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1/30/2017
1
Theranostics: Quantitative
Diagnostics and Targeted Radio-
Therapy in Solid tumors
Frontiers in Oncology
Friday-Saturday, January 27-28, 2017
The Biltmore Hotel, Coral Gables, Florida
Steven M. Larson, M.D. FACM, FACR
Donna and Benjamin M. Rosen Chair Molecular Imaging and Therapy Service
Department of Radiology
Member and Lab Head, Molecular Pharmacology Program
Sloan Kettering Institute
Memorial Sloan Kettering Cancer Center
Disclosures
• Financial or Material Support from:
Regeneron, Genentech and Bristol Myers
• Shareholder: Voreyda Theranostics, Inc. and
Claymore Inc.
Key Concepts
• Theranostics
• Re-differentiation therapy in
thyroid cancer
• Therapeutic Index (TI)
Theranostics at MSKCC
•Thyroid Cancer Redifferentiation for 131I Rx
•Recurrent CNS NB and other GD2 expressing tumors
: 131,124I-8H9; 131,124I-3F8
•Diffuse intrapontine Glioma 124I-8H9
•DOTA-PRIT in solid tumors
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Theranostic Drug
•A drug or biologic with intrinsic diagnostic
and therapeutic properties
•E.g. Na 124I/131I for Dx/Rx thyroid Ca
•Related concept “Companion Diagnostic”
•E.g. 89Zr-MSTP (STEAP , Prostate Ca)
To select patients for Rx who have target
antigen
Thyroid Cancer Treatment
Redifferentiation Therapy for 131I-
uptake
• Distant metastases are the most frequent cause of
death for patients with differentiated thyroid cancer1
• Decreased RAI incorporation into metastatic sites is
associated with higher mortality2
• New therapies for RAI-refractory thyroid cancer are
desperately needed
The Clinical Problem: RAI-Refractory Thyroid Cancer
James Fagin Alan Ho Mike Tuttle
MAP Kinase Signaling and PapillaryThyroid Cancer (PTC)
BRAF V600E
45%(9/20) patients
Integrated Genomic Characterization of Papillary Thyroid Carcinoma The Cancer Genome Atlas Cancer Network. Cell 159:676-690, 2014
Driver oncogenes
are known for
~95% of PTC
tumors, and
~75% involve
MAPK pathway
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124I-Iodine in Thyroid Cancer
At time of surgery, WD
thyroid Ca 2.0 cm
Mets to neck nodes and lung
4.28.2000 TG 11,000
12.2003 TG 7
3.14.2013 TG < .2
12/2000-10/2003 131I Rx in
4 doses to 1527 mCi. Est
dose > 50,000
Last F/U 3/14 /2013 NED
many punctate
bilateral CT lesions
Dry mouth, otherwise no
sequelaePre-Treatment PET
Thyroid Differentiation Score
and Thyroid Cancers CGA
NIS
Primary ObjectiveTo determine whether RAI incorporation increases in RAI-refractory thyroid cancer metastases after 4 weeks of treatment with a MAPK pathway inhibitor.
124I –Positron Emission Tomography (PET)/CT
CT imagesPET images Ffused images
Advantages of 124I –PET
Quantitative, allows lesional dosimetry
Structural correlates for iodine incorporation
Selumetinib (AZD6244 Hyd-Sulfate, ARRY-142886)Highly selective, allosteric inhibitor of MEK 1/2
Inhibits MEK1 in vitro with an IC50 of 14.1 +/- 0.79 nM1
RTK
Ras
B-Raf
MEK 1/2
Erk 1/2
Selumetinib
NISNormal Biodistribution of 124I
Restoring Radiodine Uptake in Thyroid Cancer
Ho et al: N Engl J Med. 2013 Feb 14; 368(7): 623–632.
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124I for lesion specific dosimetry
in thyroid cancer
*Selecting for >2000 cGy lesion dose improved
response rate for 131I Rx
Ho A et al: N Engl J Med. 2013 Feb 14;368(7):623-32
Simplified dose modelUptake
Amax @48 Time (hr)
Dose (cGy) = ʃ Amax exp – (0.693 * t)
m_ _____ . Δφ
τewhere τe = 48hr which is an average effective half-life in each lesion and Δφ
= 0.405 g.cGy/ µCi.hr which is the equilibrium dose constant.
It can be shown that SUV > 20 would get > 2000 cGy, per lesion for an
administered dose of 250 mCi, the usual maximum outpatient treatment
dose
The simplified model relies
on the PET information from
a single 48hr PET scan.
0
.
L,Ho et al Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.
New Engl J Med 2013 Feb 14;368(7):623-32
MEK inhibition restores radioactive iodine uptake
• RET, BRAF, RAS mutant thyroid cancer → ↑MAPK signaling → RAI
refractory
• MEK inhibition restores iodine uptake
• 124I effective for 131I dosimetry
• Selumetinib increased 124I uptake in 12/20 pts (4/9 RAF, 5/5 NRASmutant)
• 8/12 pts reached 131I dosimetry level
• Phase III trial planned
Lesions with 124I uptake at baseline
Individual tumors
Essential Cores
Radiochemistry and Molecular Imaging Probes
Pathology
Biostatistics
Collaborators
Fagin (CBEP, CR)
Larson (IMRAS, CR)
Ho (CR)
124I PET/CT
Baseline
124I PET/CT
After Selumetinib
Best Response For Patients Treated with RAI
-100%
-90%
-80%
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%
Ch
ang
e in
Tar
get
Les
ion
s b
y R
EC
IST
(%)
Confirmed PR
Confirmed SD
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Summary
• Selumetinib enhances iodine incorporation in patients with RAI refractory thyroid cancer and reverses RAI resistance
• Selumetinib effects upon iodine incorporation may be dependent upon clinical factors (degree of residual iodine incorporation, FDG avidity, number of previous RAI treatments) and/or tumor genotype.
• Ho et al: N Engl J Med. 2013 Feb 14;368(7):623-32. doi:
10.1056/NEJMoa1209288
16 genes used by TCGA for TDS score
TDS correlated genes (29 pos + 20 Neg+15 mIRs)
Enhanced TDS
Pathway/Cell Purity
Gene SetsSource
BRAF/RAS classifier TCGA, Cell 2014
ERK output Pratilas et al, PNAS 2009
Tumor purity score TCGA, Cell 2014
Housekeeping controls Nanostring + TCGA
Nanostring RAI Response Predictor: Thyroid Differentiation Classifier (TDC)
Enhancing the thyroid differentiation score
J Knauf
Y Senbabaoglu
V Seshan
L Boucai
J Fagin
Mechanism of Action
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Immunoconjugates at MSKCC
•Radioimmunoconjugate
•Diagnostic and or Therapeutic Use
•PET emitters, Beta Emitters, Alpha emitters
•18 clinically active, 2 Pending
•Drug Conjugates
•e.g. STEAP* - Aurestatin E
Genetech
Therapeutic Index for Targeted Radiotherapy
• Radiation absorbed dose (cGy) in tumor vs
radiosensitive tissue (marrow, kidney, lung)Tumor Blood Kidney
AUCTumor = 812 AUCBlood = 24 AUCKidney = 98
TITumor:Blood = 34 TITumor:Kidney = 8
Targeted Radiotherapy of Solid Tumors
• Curative Tumor Dose> 10,000 cGy
•Renal dose < 1500 cGy
•~7-10 Therapeutic Index (TI)
•Bone Marrow dose < 150 cGy
•~40-100 TI
•Colon mucosa dose < 250 cGy
•~40-60 TI
MSKCC (Finn) Solid Target Assembly
124Te(p,n)124I (incident energy 15 MeV)
Ronald D. Finn, Ph.D.
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Neuroblastoma and Glioma
Theranostics with
Radioimmuno-conjugates
• Nai Kong Cheung et al in Pediatric Oncology
• Unmet clinical need: better therapy for CNS recurrence of NB and primary Rx of Glioma
• 3F8 and 8H9 excellent antibodies
• PET scanning of iodine-124-3F8 for tumor dosimetry during treatment planning for radioimmunotherapy
• Long term collaboration including development of novel antibody forms
8H9 injection through filtercRIT: Outpatient intraOmmaya injections at the bedside
Sagittal section from serial 124I-3F8 PET images of
pediatric patient with neuroblastoma
Quantitative PET images used to estimate the radiation dose from
50mCi of 131I-3F8. Tumor dose estimates 12000 to 90000. Blood
dose is 75 cGy. TI = 250-1200
4 hours 24 hours 48 hours John Humm
Leptomeningeal Disease Uptake
of 124I-8H9 (48 hours)
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PFS at 5 yrs PFS at 4 yrs
Patient #1: Patient #2:
Salvage Regimen Salvage Regimen
Demographics N=188
8H9
• Assessment n=154
• Treated n=113» 332 injections
• Diagnoses
– Neuroblastoma 81
– Ependymoma 9
– Medullo 9
– MelanoMA 4
– RMS 3
– CPC 2
– Chordoma 1
– Retinoblastoma 1
• Median age
-5.3 yrs (10 mon- 53 years)
3F8
• Treated n=75» 255 injections
• Diagnoses
-Medullo 49
-Ependymoma 2
-ATRT 3
-Melanoma 2
-NB 12
-Retinoblastoma 5
• Median age
– 6.5 yrs (1 yrs- 63 years)
Months from CNS event
Pro
po
rtio
n o
f p
ati
en
ts s
urv
ivin
g CNS salvage regimen
containing131I-3F8 or 131I-8H9
Historical control
(Kramer and Cheung, MSKCC, 5/08)
Recurrent neuroblastoma metastatic to the CNS•MSKCC
•Phase I Study of Convection-Enhanced Delivery of 124I-8H9 for
Patients with Non-Progressive Diffuse Pontine Gliomas
Previously Treated with External Beam RT Therapy
(PIs: Drs. Mark Souweidane/Ira Dunkel/Kim Kramer)
Kim Kramer Neeta Pandit-TaskarJorge Carrasquillo Jason Lewis
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Conventional
Radioimmunotherapy
e.g. 131I-Bexxar or 90Y-Zevulin
%
Radioactivity
per
kilogram
0
10
20
30
0 50 100 150
Time (hrs)
Blood
Tumor
AUC Tumor / AUC Blood ~ 3 --7 5
CH2
CH3
CH1
VH
VL
CL
carbohydrate
Targeting Challenge: Radiation directly bound
to an antibody
Figure obtained from Donald Axworthy
Pre-targeted
Radioimmunotherapy
DOTA-PRIT
A33 (GPA33)
3F8 (GD2)
Herceptin (Her2)
Separate the antigen targeting step and the radioactivity targeting step
Collaborators
Nai-Kong Cheung
K. Dane Wittrup, Ph.D. CP Dubbs Professor of Chemical Engineering
and Biologic Engineering; Assoc. Director , Koch Institute of Technology
Steven M. Larson, M.D. Donna and Benjamin M. Rosen Chair in
Radiology; Memorial Sloan Kettering Cancer Center; Director Ludwig
Center for Radioimmunotherapy and Theranostics, Member and Lab
Head, Molecular Pharmacology Program, Sloan Kettering Institute
Nai-Kong V. Cheung, MD, Ph.D. Enid Haupt A. Chair in Pediatrics,
Memorial Sloan Kettering Cancer Center; Director, Neuroblastoma
Program; Head, Robert Steele Laboratory
Key PersonnelSarah Cheal, Ph.D. Senior Scientist Molecular
Pharmacology Program; Radio chemist, pre-Doc under
Claude Meares and Post-Doc in Larson Lab
Hong Xu, Ph.D., Senior Scientist, Robert Steele Lab.
Immunobiologist, Memorial Sloan Kettering Cancer Center
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0
10
20
30
0 50 100 150
Time (hrs)
Blood
Tumor
%
Radioactivity
per
kilogram
AUC Tumor / AUC blood > 100
DOTA-PRIT: Separate antigen targeting and
Radioactivity targeting to tumor
Figure obtained from Donald Axworthy.
Radionuclides: 86Y (14.7 hr.s) β+ decay90Y (64 hr.s) β- decay177Lu(6.73 days) β- ,γ decay
Positron Emission Tomography
(PET): based on positron decay
advantages, resolution,
sensitivity. Available at tertiary
care and referral centers
throughout US, Europe, Asia
Animal PET Human PET
Single Photon Computed
Tomography(SPECT): Based on γphotons. Advantages: many
common radionuclides and widely
available, in every hospital in US and
Europe Animal SPECT Human SPECT/CT
Targeting Components for DOTA PRIT
huA33
GPA33 antigen
Junctional Membrane Complex Ag
Metastatic Colorectal Cancer
A33 extensively studied in colorectal cancer patients in vivo: an optimal antibody for DOTA-PRIT
O’Donoghue et al. JNM (2011) 52: 1878-1885
• huA33 is a humanized mAb
which binds to GPA33 antigen
• At MSKCC: 124I-huA33
in patients with advanced
colorectal cancer
• GPA33(+) cancers:
95% of colon carcinomas
Zanzonico et al. EJNMMI (2015) 42: 1700-1706
Autoradiography H/E stain GPA33 IH
124I-A33 PETCT
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GPA33
86Y,90Y 15.4 ± 2.0 pM177Lu 10.8 ± 2.5 pM
M
(M)DOTA-Bn
Orcutt KD, et al. (2011) Nucl Med Biol, 38: 223-233
2D12.5: Reardon, et al. (1985) Nature, 316: 265-268
MW ~ 210 kD
)
= “huA33-C825”
DOTA PRIT PLATFORM
Step 1: Inject huA33-C825 @ t = 0
Step 2: Inject clearing agent (CA) @ t = 24 h
Step 3: Inject 177Lu-Benzyl-DOTA or 86Y-Benzyl-DOTA @ t = 28 h
Cheal et al. EJNMMI (2016) 43: 925-937
Anti-GPA33 DOTA-PRIT: theranostics
2 h post-177Lu-DOTA 20 h post-177Lu-DOTA
Curative therapy for SW1222 Colon Cancer
Twin Benefits of High Therapeutic Index:
Safe Treatment (A) and Superior Diagnosis (B)
CR’s , no
Toxicity
tumor
2 h 20 h
9 %ID/g
0 %ID/g
A.
B.177Lu SPECT
86 Y PET
18 Days
~10 mg
Rx tumor
Tissue Absorbed Dose
Delivered for 3
Cycles
(rad)
Minimum Effective
or Maximum
Permissible Dose
(rad)
Blood 150 (TI = 93) 200 (marrow)
GPA33(+) tumor 14,000 7,000
Kidney 875 (TI = 16) 1,500
Curative Anti-GPA33 DOTA-PRIT is below estimated MTD
At 96 days post treatment, 5/10 examined for normal organ toxicity
No toxicity detected*
*Examined for:
Bone marrow hypocellularity
Renal Damage (tubular damage, sub-cortical atrophy,glomerular
proliferation).
CBC’s and blood chemistry abnormalities
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SPECT/CT imaging for Dosimetry of
cycle 1-3
SPECT/CT imaging for Dosimetry of
cycle 1-3: Relative Dose distribution
0
20
40
60
80
100
120
140
160
0 50 100 150 200 250 300 350 400 450
Act
ivit
y C
on
cen
tra
tio
n
Hours Postinjection
3
2
1
Fitted exponential decay curves on three-cycle
treatment regimen. Units for activity
concentration (y-axis) are µCi/mL.. Of the total
dose of ~100 Gy, the first dose contributes 30%;
the second dose 60%; and the third dose 10%
Harnessing Atomic Energy to Cure
Cancer : DOTA PRIT*
• Novel Immuno-oncology Rx
• Improve therapeutic index >10-fold over conventional Radioimmunotherapy
• Potential to greatly Reduce toxicity for ADC– Radioactive payloads
– Toxins
– Chemotherapies
• A platform technology, Applicable to the Common Solid Tumors: Colon, Ovary, Breast, Gastric, Lung (SCLC), Sarcoma
Support
• Ludwig Center for Radioimmunotherapy and
Theranositcs
• ICMIC NCI P50 SM Larson PI
• Thyroid SPOR P50 J Fagin PI
• NCI P30 Cancer Center Suport Grant
G. Thompson, PI>
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Larson Lab Molecular Imaging and Therapy
Service
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