1) Targeted kinase inhibitors such as sorafenib show promise in treating radioactive iodine refractory thyroid cancer, with sorafenib demonstrating a partial response rate of 36% and clinical benefit in 82% of patients in one study. 2) Management of radioactive iodine refractory thyroid cancer involves local therapies when possible and enrollment in clinical trials of small molecule tyrosine kinase inhibitors like sorafenib, which target pathways important in thyroid cancer signaling and growth. 3) Guidelines recommend targeted kinase inhibitors as first-line treatment for radioactive iodine refractory thyroid cancer based on their improved efficacy over chemotherapy and ability to potentially prolong progression-free and overall survival.

1. TARGETED THERAPY IN
THYROID CANCER
DR. R. RAJKUMAR M.D., D.M.
MEDICAL ONCOLOGIST
GURU HOSPITAL

3. THYROID CANCER
CLINICAL PATHOLOGY
American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and
Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott
Williams and Wilkins. 2005.
Parafollicular cells
Follicular cells
Differentiated
Anaplastic
Medullary
Papillary
Follicular
Hurtle Cell
Sporadic
Familial

4. US EU Japan
Estimated Thyroid Cancer Incidence in 2008
0
5000
10000
15000
20000
25000
30000
35000
40000
Annual
Incidence
LA/C
~37,000
~33,000
~18,000
~6,000
GLOBAL INCIDENCE OF
THYROID CANCR
LA/C = Latin America and Caribbean.
1. GLOBOCAN 2008, International Agency for Research on Cancer. http://globocan.iarc.fr/.
2. Sherman. Lancet. 2003;361:501-511.
3. Eustatia-Rutten et al. J Clin Endocrinol Metab. 2006;91:313-319.
• Thyroid cancer is
the most common
form of endocrine
malignancy1
• DTC represents
> 90% of all thyroid
carcinomas2
• The prognosis of
patients with DTC
is generally good
due to tumor
biology and efficacy
of the initial surgery
and 131I therapy3

5. DIMENSIONS OF THE
PROBLEM
• Increasing in incidence
– 95% sporadic or RT-induced, 5% familial
• 3.5 to 4:1 female to male gender distribution
• > 95% of carcinomas arise from thyroid follicular
cells and are well-differentiated
• Surgery +/- I-131 remains the standard of care
– Vast majority treated in this manner are cured
• Emergence of Multiple TKIs in Iodine-Refractory
TC and MTC that can affect response and likely
prolong PFS and OS

6. THYROID CANCER IN THE
UNITED STATES
New Diagnosis Cancer Deaths
Pfister, D. Treatment of Radioactive Thyroid Cancer. Presentation. ASCO, 2007.

7. >5.0cm
2.1-5.0cm
THYROID CANCER IN THE
UNITED STATES
0-1.0cm
1.1-2.0cm
Davies, JAMA 2006
295:2164

8. 0 10
8
4 6
2 12 14
0%
20%
40%
60%
80%
100%
Survival
Stage I
Stage II
Stage III
Stage IV
DTC: INITIAL DISEASE STAGE PREDICTS
OVERALL SURVIVAL
Years
75%
of all
tumors
25%
of all
tumors
p<0.001
Jonklaas J et al. Thyroid. 2006, 16(12): 1229-1242.

9. Principles of
High Risk Patients
Treatment
•
•
Total Thyroidectomy
Radioiodine
–
–
–
Gross Extrathyroidal
> 4cm primary
Distant metastases
Extension
• Neck Dissection
– Clinical or US-detected disease
– Locoregional recurrence
TSH Suppression
– <0.1 for those at high risk or with
disease
•
known residual
ATA Guidelines. Cooper et al. Thyroid 2009. 19(11).
NCCN Guidelines. Thyroid Carcinoma v2.2013.

10. 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

11. TSH SUPPRESSION IMPROVES
SURVIVAL FOR DTC PATIENTS WITH
METASTASES
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18
Survival,
%
Years
All > 45 yr
TSH suppressed 15 yr 10 yr
TSH unsuppressed 11 yr 6 yr
p < 0.01 p < 0.005
Median
n = 450
Jonklaas et al. Thyroid. 2006;16:1299-1242.

12. Survival
(%)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Years after the discovery of metastases
0 5 10 15 20 25 30 35 40
1
2
3
127 patients
4 cancer related
deaths
168 patients
149 patients
SURVIVAL AND RESPONSE
TO TREATMENT
• Group 1: initial 131I uptake
and CR
– Age < 40 years
– Well-differentiated cancer
– Small size of metastases
• Group 2: initial 131I uptake
and persistent disease
• Group 3: no initial 131I uptake
Durante et al. J Clin Endocrinol Metab. 2006;91:2892-2899.

13. Radioiodine Refractory Prognosis
Outcome1
– Median Survival 3-6
years
– 10-year survival less
than 15%
Prognostic Factors2,3
–
–
–
Age
BRAF Mutation
PET positivity
Durante et al. J Clin Endocrinol Metab 2006;91(8):2892–2899.
Elisei et. al, J Clin Endocrinol Metab 2008;93(10):3943-9
Robbins and Weil. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047-59

14. Radioiodine Refractory Criteria
A. One or more (measurable) lesions that do
131I
not demonstrate
radioiodine scan
uptake on diagnostic
B. One or more lesions that has progressed
131I
within 12 months of therapy.
131I
C. Cumulative activity of of > 600 mCi

15. RAI-REFRACTORY DISEASE
• 25–50% of metastatic thyroid cancers lose
ability to take up iodine
• RAI refractory means that there are
progressing lesions that do not take up
RAI (Note: there may still be some that do)
• Loss of iodine uptake inversely correlates
with survival
Cooper DS, et al. Thyroid. 2009;9:1176-214.
Hodak SP, Carty SE. Oncology. 2009;23:775-6.
Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.

16. RAI-REFRACTORY THYROID
CANCER
• L-T4 treatment: serum
TSH < 0.1 mU/L
• Local treatments when
needed: surgery, radiation,
radiofrequency or cryoablation
• Imaging follow-up every
6 months
• Stable disease: follow-up
• Progression:
– > 20% (RECIST) in
6-15 months
– Inclusion in a trial
• Chemotherapy: low
efficacy, significant
toxicity (eg, doxorubicin:
5% PR, 47% SD,
median PFS 7 months)
• Targeted therapy as
first line (ATA, 2009)
Cooper et al. Thyroid. 2009;9:1167-1214.

17. NCCN AND ATA GUIDELINES FOR THE
TREATMENT OF DIFFERENTIATED THYROID
CANCER (DTC)
Initial treatment
• Total thyroidectomy, except in patients with unifocal microcarcinoma
(individualized to patient and extent of disease)1,2
Postoperative treatment
• Radioactive iodine (131I) (RAI) therapy1,2
Follow-up treatment
• Levothyroxine to suppress TSH levels to < 0.1mU/L1,2
Recurrent or metastatic disease treatment
• Local therapy (re-operation, external radiation)
• Systemic therapy
– RAI therapy
– patients with refractory advanced disease
• chemotherapy (limited efficacy and considerable toxicity)1,2
• participation in clinical trials with small molecule tyrosine kinase
inhibitors is recommended1,2
1. NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V.1.2010.
2. Cooper DS, et al. Thyroid .2009;9:1167-214.
NCCN = National Comprehensive Cancer Network.
ATA = American Thyroid Association .

18. CYTOTOXIC AGENTS IN DTC
• ADRIAMYCIN IS THE MOST STUDIED
AGENT.
• Others include- Bleomycin, platinums,
etoposide, and Pemetrexed.
• <20% Response Rate.

19. 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% 0%
RAS 8-10% 17-45%
PI3KCA mutations 3% 6%
PI3KCA copy gain 12% 28%
PTEN 2% 7%
Pax8/PPARγ 0% 35%
Total >70% >65%
MAP
Kinase
PI3K/AKT
Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

20. RAS/BRAF MUTATIONS ARE MORE
PREVALENT IN RAI REFRACTORY
THYROID CANCER
Ricarte-Filho JC, Cancer Research 2009 Jun 1;69(11):4885-93

21. CELL SIGNALLING IN DIFFERENTIATED
THYROID CANCER
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
RET/PTC
• HIF1a
• Inhibition of apoptosis
• Migration
EGFR
PI3K
VEGFR-2
Endothelial Cell
• Migration
• Angiogenesis
Ras
B-Raf
MEK
ERK
PI3K
AKT
mTOR
S6K
Ras
Raf
MEK
ERK
AKT
mTOR
S6K
Tumor Cell
• Growth
• Survival
• Proliferation
• Growth
• Survival
• Proliferation

22. WHO IS APPROPRIATE FOR
KINASE INHIBITOR THERAPY?
1. Patients whose tumors no longer take up
radioactive iodine or who have exceeded
their lifetime dose
2. Patients with disease measurable by
exam or CT scan
3. Patients with >1 lesion which is >1 cm in
size and who are symptomatic
4. Patients with progressive disease

23. KINASE INHIBITORS
KI
ATP KI
P
Y Y
ATP
Activated pathway
Cancer
Activated Pathway
Cancer
VEGFR inhibition
Tumor
angiogenesis
Tumor
growth
RET, BRAF…..
inhibition

24. Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Axitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
Vandetanib
Sorafenib Sorafenib
TARGETING CELL SIGNALLING IN
THYROID CANCER
RET/PTC
• HIF1a
• Inhibition of apoptosis
• Migration
EGFR
PI3K
VEGFR-2
Endothelial Cell
• Migration
• Angiogenesis
Ras
B-Raf
MEK
ERK
PI3K
AKT
mTOR
S6K
Ras
Raf
MEK
ERK
AKT
mTOR
S6K
Tumor Cell
• Growth
• Survival
• Proliferation
• Growth
• Survival
• Proliferation
Everolimus
Sirolimus
Everolimus
Sirolimus

25. UPCC 03305: SORAFENIB IN
ADVANCED THYROID CANCER
Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9
n=55
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
Sorafenib
400mg b.i.d.
Primary endpoints
• RECIST
• PFS
• Response rate
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In
Solid Tumors; ULN = upper limit of normal

26. Update UPCC O3305: May
2009
Results:
• Response for all 50 evaluable patients
– PR 36% (18 patients)
– SD 46% (23 patients)
– clinical benefit 82% (41 patients)
• Exact binomial confidence interval excludes the null
hypothesis (p<0.0001)
• PFS is 63 weeks for all patients, and 84 weeks in patients
with DTC
Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)

27. UPCC 03305: BEST RESPONSE IN
46 EVALUABLE PATIENTS
Papillary
Follicular/Hürthle Cell
Medullary
Poorly Differentiated/Anaplastic
30
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–10
Change
in
sum
of
target
lesion
by
RECIST
compared
to
baseline
(%)
PD SD PR
Best response of advanced thyroid cancer patients to sorafenib
Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)

28. CUTANEOUS ADVERSE EVENTS WITH
SORAFENIB IN THYROID CARCINOMA
PATIENTS
1. Cutaneous toxicity peaks in the second
cycle
2. Brief dose holidays and dose reductions
are reasonable. Rash usually improves
with continued sorafenib treatment
3. Rash is more common in patients with
extensive sun exposure in the past
4. Skin creams may be used as well as
NSAIDs for control of the pain from the
rash

29. [TITLE]

30. Eligibility criteria
• Locally advanced
or metastatic DTC
• Progression
within 14 months
• RAI refractory
• No prior targeted
therapy,
chemotherapy or
thalidomide
PHASE III STUDY OF SORAFENIB IN LOCALLY
ADVANCED OR METASTATIC PATIENTS WITH
RADIOACTIVE IODINE REFRACTORY THYROID
CANCER (DECISION) TRIAL – PRIMARY ENDPOINT
POSITIVE
• An International, multicentre, randomised, double-blind, phase III study of
sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC
www.clinicaltrials.gov. NCT00984282
Off
study
Disease
progression
Crossover or
continue
sorafenib 400mg
orally b.i.d.
Randomisation
(1:1)
(n=380) Progression
Sorafenib
400mg orally
b.i.d.
Placebo
Investigator’s decision
n=190
n=190
Primary Endpoint:
PFS (RECIST)
Independent review
Secondary Endpoints:
OS, TTP, RR, DCR, PRO, PK
Safety
Exploratory Biomarkers

31. PHASE III DECISION Trial
• Over 400 patients enrolled in the trial
world wide
• January 3, 2013 press release revealed
that the primary endpoint of Progression
Free Survival significantly favored the
Sorafenib arm

32. [TITLE]

33. [TITLE]

34. [TITLE]

35. [TITLE]

36. [TITLE]

37. [TITLE]

38. [TITLE]

39. [TITLE]

40. RAI-refractory DTC 2013
DECISION establishes sorafenib as a
standard therapy
Multiple Questions Raised
 Who to treat?
 With what agent?
 Can we identify alternative targets?
• Will selective BRAF V600E inhibitors be effective?
 Sorafenib resistance?
 Is this the right strategy?

41. THERAPEUTIC OPTIONS BEYOND
FRONTLINE TKI THERAPY
1. Single progressive lesions can be resected or
irradiated and the frontline TKI continued
2. Minimally progressive lesions can often be
observed on the original TKI as this disease
frequently progresses very slowly
3. For patients progressing on a frontline TKI, an
m-TOR inhibitor can be added to block the
PI3K escape pathway
4. For disease progressing in multiple areas one
might switch to another available TKI or a
clinical trial with an investigational agent

42. ADVANCED THYROID CANCER’S NEW
UNMET NEED:
PROGRESSION ON SORAFENIB/VEGFR2
INHIBITOR
• What to do with patients who progress but
maintain good performance status
• Most patients respond to frontline TKI
therapy but then progress in a new lesion
or a subset of lesions

43. TARGETS OF KINASE INHIBITORS
Compound Name VEGFR BRAF PDGFR KIT RET Other
Sorafenib
(Nexavar) + + + + + FLT-3
Sunitinib (Sutent) + + + FLT-3
Axitinib
(AG-013736) + + +
Motesanib (AMG-
706) + + + +
Pazopanib
(GW786034) + + +
Vandetanib
(Zactima) + + EGFR
Cabozotanib
(XL184) + + C-MET
Lenvatinib
(E7080) + + + + FGFR

44. MSB
05/30/09
TARGETED AGENTS PHASE II CLINICAL
DATA
Drug Key Baseline
Characteristics
n PFS
Months
PR SD PD
Sorafenib
(Brose)
•DTC+ PDTC(90%), 47 20 38% 47% 2%
Sunitinib
(Cohen)
• DTC (74%); MTC
(26%)
51 - 17%
DTC
74%
DTC
9% DTC
Axitinib
(Cohen)
•Papillary (50%);
Medullary (18%);
Follicular/Hurthle
(25%/18%); Anaplastic
(3%)
60 18.1 30% 48% 7%
Motesanib
(Sherman)
•Papillary (61%);
Follicular/Hurthle (34%)
93 10 14% 67% 8%
Pazopanib
(Bible)
PD and DTC
(Progression <6months)
37 12 49% - -
Lenvatinib
(E7080,
Sherman)
•DTC 100% 58 13.3 45% 46% 5%

45. Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Axitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
Vandetanib
Sorafenib Sorafenib
TARGETING CELL SIGNALLING IN
THYROID CANCER
RET/PTC
• HIF1a
• Inhibition of apoptosis
• Migration
EGFR
PI3K
VEGFR-2
Endothelial Cell
• Migration
• Angiogenesis
Ras
B-Raf
MEK
ERK
PI3K
AKT
mTOR
S6K
Ras
Raf
MEK
ERK
AKT
mTOR
S6K
Tumor Cell
• Growth
• Survival
• Proliferation
• Growth
• Survival
• Proliferation
Everolimus
Sirolimus
Everolimus
Sirolimus

46. UPCC 19309: EVEROLIMUS +
SORAFENIB FOR DTC PATIENTS
WHO PROGRESS ON SORAFENIB
ALONE
n=35
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
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In
Solid Tumors; ULN = upper limit of normal
22 patients accrued so far

47. Eligibility criteria:
• Locally advanced
or metastatic DTC
• Progression
within 14 months
• RAI refractory
UPCC 18310: NO25530: An Open-Label, Multi-Center
Phase II Study of the BRAF Inhibitor Vemurafenib in
Patients with Metastatic or Unresectable Papillary
Thyroid Cancer (PTC) positive for the BRAF V600
Mutation and Resistant to Radioactive Iodine
Vemurafenib
960mg BID
Primary Endpoint:
Best Overall response Rate (BORR)
(RECIST 1.1) (Partial and complete
RR) in sorafenib naïve pts
Independent review
Secondary Endpoints:
•PFS, TTP, OS, TTP, in
sorafenib naïve pts
•BORR, CB, TTP, PFS and
OS, in soraefnib exposed
patients
Informed
Consent
BRAF
V600E
testing
+ First Line
Sorafenib Naïve
(n=25)
Second Line
Prior Sorafenib
(n=25)
+

48. E7080 (lenvatinib) phase II results
Sherman et al.ASCO 2011, abstr 5503
Overall (n=58)
CR 0
PR 26 (45%)
SD 27 (46%)
PD 3 (5%)
DCR 53 (91%)

49. Overcoming sorafenib resistance
Targeting alternative pathways
J Clin Oncol 31, 2013 (suppl; abstr 6024)

50. MSB
10/16/10
CLINICAL TRIALS ONGOING FOR
METASTATIC DIFFERENTIATED THYROID
CANCER
Compound Name DTC/MTC Status
Sorafenib (Nexavar) DTC
First Line – International Phase III –
Positive Study
Lenvatinib (E7080) DTC First and Second Line – Phase III
Vemurafenib
(BRAF V600E inhibitor) DTC (PTC) First and Second Line Phase II – (Phase III?)
Everolimus+Sorafenib DTC Second Line – Phase II
Cabozantinib DTC
First Line – Phase I complete
First Line and Second Line Phase II– Pending
Pioglitazone (PPARγ) DTC (FTC*) First and Second Line - Phase II
Pazopanib (GW786034) DTC First and Second line – Phase II Done
Sunitinib (Sutent) DTC First line Phase II – Done.

51. Are there better strategies?
Restoration of Radioiodine Sensitivity
Ho et al. N Engl J Med 2013;368:623-32.

52. TAKE HOME MESSAGES-I
• Multiple VEGFR agents in DTC have activity that affect the vast
majority of patients with advanced RAI-refractory thyroid cancer
needing therapy
• Results of phase III trial with sorafenib (DECISION) showing that
patients treated with sorafenib have a longer progression free
survival than those on placebo. We look forward to a future major
oncology meeting for these results. Results from the Phase III trial of
lenvatinib (SELECT ) are likely to follow in another year.
• Molecular markers (eg. BRAF V600E mutation) are newer targets
being tested in Phase II clinical trials. If positive, patients will need
routine molecular testing for these mutations
• Many studies for second line treatment of DTC are underway and
now a primary focus of our research program at the Abramson
Cancer Center and at other sites. These trials target new molecular
mechanisms and hope to add to the success of the VEGFR inhibitors
in this disease.

53. Take Home Messages-II
1. Patients with progressive RAI-refractory TC should be
referred to an oncologist with access to all the available
and investigational kinase inhibitors.
2. Treatment with a kinase inhibitor should be initiated in
patients with progressive, measurable disease.
3. The physician managing these patients should be
comfortable with and skilled in managing the adverse
events related to kinase inhibitors.
4. Many clinical trials are now available for patients
progressing on frontline kinase inhibitor therapy.

54. Take Home Message
Who To Treat? Who Not To Treat?
• Radioiodine Refractory • No radiographic disease
(TG only)
RAI Sensitive
No progression
Very slow progression
without threatened
symptoms
–
–
Negative RAI Scan
Progression Despite
Recent RAI
>600 mCi prior RAI
•
•
•
–
•
•
Non-surgical candidates
Established Progression
– Threatened Symptoms

55. REFERENCES
1. Giuffrida D, Prestifilippo A, et al; Journal of Oncology Volume 2012,
Article ID-391629, “New Treatment in Advanced Thyroid Cancer”
2. Brose M, Nutting C, et al; BMC Cancer 2011, 11:349 “Rationale
and design of DECISION: a double blind, randomized, placebo
controlled phase III trial evaluating the efficacy and safety of
sorafenib in patients with locally advanced or metastatic, RAI-
refractory, differentiated thyroid cancer”
3. Harris P, Bible K; Expert Opinion Investigational Drugs; October
2011 20(10): 1357-1375; “Emerging Therapeutics for Advanced
Thyroid Malignancies: Rationale and Targeted Approaches”
4. Gupta-Abramson V, Troxel A, et al; JCO 2008 Vol. 26: 4714
“Phase II Trial of Sorafenib in Advanced Thyroid Cancer”
5. Kojic K, Kojic S & Wiseman S; Expert Reviews in Anticancer
Therapy 2012 Vol.12(3):345; “Differentiated thyroid cancers: a
comprehensive review of novel targeted therapies