Targeted Therapy for Thyroid Cancer

R Michael Tuttle, MDProfessor of Medicine , Endocrine ServiceMemorial Sloan Kettering Cancer Center

New York, NY

Management of Advanced Non-Medullary Thyroid

Cancer

Systemic TherapiesChemotherapy/Novel Therapies

Targeted TherapiesWhat are our options?

Surgery External Beam RadiationEmbolization

Radioactive Iodine

Often, multiple “targeted therapies” are used over the life time of a patient with

advanced thyroid cancer

23 year old females/p total thyroidectomy

3.5 cm PTC, 18/26 lymph nodes positiveHer first diagnostic WBS in preparation for RRA

CXRRAI

42 year old maleWide spread metastatic moderately differentiated

papillary thyroid cancer

38 year old female, metastatic papillary thyroid cancerdiagnosed age 15, multiple RAI therapies for RAI avid pulmonary

mets, at age 36 developed bone mets

73 year old male with poorly differentiated papillary thyroid cancerPositive on diagnostic RAI scan

CT ScanT10 Lesion

58 year old male with wide spread metastatic Hürthle Cell Carcinoma

41 year old femaleLocally aggressive, poorly differentiated

Wide spread progressive distant mets

67 year old female5 cm tall cell variant PTC with extrathyroidal extension

150 mCi RRA one year ago, neck uptake onlyNow with suppressed Tg 378 ng/mL

FDG PETCXR Post therapy

Traditional chemotherapy

• Overall response rates less than 0-20%–Doxorubicin (FDA approved for

thyroid cancer), Cisplatin–Responses

• Generally partial and short lived• Response rates not determined by RECIST criteria

• Seldom used in clinical practice

• NCCN & ATA guidelines specifically note that failure of traditional chemotherapy is not a requirement prior to entry into experimental trials

Molecular Abnormalities in the Primary Tumor

Tyr

MAP Kinase Pathway

70% of all PTC have mutations in either the RET/PTC, RAS

or BRAF

RAS

GTP

BRAF

MEK

ERK

c-junc-fos

P

Grb2mSos

RAS

GDP

RET/PTC

MTOR

PI3K

AKT

Molecular Abnormalities in the Primary Tumor

Tyr

MAP Kinase Pathway

RAS

GTP

BRAF

MEK

ERK

c-junc-fos

P

Grb2mSos

RAS

GDP

RET/PTC

MTOR

PI3K

AKT

VEGFRET

PDGFEGF

InsulinIGFHGFFGF

VEGF RET RET/PTC

BRAF C-KIT EGFR C-MET PDGFR

Imatinib √ √ √

Axitinib √

Motesanib √ √ √ √

Sorafenib √ √ √ √ √

Sunitinib √ √ √ √ √

Vandetanib √ √ √ √

Cabozantinib √ √ √ √

Linvatinib √ √

Pazopanib √ √ √

Vemurafenib √

Specific Targets Differ Between Agents

Adapted from Licitra, E Journal Cancer 2010

VEGFR1, 2, 3

VEGFR 1, 2

VEGFR 2

VEGFR 3

Imatinib

Axitinib √

Motesanib √

Sorafenib √

Sunitinib √

Vandetanib √

Cabozantinib √

Linvatinib √

Specific Targets Differ Between Agents

Adapted from Licitra, E Journal Cancer 2010

Clinical Trials in Non-Medullary Thyroid Cancer

Agent Mechanism Cohorts

Ain 2000 Paclitaxel Anti-microtubule 20 ATC

Mrozek 2006 Celecoxib Cox-2 inhibitor 32 DTC

Ain 2007 Thalidomide Anti-angiogenesis 29 DTC, 7 MTC

Woyach 2008 Vorinostat HDAC-I 16 DTC, 3 MTC

Arigiris 2008 Adria & IF2 Cytotoxic & Immun 15 DTC, 2 ATC

Pennell 2008 Gefitinib EGFR 18 DTC, 5 ATC, 4 MTC

Sherman 2008 Motesanib VEGF, PDGFR, Kit 93 DTC

Cohen 2008 Axitinib VEGF 46 DTC, 12 MTC, 2 ATC

Gupta-Abramson

2008 Sorafenib VEGF, BRAF 27 DTC, 1 MTC, 2 ATC

Kloos 2009 Sorafenib VEGF, BRAF 43 DTC, 9HC, 4 ATC

Bible 2010 Pazopanib VEGF, PDGFR, Kit 26 DTC, 11 HC

Hayes 2012 Selumetanib MEK 32 PTC

Modified from Tuttle RM. Clinical Thyroidology 2009; 21(1):3-7.

1

Pazopanib (DTC)

Sorafenib (DTC/ATC)

Sorafenib (DTC/ATC/MTC)

Axitinib (DTC/MTC/ATC)

Motesanib (DTC)

Gefitinib (DTC/ATC/MTC)

Adria/IF alpha (DTC/ATC)

Vorinostat (DTC/MTC)

Thalidomide (DTC/ATC)

Celecoxib (DTC)

Paclitaxel (ATC)

0% 20% 40% 60% 80% 100%

46%64%

51%

67%

81%63%

56%

32%

38%5%

5

49%

28%

40%

40%

14

6

3%

47%47

Progression Stable Partial Complete

1Ain 2000, 2Mrozek 2006, 3Ain 2007, 4Woyach 2008, 5Argiris 2008, 6Pennell 2008, 7Sherman 2008, 8Cohen 2008, 9Gupta-Abramson 2008, 10Kloos 2009,

11Bible 2010

2

3

4

9

8

7

6

5

Phase 2 Clinical Trials

Adapated from Tuttle RM. Clinical Thyroidology 2009

10

11

Clinical Implications of Trial Design

• Phase 2 Trials

• Entry criteria• RAI refractory disease• Included all histology subtypes (PTC, FTC, ATC,

HCC)• No placebo arm• Variable requirements for progression prior to

entry• Variable definitions of progression prior to

entry– Magnitude of the change in size– Time interval

• Endpoint• Evaluation of change in size of lesions• RECIST criteria

As described in the published thyroid cancer clinical trials

Variations in Rate of Progression in Patients with Metastatic Disease

Normal Life Span

Goal Line

Volu

me o

f D

isease

RAIResponsi

ve

Impact on Eligibility Criteria For Clinical Trials

Anaplastic

RAI Refractory

TKI therapy may alter rate of growth

Cabanillas et al. JCEM June 2010

MD Anderson Experience: Sorafenib/Sunitinib

TKI therapy may alter rate of growth

Bible et al. Lancet Oncology 2010

Pazopanib therapyP

erce

nta

ge c

han

ge in

tu

mor

siz

e (%

)

Time

Toxicity Profile

• Dose related and usually reversible

• Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension

• About 1% risk of death related to the drugs

• Results in discontinuation of the drug in 15-20% of study subjects

• Temporary interruption of drug and re-institution at lower doses in as many as 30-50% of study subjects

Translating All This Into the Clinic

• Patient Selection• Clinically significant

• Structurally progressive

• RAI refractory thyroid cancer

• Shortened life span if untreated

• Likely Outcomes• Unlikely to “cure”

• Occasionally cause the tumors to shrink

• More commonly result in stable disease (50% of the time)

• Toxicities are real, but tolerable, and usually reversible

• May or may not prolong overall survival

The essence of my clinical consults in October 2012

Can we use targeted therapy to improve RAI avidity?

Sgouros et al, J Nucl Med. 2004 Aug;45(8):1366-72

Lesional Dosimetry

124I PET

Metastatic Papillary Thyroid Cancer

Serum thyroglobulin is 13,470 ng/mL

Post-Therapy ScanCT Scan

Metastatic Papillary Thyroid Cancer

Before RAI After 2 RAI therapies

Lesional Dosimetry 124 I PET Scan

Therapeutic Goal: 8,500 – 10,000 rads

9,500 rads 9,000 rads

8,500 rads

120 mCi administered activity

Whole Body RAI Scan

64 year oldStage IV, Follicular Thyroid Cancer

Anterior Posterior

3500 rads

Lesional Dosimetry

If 400 mCi 131I administered

800 rads

Therapeutic Goal: 8,500 – 10,000 rads

Heterogeneity in absorbed dose distribution in individual patient

67 yo male, 9 cm, locally invasive, poorly differentiated thyroid cancerPresented with pulmonary mets on pre-op CXR

Stimulated Tg 245 ng/mL

CT RAI Fused

250 mCi

42 Gy 3.7 Gy

437 mCi I131

Heterogeneity in absorbed dose distribution in individual patient

Desiree Deandreis, MSKCC

124I PET

124I PET

Heterogeneity in absorbed dose distribution in individual lesion

Sgouros et al. J Nuc Med. 45(8):1366-72, 2004.

75% Yellow50% Red25% Blue10% Green

Tyr

ret/PTC

Targeted Therapy to Improve RAI Avidity

P

Grb2mSos

p21 ras

p21 ras

B-Raf

MEK

ERK

c-junc-fos

mTOR

PI3K

AKT

BRAF ActivationDecreases NIS

Decreases TSH receptorDecreases Tg

GTP

Chakravarty, Fagin. JCI 2011

BRAFInhibitor

MEK Inhibitor

BRAFOn

BRAFOff

BRAFOff

BRAFOn

BRAFOn

MEK Inhibitor (AZD6244) Re-differentiation Trial

Treat with oral MEK inhibitor for 4 weeks

Pre- MEK 124I PET scan Post- MEK 124I PET scan

Ho et al, In press, NEJM 2012

Baseline After MEK

Baseline

Baseline

After MEK

After MEK

0 10 20 30 40 50 600

10

20

30

40

50

60MEK

100(+50%)(+25%)(+0%)(-25%)(-50%)

Pre-therapy SUVmax

Post

-the

rapy

SU

Vmax

n= 4

6 le

sion

s

n= 31 lesions

124-I SUV Max

Trial ContinuesLesional dosimetry promising

Treat with RAIDiscontinue MEK inhibitor 2 days later

Repeat CT scans 2 months later

Ho et al, In press, NEJM 2012

LESION 3

LESION 4

19mm 10.8 mm

12.9 mm 6 mm

LESION 5 11.4 mm 5.2 mm

Serum Thyroglobulin ResponsePrior to MEK and RAI: 789 ng/mL (negative antibodies)

2 months after MEK and RAI: 35 ng/mL (negative antibodies)

Radioiodine Responses of Advanced Thyroid Cancers Treated with

Selumetinib

20 patientsRAI refractory distant mets

25% PTC, 40% TCV, 35% PDTC61 yrs old (44-77)

11M:9F

Genotype of Primary45% BRAF25% NRAS

15% RET/PTC15% Wild Type

Ho et al, In press, NEJM 2012

Radioiodine Responses of Advanced Thyroid Cancers Treated with

Selumetinib20 pts

12/20 had increased RAI uptake after 1 month selumetinib pre-treatment

8/20 had increase in RAI uptake sufficient to justify additional RAI therapy

5/8 had partial response by RECIST on follow up CT after RAI therapy

3/8 had stable disease after RAI therapy

8/8 had decrease in Tg (median 89% decrease) after RAI therapy

Ho et al, In press, NEJM 2012

Receptor Tyrosine Kinase

Tyr

ret/PTC

Molecular Profile of Differentiated Thyroid Cancer

GTP

P

Grb2mSos

p21 ras

GDP

p21 ras

B-Raf

MEK

ERK

c-junc-fos

mTOR

PI3K

AKT

MEK InhibitionDramatic increase in RAI

avidityClinical significant response to

therapy

Future UsesEnhance RAI effectiveness

Distant metastasesLoco-regional metastases

Remnant ablation

BRAF MutationResponse did not correlate with

BRAF mutation status

Not restricted to BRAF tumors

Systemic TherapiesChemotherapy/Novel Therapies

Targeted TherapiesWhat are our options?

Surgery External Beam RadiationEmbolization

Radioactive Iodine

Often, multiple “targeted therapies” are used over the life time of a patient with

advanced thyroid cancer