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
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