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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