1. Advances in the management of iodine-refractory thyroid cancers
Marcia Brose MD PhD
Department of Otorhinolaryngology: Head and Neck Surgery
Department of Medicine, Division of Hematology/Oncology
Abramson Cancer Center
The University of Pennsylvania
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
MSB
05/30/09

2. Disclosure Elements
My goal is to present information on several agents currently under investigation for the treatment of advanced thyroid. As none of the agents other than doxorubicin and vandetanib and cabozantinib are FDA approved for the use in thyroid cancer, the rest of the new agents that will be discussed here are in clinical trials (not FDA approved) at this time.
Marcia S. Brose MD PhD

3. DISCLOSURE:
In the last three years I have financial interest/arrangement or affiliation with:
Name of Organization Relationship
Bayer Healthcare research funding, honorarium
Onyx research funding, honorarium
Novartis research funding,
Exelixis research funding
honorarium
Astrazeneca consulting
Bristol-Myers Squibb consulting
Genentech/Roche research funding

4. Thyroid Cancer: Clinical Pathology
Papillary
Follicular
Hurtle Cell
Differentiated
Anaplastic
Follicular cells
Sporadic
Familial
Medullary
Parafollicular cells
American Cancer Society. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins
MSB
05/30/09 4 4

5. Thyroid cancer in the United States
>5.0cm cm
0-1.0cm cm
Davies, JAMA 2006
295:2164

6. Differentiated Thyroid Cancer
MSB
09/21/09

7. Thyroid Cancer: Treatment Strategy
High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm)
Total Thyroidectomy
RAI (131I) Ablation
TSH Suppression Therapy with Thyroid Hormone
Follow Serial Thyroglobulin Levels (Tg)
XRT for recurrent local disease/positive margins
Surveillance: NeckUS, Tg, Neck MRI, Chest CT, RAI Whole body scan, FDG-PET
We use a multi-Modality approach to treat thryoid cancer
Low risk, are usually cured by the surgeons.
High risk disease requires in many cases a total thryoidectomy, followed by Radionine ablation in most cases and the TSH supressive therapy.
If a patient recurrs or has positive margins at surgery, XRT is often employed.
…The degree of TSH supression, and indeed their follow-up is determined by the risk of recurrent disease….
MSB
05/30/09

8. RAI-Refractory Disease
25-50% of Metastatic Thyroid Cancers loose ability to take up Iodine
This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism
In other words, the cancer cells “forget” how to take up iodine and so they are immune to the treatment.
25%-50% will loose their ability to take up RAI
Loss of Iodine uptake correlates inversly with survival
Due to loss of expression of the NIS, and data shows that this is mostly due to increasing methylation of the NIS promotoer.
…Once TSH, RAI is ineffective, and XRT has already been maxed, or pt has distant disease, what do we have to offer….?
MSB
05/30/09

9. RAI-refractory disease
Standard Chemotherapy has minimal efficacy Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer.
No longer used because recent data shows response is 5%
High toxicity in patient with otherwise good QOL
25%-50% will loose their ability to take up RAI
Loss of Iodine uptake correlates inversly with survival
Due to loss of expression of the NIS, and data shows that this is mostly due to increasing methylation of the NIS promotoer.
…Once TSH, RAI is ineffective, and XRT has already been maxed, or pt has distant disease, what do we have to offer….?
Cooper DS, et al. Thyroid. 2009;9:
Hodak SP, Carty SE. Oncology. 2009;23:775-6.
Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22: ,xi. 9 9

10. Thyroid Cancer is associated with aberrant cell signaling
Genetic Alteration
PTC
FTC
BRAF V600E
44% 0%
BRAF copy gain 3%
35%
RET/PTC (1 and 3)
20%
RAS
8-10%
17-45%
PI3KCA mutations 6%
PI3KCA copy gain
12%
28%
PTEN 2% 7%
Pax8/PPARγ
Total
>70%
>65%
MAP Kinase
PI3K/AKT
So it makes sense that kinase inhibitors are active in this disease however…
Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

11. Cell signalling in differentiated thyroid cancer
Tumor Cell
Endothelial Cell
RET/PTC
EGFR
VEGFR-2
Ras
Ras
B-Raf
PI3K
Raf
PI3K
AKT
MEK
AKT
MEK
Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.
mTOR
ERK
mTOR
ERK
S6K
S6K
• Growth
• Survival
• Proliferation
• HIF1a
• Inhibition of apoptosis
• Migration
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:

12. Targeting cell signaling in thyroid cancer
Tumor Cell
Endothelial Cell
RET/PTC
EGFR
VEGFR-2
Axitinib Motesanib
Sorafenib
Sunitinib
Vandetanib
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Vandetanib
Ras
Ras
B-Raf
PI3K
Raf
PI3K
AKT
Sorafenib
Sorafenib
MEK
AKT
MEK
Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.
mTOR
ERK
Everolimus
Sirolimus
mTOR
ERK
Everolimus
Sirolimus
S6K
S6K
• Growth
• Survival
• Proliferation
• HIF1a
• Inhibition of apoptosis
• Migration
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:

13. UPCC 03305: Sorafenib in Advanced Thyroid Cancer February 2006-February 2011
Eligibility criteria
Metastatic, iodine refractory thyroid cancer
Life expectancy >3 months
Evidence of PD within 6 months of study entry
ECOG 0–2
Good organ and bone marrow function
Primary endpoints
RECIST
PFS
Response rate
n=55
Sorafenib 400mg b.i.d.
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9 13 13

14. Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial
An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC
Eligibility criteria
Locally advanced or metastatic DTC
Progression within 14 months
RAI refractory
No prior targeted therapy, chemotherapy or thalidomide
Randomisation (1:1) (n=380)
Sorafenib 400mg orally b.i.d.
Progression
n=190
Investigator’s decision
Placebo
Crossover or continue sorafenib 400mg orally b.i.d.
Off study
n=190
Secondary Endpoints:
OS, TTP, RR, DCR, PRO, PK
Safety
Exploratory Biomarkers
Disease progression
Primary Endpoint:
PFS (RECIST)
Independent review
Met primary endpoint
January 2013
NCT 14

15. Targets of Kinase Inhibitors
Compound Name
VEGFR
BRAF
PDGFR
KIT
RET
Other
Sorafenib +
FLT-3
Sunitinib
Axitinib
(AG )
Motesanib (AMG-706)
Pazopanib
(GW786034)
Vandetanib
EGFR
Cabozantinib (XL184)
C-MET
Lenvatinib
(E7080)
FGFR
When you look at the inhibitors that are active they are all angiogenesis inhibitors
Most are VEGFR inhibitors and are angiogenesis inhibitors. This is important because Thyroid cancer which is a highly vascular agent.
I will present more intriguing data about this later.

16. Summary
DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways
Iodine-refractory patients have an average survival of 3 years
Phase III study of sorafenib in this patient population is positive. Results are expected at ASCO 2013.
Results of phase II trials with lenvatinib have led to the initiation of a phase III trials for patients with RAI-refractory DTC
Additional MKIs are also now in development many of which target VEGFR2, but also mTOR, MEK, and BRAF 16 16

17. Patients progress but maintain good performance status
Advanced Thyroid Cancer’s New Unmet Need: Progression on Sorafenib/VEGFR2 inhibitor
Patients progress but maintain good performance status
Most patients respond then progress in a new lesion or a subset of lesions
What to do?
We need additional treatment options

18. Targeting cell signalling in thyroid cancer
Tumor Cell
Endothelial Cell
RET/PTC
EGFR
VEGFR-2
Axitinib Motesanib
Sorafenib
Sunitinib
Vandetanib
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Vandetanib
Ras
Ras
B-Raf
PI3K
Raf
PI3K
AKT
Sorafenib
Sorafenib
MEK
AKT
MEK
Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.
mTOR
ERK
Everolimus
Sirolimus
mTOR
ERK
Everolimus
Sirolimus
S6K
S6K
• Growth
• Survival
• Proliferation
• HIF1a
• Inhibition of apoptosis
• Migration
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:

19. UPCC 19309: Everolimus + Sorafenib for DTC patients who progress on Sorafenib alone
Eligibility criteria
Metastatic, iodine refractory thyroid cancer
Life expectancy >3 months
PD on sorafenib
ECOG 0–2
Good organ and bone marrow function
Sorafenib
+ Everolimus
Intra-patient
Dose escalation
Primary endpoints
RECIST
PFS
Response rate
n=35
22 patients accrued so far
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal 19 19

20. NO25530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor RO in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine
First Line
Sorafenib Naïve
(n=25)
Eligibility criteria:
Locally advanced or metastatic DTC
Progression within 14 months
RAI refractory
RO BID
Informed Consent
BRAF V600E testing +
Second Line
Prior Sorafenib
(n=15+) +
To evaluate best overall response rate (BORR) (complete +
partial response) in Cohort 1 (sorafenib-naïve patients).
− BORR will be based on investigator assessment, based
on the findings on computed tomography (CT) or
magnetic resonance imaging, using RECIST 1.1
Secondary:
1. To evaluate clinical benefit rate (CBR) in sorafenibnaïve
patients
2. To further assess efficacy of RO using the
following secondary variables: duration of response,
progression free survival (PFS), and overall survival
(OS) in sorafenib-naïve patients
3. To evaluate the efficacy (BORR, CB, duration of
response, PFS, and OS) in sorafenib-exposed patients
4. To evaluate the tolerability and safety profile of
RO using the NCI CTCAE (version 4.0) in
both sorafenib naïve and sorafenib treated patients
5. To characterize the pharmacokinetic (PK) profile of
RO in patients with thyroid cancer
Exploratory:
1. To evaluate potential exploratory biomarkers that may
Secondary Endpoints:
PFS, TTP, OS, TTP, in sorafenib naïve pts
BORR, CB, TTP, PFS and OS, in soraefnib exposed patients
Status:
Accrual Complete
Primary Endpoint:
Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve pts
Independent review 20

21. Phase II – Add Everolimus or
Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced DTC
First Line:
Sorafenib
Second Line:
VEGR2+BRAF+mTOR
Phase II – Add Everolimus or
off label - Sirolimus
Third Line:
VEGFR/MET/RET
Inhibitors
Personalized
Pazopanib
Cabozantinib
For PTC only:
BRAF V600E
Inhibitor
Phase II – vemurafenib

22. ASCO 2012: Selumetinib: MEK inhibition to increase RAI uptake (Ho et al)
Going forward as an earlier treatment:
Use for patients with high risk disease to increase uptake,
Unclear where in the treatment paradigm this will end up.

23. Summary Second Line Agents
Due to tumor heterogeneity, a patient with progression on a multikinase inhibitor may continue to derive benefit from that inhibitor
Combination or Sequential treatments with MKIs (sorafenib + everolimus, or sorafenib + vemurafenib) are likely to aid patients with progression
New agents in development that specifically target mutations (BRAF V600E) may also play a role in the treatment of thyroid cancer in the first or second line settings and carry the most promise

24. Medullary Thyroid Cancer
MSB
09/21/09

25. Signaling pathways in MTC
C-MET
BRAF
MEK
ERK
RAS
AKT
VEGF
VEGFR
Tumor
cell
Endothelial
Y1062 -P X
RET
PI3K
EGFR
PLC-g
PKC 25

26. Multikinase inhibitor activities relevant to MTC
Drug
In vitro IC50 (nm)
VEGFR1
VEGFR2
VEGFR3
RET
RET/PTC3
RAF
Other
Sorafenib - 90 20 49 50 6
PDGFR 58
Vandetanib
1600 40
110
100
50-100
EGFR 500
Cabozantinib (XL 184)
0.035
4.5
C-MET 1.8
Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494 26

27. ZETA Study: Vandetanib Significantly Prolonged PFSa vs Placebo
HR=0.35 (95% CI: ) P<0.0001
▬▬ CAPRELSA 300 mg ▬▬ Placebo
Events/Patients / /100
1.0
0.75
0.50
0.25
0.0
PFS: 65% Relative Reduction in Risk of Progression1
Talking Points
The result of the PFS analysis, based on central review Response Evaluation Criteria in Solid Tumors (RECIST) assessment, showed a statistically significant improvement in patients randomized to CAPRELSA® (vandetanib) (hazard ratio [HR]=0.35, 95% confidence interval [CI], , P<0.0001)1
The median PFS for patients randomized to placebo was 16.4 months.1 For the CAPRELSA group, the median PFS was not reached
Additional Information
Similar PFS results were observed for analyses in the subgroups of patients who were symptomatic (HR=0.31, 95% CI, ) or had progressed within 6 months prior to enrollment (HR=0.41, 95% CI, )1
PFS is defined as time from the date of randomization until the date of objective disease progression based on RECIST assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.2 Centralized, independent blinded review of the imaging data was used in the assessment of PFS1
References
1. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):
Number at Risk
CAPRELSA 300 mg
231
173
145
118 33 1
Placebo
100 47 30 24 6
CI=confidence interval; HR=hazard ratio.
aPFS is defined as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria In Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.2 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.1 1. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2. Wells SA Jr et al. J Clin Oncol. 2012;30(2):

28. Cabozantinib Ph III in MTC Progression Free Survival by IRC
Placebo
Median PFS
(months)
11.2
4.0
1 year PFS
47.3%
7.2%
HR (95% CI)
0.28 (0.19, 0.40)
p <
Speaker Notes:
Significant difference in tumor response rate
28% in cabozantinib vs. 0% placebo; p<0.0001
Median duration of response: 14.6 months
ASCO 2012 oral presentation

29. Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced MTC
First Line:
Vandetanib
Cabozantinib
Second Line:
Third Line/(First):
Sorafenib
Pazopanib
Third Line:
Sunitinib/Other?

30. Summary: Agents for MTC
Phase II data shows that several multikinase inhibitors are clinically active in patients with advanced Differentiated and Medullary thyroid cancer.
Vandetanib was approved last year and Cabozantinib just received FDA approval for MTC
Response in these patients result in prolonged disease control
Additional agents are needed as these agents last only months, there is a great unmet need to identify additional agents for this disease.
25%-50% will loose their ability to take up RAI
Loss of Iodine uptake correlates inversly with survival
Due to loss of expression of the NIS, and data shows that this is mostly due to increasing methylation of the NIS promotoer.
…Once TSH, RAI is ineffective, and XRT has already been maxed, or pt has distant disease, what do we have to offer….?

31. Summary: Targeted therapy for Advanced Thyroid Cancer
Where do we go from here?
Completion of large randomized trials:
Phase III of sorafenib is positive. Phase III of lenvatinib is underway.
More data on the activity of the targeted agents used sequentially:
So patients are to benefit from the number of agents available
Novel strategies for treatment bear investigating:
including novel targets and the use of combination therapies to improve outcome.(Sor+Ev, Sor + Vem)
Further subgroup analysis to identify subpopulations:
use of clinical and molecular markers to identify patients that may benefit better with some therapies over others. Pts with Ras mutations, Poorly differentiated TC
Registration trial for sorafenib in MTC!!! 31 31

32. Agents currently available in our Thyroid Cancer Therapeutics Program
Sub-types
Vandetanib
MTC, (DTC)
Sorafenib
DTC, MTC, ATC
Everolimus
DTC
Pazopanib
Lenvatinib (E7080)
Cabozantinib (XL184)
MTC, DTC
Vemurafenib (PLX4322 – BRAF V600Ei)
PTC
Combretastatin
ATC
PLX3397
MSB
10/16/10

33. University of Pennsylvania Thyroid Cancer Therapeutics Program
Brose Group
Carolyn Grande RN, CRNP
Steve Keefe MD
Thelma McClosky
Tatyana Kuznetsova, PhD
Waixing Tang MD
Stephen Stopenski
Thyroid Cancer Clinical Trials Unit
Larisa Zifchak RN
Parna Prajapati
Ramkrishna Makani
Jillilan Stanley
Experimental Therapeutics Program
Andrea Troxel PhD
Peter O’Dwyer MD
Pathology/Imaging
Michael Feldman MD PhD
Laurie Loevner MD
Thyroid Cancer Interest Group
Susan Mandel MD
Ara Chalian MD
Kelly Malloy MD
Douglas Fraker MD
Robert Lustig MD
Virginia LiVolsi MD
Zubair Baloch MD
MSB is a Damon Runyon-Siemens Clinical Investigator
Many Community Endocrinologists that have referred their patients, and the patients that have agreed to participate in our trials.

34. Questions? Marcia S. Brose MD PhD Email: Marcia.Brose@uphs.upenn.edu
Telephone:
Thank you for your courage and attention!
MSB
10/16/10