only
RA only
Study Design1,2
Unituxin/RA

11. Section
page 7
US/UTX/SEPT16/051
Please see continued Important Safety Information for Unituxin on slides 4-10.
REFERENCES
CLINICAL
TRIALS DATA
Side Effect
Cycles
1 2 3 4 5 6
Injection
RA RA RA
RA
RA RA
Unituxin Unituxin Unituxin
Unituxin Unituxin
GM-CSF GM-CSF GM-CSF
IL-2 IL-2
49%
28% 25%
35%
17%
5%
7% 10% 7%
13%
5% 5%
6%
15%
5%
13%
5% 5%
Selected Adverse Events by Treatment Cycle in
Patients Receiving Unituxin® (dinutuximab) Injection1*
FPO
WIP
need data
1| Data on file. United Therapeutics Corporation. Research Triangle Park, NC 27709. March 2014.
Pain-related AEs†
Hypersensitivity
reaction
Capillary leak
syndrome‡
GM-CSF=granulocyte-macrophage colony-stimulating factor; IL-2=interleukin 2; RA=13-cis-retinoic acid.
Key
All Grades
Grades 3-4
‡ Grade 5 adverse reactions occurred
in 1 patient only with IL-2.
† Grade 3 pain refers to pain or severe
pain or use of analgesics severely inter-
fering with activities of daily living;
Grade 4 pain refers to disabling pain.
* Adverse events
(all grades) oc-
curring in ≥5%
of patients