Transcript Visions of Future Thyroid Cancer Management An American

Targeted Therapy for Thyroid Cancer
Management of Advanced Non-Medullary Thyroid Cancer
R Michael Tuttle, MD
Professor of Medicine , Endocrine Service
Memorial Sloan Kettering Cancer Center
New York, NY
Targeted Therapies
What are our options?
Systemic Therapies
Chemotherapy/Novel Therapies
Radioactive Iodine
Surgery
External Beam Radiation
Embolization
Often, multiple “targeted therapies” are used
over the life time of a patient with advanced
thyroid cancer
23 year old female
s/p total thyroidectomy
3.5 cm PTC, 18/26 lymph nodes positive
Her first diagnostic WBS in preparation for RRA
RAI
CXR
42 year old male
Wide spread metastatic moderately differentiated
papillary thyroid cancer
38 year old female, metastatic papillary thyroid cancer
diagnosed 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 cancer
Positive on diagnostic RAI scan
CT Scan
T10 Lesion
58 year old male with wide spread metastatic Hürthle Cell Carcinoma
41 year old female
Locally aggressive, poorly differentiated
Wide spread progressive distant mets
67 year old female
5 cm tall cell variant PTC with extrathyroidal extension
150 mCi RRA one year ago, neck uptake only
Now with suppressed Tg 378 ng/mL
CXR
Post therapy
FDG PET
Traditional chemotherapy
• Overall response rates less than 0-20%
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•
•
•
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
MAP Kinase Pathway
RET/PTC
RAS
RAS
Tyr
PI3K
AKT
P
GTP
GDP
mSos
Grb2
70% of all PTC have
mutations in either
the RET/PTC, RAS
or BRAF
BRAF
MEK
ERK
MTOR
c-jun
c-fos
Proliferation
Growth
Molecular Abnormalities in the Primary Tumor
MAP Kinase Pathway
VEGF
RET
PDGF
EGF
Insulin
IGF
HGF
FGF
RET/PTC
RAS
RAS
Tyr
PI3K
P
GTP
GDP
mSos
Grb2
BRAF
MEK
AKT
ERK
MTOR
c-jun
c-fos
Proliferation
Growth
Specific Targets Differ Between Agents
VEGF RET
Imatinib
RET/
PTC
C-KIT
EGFR
C-MET
PDGFR
√
√
√
√
√
Axitinib
√
Motesanib
√
√
Sorafenib
√
√
√
Sunitinib
√
√
√
Vandetanib
√
√
√
Cabozantinib
√
√
Linvatinib
√
Pazopanib
√
Vemurafenib
BRAF
√
√
√
√
√
√
√
√
√
√
Adapted from Licitra, E Journal Cancer 2010
√
Specific Targets Differ Between Agents
VEGFR
1, 2, 3
VEGFR
1, 2
VEGFR
2
VEGFR
3
Imatinib
Axitinib
√
Motesanib
√
Sorafenib
√
Sunitinib
√
Vandetanib
√
Cabozantinib
√
√
Linvatinib
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
GuptaAbramson
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.
Phase 2 Clinical Trials
Progression
Stable
Paclitaxel (ATC)
1
Celecoxib (DTC)
2
Thalidomide (DTC/ATC)
3
Vorinostat (DTC/MTC)
4
Adria/IF alpha (DTC/ATC)
5
Gefitinib (DTC/ATC/MTC)
6
Motesanib (DTC)
7
81%
Axitinib (DTC/MTC/ATC)
8
67%
Sorafenib (DTC/ATC/MTC)
9
Sorafenib (DTC/ATC)
Pazopanib (DTC)
Partial
5
0%
47
5%
47%
38%
3%
32%
56%
63%
6
14
40%
40%
28%
51%
64%
10
11
Complete
46%
20%
49%
40%
60%
80%
100%
1Ain
2000, 2Mrozek 2006, 3Ain 2007, 4Woyach 2008, 5Argiris 2008, 6Pennell 2008,
7Sherman 2008, 8Cohen 2008, 9Gupta-Abramson 2008, 10Kloos 2009, 11Bible 2010
Adapated from Tuttle RM. Clinical Thyroidology 2009
Clinical Implications of Trial Design
As described in the published thyroid cancer clinical trials
• Phase 2 Trials
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•
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
Variations in Rate of Progression in Patients
with Metastatic Disease
Impact on Eligibility Criteria For Clinical Trials
Volume of Disease
G
o
a
Anaplastic
RAI Refractory
l
L
i
RAI
Responsive
n
e
Normal Life Span
TKI therapy may alter rate of growth
MD Anderson Experience: Sorafenib/Sunitinib
Cabanillas et al. JCEM June 2010
TKI therapy may alter rate of growth
Percentage change in tumor size (%)
Pazopanib therapy
Time
Bible et al. Lancet Oncology 2010
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
The essence of my clinical consults in October 2012
• Patient Selection
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•
•
•
Clinically significant
Structurally progressive
RAI refractory thyroid cancer
Shortened life span if untreated
•
•
•
•
•
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
• Likely Outcomes
Can we use targeted therapy to
improve RAI avidity?
Lesional Dosimetry
124I
PET
Sgouros et al, J Nucl Med. 2004 Aug;45(8):1366-72
Metastatic Papillary Thyroid Cancer
Serum thyroglobulin is 13,470 ng/mL
CT Scan
Post-Therapy Scan
Metastatic Papillary Thyroid Cancer
Before RAI
After 2 RAI therapies
Lesional Dosimetry
124
I PET Scan
120 mCi administered activity
9,500 rads
9,000 rads
8,500 rads
Therapeutic Goal: 8,500 – 10,000 rads
Whole Body RAI Scan
Anterior
Posterior
64 year old
Stage IV, Follicular Thyroid Cancer
Lesional Dosimetry
If 400 mCi
800 rads
131I
administered
3500 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 cancer
Presented with pulmonary mets on pre-op CXR
Stimulated Tg 245 ng/mL
CT
RAI
250 mCi
Fused
Heterogeneity in absorbed dose distribution in individual patient
124I
PET
42 Gy
124I
3.7 Gy
PET
437 mCi I131
Desiree Deandreis, MSKCC
Heterogeneity in absorbed dose distribution in individual lesion
75%
50%
25%
10%
Yellow
Red
Blue
Green
Sgouros et al. J Nuc Med. 45(8):1366-72, 2004.
Targeted Therapy to Improve RAI Avidity
ret/PTC
p21 ras
GTP
p21 ras
Tyr
P
PI3K
B-Raf
mSos
Grb2
MEK
AKT
ERK
mTOR
c-jun
c-fos
BRAF Activation
Decreases NIS
Decreases TSH receptor
Decreases Tg
BRAF
Off
BRAF
On
BRAF
Off
BRAF
On
BRAF
Inhibitor
BRAF
On
MEK
Inhibitor
Chakravarty, Fagin. JCI 2011
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
After MEK
Baseline
After MEK
124-I SUV Max
60
MEK
Trial Continues
Lesional dosimetry promising
Treat with RAI
Discontinue MEK inhibitor 2 days later
Repeat CT scans 2 months later
40
n= 46 lesions
Post-therapy SUVmax
50
30
100
(+50%)
(+25%)
(+0%)
20
(-25%)
(-50%)
10
MEk
0
0
0
10
20
30
40
50
60
Pre-therapy SUVmax
n= 31 lesions
Ho et al, In press, NEJM 2012
LESION 3 19mm
10.8 mm
LESION 4 12.9 mm
6 mm
LESION 5
11.4 mm
5.2 mm
Serum Thyroglobulin Response
Prior 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 patients
RAI refractory distant mets
25% PTC, 40% TCV, 35% PDTC
61 yrs old (44-77)
11M:9F
Genotype of Primary
45% BRAF
25% NRAS
15% RET/PTC
15% Wild Type
Ho et al, In press, NEJM 2012
Radioiodine Responses of Advanced Thyroid
Cancers Treated with Selumetinib
20 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
Molecular Profile of Differentiated Thyroid
Cancer
MEK Inhibition
Dramatic increase in RAI
avidity
Clinical significant response to
therapy
Receptor Tyrosine Kinase
ret/PTC
p21 ras
p21 ras
TyrP
BRAF Mutation
Response did not correlate with
BRAF mutation status
PI3K
Not restricted to BRAF tumors
AKT
Future Uses
Enhance RAI effectiveness
Distant metastases
Loco-regional metastases
Remnant ablation
mTOR
GTP
GDP
B-Raf
mSos
Grb2
MEK
ERK
c-jun
c-fos
Targeted Therapies
What are our options?
Systemic Therapies
Chemotherapy/Novel Therapies
Radioactive Iodine
Surgery
External Beam Radiation
Embolization
Often, multiple “targeted therapies” are used
over the life time of a patient with advanced
thyroid cancer