1. Management Advances for Differentiated and Medullary Thyroid Carcinoma
Marcia S. Brose MD PhD
Abramson Cancer Center of the University of Pennsylvania Philadelphia, PA
On behalf of: Christopher Nutting, Barbara Jarzab, Rossella Elisei, Salvatore Siena, Lars Bastholt, Christelle de la Fouchardiere, Furio Pacini, Ralf Paschke, Young Kee Shong, Steven I. Sherman, Johannes WA Smit, John Woojune Chung, Harald Siedentop, Istvan Molnar and Martin Schlumberger

2. Disclosures
Companies: AstraZeneca, Bayer/Onyx, Eisai, Exelixis, Novartis, Oxigene, Plexxikon, Roche
Relationships: Advisory board consultant, honoraria, research grants, and primary investigator
As there are currently no FDA approved agents for progressive DTC, all agents I will discuss will be off label use or in the context of a clinical trial 2

3. Thyroid cancer: clinical pathology
Papillary (87%)
Differentiated
Follicular cells
Follicular (6%)
Hürthle cell (3%)
Anaplastic (1%)
Medullary (2%)
Parafollicular cells
Treatment of Differentiated Thyroid Cancer includes:
Surgery – thyroidectomy
Radioactive iodine
Thyroid stimulating hormone (TSH) suppression
Recurrent progressive RAI refractory disease treated with sorafenib
Carling T and Uldesman R. Cancer of the Endocrine System: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins
Howlader N et al. SEER Cancer Statistics Review;

4. Radioactive Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)
It is estimated1 that in the USA in 2013 there will be:
> new cases of thyroid cancer, and
1850 deaths due to thyroid cancer
In approximately 5–15% of patients with thyroid cancer, the disease becomes refractory to RAI2,3
Median survival for patients with RAI-refractory DTC and distant metastases is estimated to be 2.5–3.5 years4,5
Patients often suffer multiple complications associated with disease progression
1. Howlader N et al. SEER Cancer Statistics Review; Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892– Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505.

5. FDG-PET Predicts Survival in Patients With Metastatic Thyroid Cancer
1.00
0.75
0.50
0.25
Survival Distribution Function
Months
FDG-negative
176/179 alive
FDG-positive
156/223 alive
Median survival = 53 months
Robbins et al. J Clin Endocrinol Metab. 2006;91: 5 5

6. Genetics of Differentiated Thyroid Cancer: aberrant intracellular signaling
Poorly differentiated
RAS (25–30%)
TP53 (20–30%)
CTNNB1 (10–20%)
BRAF (10–15%)
Anaplastic
Medullary
Oncocytic
Conventional
Papillary
Mutations identified in ~70%
BRAFa (40–50%)
RASb (7–20%)
RET/PTC (clonal; 10–20%)
EGFR (5%)
TRK (<5%)
PIK3CA (2%)
Follicular
Mutations in 70–75%
RAS (40–50%; lower in oncocytic)
PAX8/PPARg (30–35%; lower in oncocytic)
TP53 (21%)
PTEN (8%)
PIK3CA (7%)
BRAF (2%)
Papillary
DTC
aBRAF mutations are mostly V600E; 1–2% are K601E and others bRAS includes N-, H-, and K-RAS (predominantly NRAS and HRAS codon 61) Nikiforov YE et al. Arch Pathol Lab Med 2011;135:569–77; COSMIC database – Catalog of Somatic Mutations in Cancer (as of February 22, 2013)

7. Targeting Cell Signaling in Thyroid Cancer
Tumor Cell
Endothelial Cell
RET/PTC
EGFR
VEGFR-2
Motesanib
Sorafenib
Sunitinib
Vandetanib
Cabozantinib
Lenvatinib
Vandetanib
Axitinib Motesanib
Sorafenib
Sunitinib
Vandetanib
Lenvatinib
Cabozantinib
Ras
Ras
B-Raf
PI3K
Raf
PI3K
AKT
Sorafenib
Sorafenib
MEK
AKT
MEK
mTOR
mTOR
ERK
Everolimus
Sirolimus
ERK
Everolimus
Sirolimus
S6K
S6K
• Growth
• Survival
• Proliferation
• HIF1a
• Inhibition of
apoptosis
• Migration
• Growth
• Survival
• Proliferation
• Migration
•Angiogenesis
EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor.
Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:

8. Targets of Kinase Inhibitors
Compound Name
VEGFR
BRAF
PDGFR
KIT
RET
Other
Sorafenib +
FLT-3
Sunitinib
Axitinib
Motesanib
Pazopanib
Vandetanib
EGFR
Cabozantinib
C-MET
Lenvatinib
FGFR
Vemurafenib
BRAF V600E
DTC, differentiated thyroid cancer; EGFR, endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
1. Perez CA , et al. Biologics. 2012;6: Pacini F. Expert Rev Endocrinol Metab. 2012;7:

9. Targeted Agents: Phase 2 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
Papillary (50%); medullary (18%); follicular/Hürthle (25%/18%); anaplastic (3%) 60
18.1
30%
48% 7%
Motesanib
(Sherman)
Papillary (61%); follicular/Hürthle (34%) 93 10
14%
67% 8%
Pazopanib
(Bible)
PD and DTC (progression < 6 months) 37 12
49%
Lenvatinib
DTC (100%) 58
13.3
45%
46% 5%
DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; PD, progressive disease; PDTC, poorly-differentiated thyroid cancer; PFS, progression-free survival; PR, partial response; SD, stable disease.

10. DECISION study design1
417 patients randomized from Oct 2009 to July 2011
Locally advanced or metastatic, RAI-refractory DTC
Progression (RECIST) within the previous 14 months
No prior chemotherapy, targeted therapy, or thalidomide
Sorafenib 400 mg orally twice daily
Primary endpoint
Progression-free survival
Randomization 1:1
Placebo orally twice daily
Secondary endpoints
Overall survival
Response rate
Safety
Time to progression
Disease control rate
Duration of response
Sorafenib exposure (AUC0–12)
Stratified by:
geographical region (North America or Europe or Asia)
age (<60 or ≥60 years)
Progression assessed by independent central review every 8 weeks
At progression:
patients on placebo allowed to cross over at the investigator’s discretion
patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

11. Key inclusion and exclusion criteria (1)
Locally advanced or metastatic DTC (papillary, follicular including Hürthle cell or poorly differentiated)
RAI-refractory DTC
At least one target lesion without iodine uptake, or
Progression following treatment dose of RAI, or
Cumulative RAI treatment ≥600 mCi
Progressive disease within the last 14 months (RECIST)
Adequate TSH suppression (<0.5 mU/l)
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

12. Key inclusion and exclusion criteria (2)
Inclusion (cont.)
Not a candidate for surgery or radiotherapy with curative intent
Adequate bone marrow, liver and renal function
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2
Exclusion
Prior anti-cancer treatment with targeted therapy or chemotherapy
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

13. Baseline disease characteristics
Sorafenib (n=207)
Placebo (n=210)
Histology, investigator assessed, %
Papillary
Follicular
Hürthle cell
Missing
66.2
21.3
11.6
1.0
67.1
26.2
6.7
Metastases
Locally advanced Distant
Most common target/non-target lesion sites, %
Lung Lymph nodes (any) Bone Pleura Head and neck Liver
86.0
54.6
27.5
19.3
15.9
13.5
86.2
48.1
26.7
11.4
16.2
14.3
Prior thyroidectomy, %
100
99.0
Locoregional therapy or EBRT, %
40.1
43.3
Median cumulative RAI activity
400 mCi
376 mCi
EBRT, external beam radiation therapy
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

14. Progression-free survival (by independent central review)
Median PFS, days (months)
Sorafenib
207
329 (10.8)
Placebo
210
175 (5.8)
PFS probability (%)
Days from randomization
100
200
300
400
500
600
700
800 10 20 40 60 80 30 50 70 90
HR: 0.587; 95% CI: 0.454–0.758; p<0.0001
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

15. Overall survival Survival probability (%) Days from randomization10 20 40 60 80
100 30 50 70 90
Median OS
Sorafenib
Not reached
Placebo
Survival probability (%)
HR: 0.802; 95% CI: 0.539–1.194
p=0.138, one-sided
100
200
300
400
500
600
700
800
900
1000
Days from randomization
At progression:
150 patients on placebo (71%) received open-label sorafenib
55 patients on sorafenib (27%) received open-label sorafenib
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

16. Other secondary efficacy endpoints
Sorafenib
n (%)
Placebo
p value
Total evaluable patients
196
201
Response rate
24 (12.2)
1 (0.5)
<0.0001
Complete response –
Partial response
Stable disease for ≥6 months
82 (41.8)
67 (33.2)
Disease control rate (CR + PR + SD ≥6 months)
106 (54.1)
68 (33.8)
Median duration of response (PRs) months (range)
10.2 (7.4–16.6) NA
CR, complete response; PR, partial response;
SD, stable disease; NA, not assessed

17. Maximum reduction in target lesion size (%)
Maximum reduction in target lesion size (by independent central review)
–70
–50
–40
–20 20 60
–30
–10 10 30 50 40
–60
73% of patients
27% of patients
Maximum reduction in target lesion size (%)
Sorafenib
Placebo
Maximum reduction is defined as the difference in the sum of the longest diameter of target lesions from baseline. Negative values refer to maximal reduction and positive values to the minimal increase.

18. Treatment and dose modifications (double-blind period)
Sorafenib
(n=207)
Placebo
(n=209)
Mean dose
651 mg
793 mg
Median (range) treatment duration
46.1 weeks (0.3−135.3)
28.3 weeks (1.7−132.1)
Dose modification due to AEs, %
Dose reduction Dose interruption
77.8
30.1
Permanent discontinuation due to AEs, %
18.8
3.8
AE, adverse event
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

19. Most common treatment-emergent AEs (double-blind period)
Sorafenib (n=207)
Placebo (n=209)
Any grade
Grade 3/4
Hand–foot skin reaction
76.3
20.3
9.6
Diarrhea
68.6
5.8
15.3
1.0
Alopecia
67.1
7.7
Rash/desquamation
50.2
4.8
11.5
Fatigue
49.8
25.4
1.4
Weight loss
46.9
13.9
Hypertension
40.6
9.7
12.4
2.4
Metabolic – lab (other)
35.7
16.7
Anorexia
31.9
Oral mucositis
23.2
3.3
Pruritus
21.3
10.5
Nausea
20.8
Hypocalcemia
18.8
9.2
*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

20. Serious adverse events and deaths (double-blind period)
Sorafenib
n=207
Placebo
n=209
Serious AEs, n (%)
77 (37.2)
55 (26.3)
Most frequent serious AEs*, n (%)
Secondary malignancy
Squamous cell carcinoma of the skin Dyspnea Pleural effusion
9 (4.3)
7 (3.4) 7 (3.4) 6 (2.9)
4 (1.9)
0 6 (2.9) 4 (1.9)
Grade 5 events (deaths), n (%)
Drug-related**
14 (6.8)
1 (0.5)
6 (2.9)
* Occurring in ≥2.0% of sorafenib-treated patients
** Myocardial infarction (sorafenib); subdural hematoma (placebo)

21. Sorafenib benefit by BRAF status (PFS) – Papillary histology only
BRAF wild-type
BRAF mutation
Median PFS, days (months)
Sorafenib (n=42)
278 (9.1)
Placebo (n=42)
170 (5.6)
Median PFS, days (months)
Sorafenib (n=32)
623 (20.5)
Placebo (n=40)
286 (9.4) 20 40 60 80
100
200
400
600
800 20 40 60 80
100
200
400
600
800
HR: 0.58, 95% CI: 0.34–1.00, p=0.049
HR: 0.40, 95% CI: 0.20–0.80, p=0.008
PFS probability (%)
Days from randomization
Days from randomization
BRAF mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.393)
Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

22. Sorafenib benefit by RAS status (PFS)
RAS wild-type
RAS mutation
Median PFS, days (months)
Sorafenib (n=102)
329 (10.8)
Placebo (n=104)
175 (5.7)
Median PFS, days (months)
Sorafenib (n=24)
167 (5.5)
Placebo (n=26)
105 (3.4) 20 40 60 80
100
200
400
600
800 20 40 60 80
100
200
400
600
800
HR: 0.60, 95% CI: 0.42–0.85, p=0.004
HR: 0.49, 95% CI: 0.24–1.00, p=0.045
PFS probability (%)
Days from randomization
Days from randomization
RAS mutation was not an independent prognostic factor for PFS
Univariate (placebo arm only): mutant vs wild type RAS, HR=1.80; p=0.022
Multivariate (placebo arm only): mutant vs wild type RAS, HR=1.56; p=0.154
RAS mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.422)
Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

23. UPCC 18310: Vemurafenib in patients with Progressive PTC with BRAF V600E
Key Eligibility Criteria
Recurrent, unresectable or metastatic PTC
BRAFV600 mutation positive by cobas
RAI refractory
Evidence of progression within 14 months
Prior chemotherapy allowed
Cohort 1:
VEGFR2i-naive
(n = 26)
Vemurafenib 960 mg bid until disease progression or unacceptable toxicity
Cohort 2:
VEGFR2i-pretreated (n = 25)
Primary end point: response rate per investigator in VEGFR2i-naive patients. Secondary end points: safety, duration of response, PFS, OS, PK, response rate in VEGFR2 inhibitor–pretreated patients
bid, 2 times a day; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; VEGFR, vascular endothelial growth factor receptor; VEGFR2i, vascular endothelial growth factor receptor 2 inhibitor.
Brose et al. ECCO-ESMO 2013

24. Max change in sum of diameters
Cohort 1: VEGFR2i-Naive Best Objective Response
25.0
0.0
–25.0
–50.0
–75.0
–100.0
–30.0
No confirmed objective response
Confirmed objective response
Cohort 1, N = 26
Max change in sum of diameters
RECIST (%)
Objective response n (%) [95% CI]
CR, n (%)
0 (0)
PR, n (%)
9 (35%)
SD ≥6 mo
6 (23%)
Clinical benefit (CR, PR, or SD ≥6 mo), n (%) [95% CI]
15 (58%) [ ]
Each bar represents one cohort 1 patient
AE, adverse event; CR, complete response; PR, partial response; SD, stable disease.
aPatients with at least 2 postbaseline tumor scans or progressive disease/withdrawal because of death or AE within first 2 cycles. 24

25. Cohort 1: VEGFR2i-Naive Survival Kaplan-Meier Curves
Median PFS 15.6 mo (95% CI: 11.2–NR)a
a13 patients continue therapy.
1.0
0.8
0.6
0.4
0.2
0.0 5 10 15 20
Survival Probability
Months
Censored
bMedian follow-up time: 11.4 mo.
Median OS: Not reachedb
PFS OS
Brose et al. ECCO-ESMO 2013 25

26. Summary: RAI-Refractory DTC
DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways, and iodine-refractory patients have an average survival of 3 years
Results of phase 3 trials with sorafenib (DECISION) were positive, This agent was the FDA approved November 2013, and is first agent to be approved since doxorubicin in 1974.
Two additional phase 3 trials of lenvatinib (SELECT) and vandetanib (VERIFY) are ongoing
Additional MKIs have also shown activity in the Phase II setting, many of which target VEGFR-2, but also mTOR, MEK, MET and BRAF and BRAF V600E and will be needed in the second- and third-line setting
DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; mTOR, mammalian target of rapamycin; RAI, radioactive iodine; VEGFR, vascular endothelial growth factor. 26 26

27. Thyroid cancer: clinical pathology
Papillary (87%)
Differentiated
Follicular cells
Follicular (6%)
Hürthle cell (3%)
Anaplastic (1%)
Medullary (2%)
Parafollicular cells
Treatment of Medullary Thyroid Cancer includes:
Surgery – thyroidectomy
Thyroid stimulating hormone (TSH) replacement
Recurrent non surgical and metastatic disease treated with Cabozantinib and Vandetanib
Carling T and Uldesman R. Cancer of the Endocrine System: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins
Howlader N et al. SEER Cancer Statistics Review;

28. Medullary Thyroid Cancer
From calcitonin-producing parafollicular C cells
Accounts for 2%-5% of thyroid cancers
~1400 cases per year in US
Disproportionate number of thyroid cancer deaths
350,000 Americans living with thyroid cancer
Heritable in 25% of cases
Mutations in the RET gene cause familial MTC–multiple endocrine neoplasia 2 (MEN2)
30%-40% of sporadic MTC bear somatic RET mutations

29. Plasma Markers in MTC Calcitonin
Synthesized and excreted by C cells of the thyroid and by some medullary thyroid tumors
Diarrhea and flushing at high levels
Calcitonin levels can be affected by RET inhibition
Carcinoembryonic antigen (CEA)
Synthesized and excreted by some medullary thyroid tumors
Synthesized by other types of tumors as well

30. Patients With Distant Metastasis at Diagnosis Have a Poor Prognosis
10-year overall survival: 40%
Median overall survival: 3.2 years
Roman et al

31. MTC: Initial Treatment
Complete surgical resection is the only curative treatment for MTC
Metastasis (lymph node or systemic) is present at diagnosis in 40%-50% of sporadic cases of MTC
Surgery :
Total thyroidectomy
Extent of surgery depends on stage of disease
Curable vs noncurable
Central neck dissection +/- Ipsilateral neck dissection or Contralateral neck dissection
Goal
Early disease: removal of all neoplastic disease
Advanced disease: airway protection

32. MTC: Treatment Radiation therapy
Adjunctive and palliative treatment for extensive neck or mediastinal disease
Palliative treatment for bony metastasis
May be effective in controlling complications associated with MTC activity in the neck and mediastinum
No evidence that radiation therapy improves survival
Radioactive Iodine is ineffective in the treatment of MTC!!!

33. MTC: Treatment Follow-up postsurgery
High level of calcitonin 2-3 months postsurgery indicates persistent disease
Most important prognostically is total calcitonin and the doubling time (DT)
Reoperation may allow removal of at least some neoplastic tissue, but less likely to prevent recurrence
Calcitonin levels normalize in 5%-35% of cases after re-operation
Radiation to the neck and mediastinum in cases of persistent elevated calcitonin levels can decrease the risk of recurrence (unlikely to affect survival)

34. Risk Stratification Using Serum Calcitonin DT
Calcitonin DT highly predictive of mortality
Independent predictor in multivariate analysis, controlled for TNM stage
Rapid DT could identify stage II and III patients at higher risk for death
Barbet. JCEM

35. Cervical nodes and thyroid bed Lungs and mediastinum
MTC: Sites of Recurrent or Persistent Disease Optimal Imaging Strategies
Cervical nodes and thyroid bed
Lungs and mediastinum
Liver and abdominal lymph nodes
Bone
Neck ultrasound
Chest CT
Liver protocol MRI
MRI spine and pelvis
CT, computed tomography; MRI, magnetic resonance imaging.
Giraudet. JCEM

36. MTC: Treatment of Metastatic Disease
No standard of care
Rate or progression is variable
Some patients survive for years with metastatic disease
Traditional chemotherapy
Prior to 4/6/2011, doxorubicin was the only FDA-approved agent; relative risk (RR) <40%; poorly tolerated, short duration response
Dacarbazine-based regimens RR< 40% and generally short-lived
NCCN practice guidelines (2008)
Disseminated symptomatic disease
Clinical trial (preferred)
Radiation therapy for focal symptoms
Sorafenib
Dacarbazine-based chemotherapy
Consider bisphosphonate therapy for bone metastases
Best supportive care

37. Rationale for RET as a Therapeutic Target
Activated by mutations in ~50% of cases (>60% of progressive cases presenting for clinical trials)
Somatic mutation of RET associated with poor prognosis
Limited expression outside the thyroid, potentially high therapeutic index

38. 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
Number at Risk
CAPRELSA 300 mg
231
173
145
118 33 1
Placebo
100 47 30 24 6
CI=confidence interval; HR=hazard ratio.
CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP.
Wells SA Jr et al. J Clin Oncol. 2012;30(2):

39. FDA Approves vandetanib in MTC 4/6/2011
[1. FDA.gov-Vandetanib Approval, p1, para1]
Approved for progressive or symptomatic disease only
MDs required to undergo Risk Evaluation and Mitigation Strategy (REMS) training for QTc prolongation detection
REMS program lays out a plan for EKG monitoring throughout therapy for all patients treated with vandetanib
Training itself takes approximately 2 hours
Starting dose 300 mg/d
[2. CAPRELSA PI, p2, col1, section 1.1, section 2, para1, p3, col1, section 5.15]

40. Cabozantinib Phase III in MTC Progression Free Survival by IRC
[1. FDA.gov-Cabozantinib Approval, p1, para1]
[2. COMETRIQ PI, p9, BLACK BOX WARNING, section 1, section 2.1, para1]
P<
Significant difference in tumor response rate
27% in cabozantinib vs 0% placebo; P<0.0001
Median duration of response: 14.7 months
COMETRIQTM (cabozantinib) Capsules [package insert]. Exelixis, Inc: San Francisco, CA.

41. FDA Approves cabozantinib in MTC 11/29/2011
[1. FDA.gov-Cabozantinib Approval, p1, para1]
Approved for progressive or symptomatic disease only
Warnings about gastrointestinal perforations and fistula formations
Starting dose 140 mg/d
[2. COMETRIQ PI, p9, BLACK BOX WARNING, section 1, section 2.1, para1]

42. Key Points: MTC for Oncologists
MTC has a distinct clinical presentation, genetics, and molecular targets compared with differentiated thyroid cancer
Importance of distinguishing progressive vs indolent disease (imaging and CEA DT)
Success of treatment will be strongly dependent on attention to kinase-related symptom management
REMS is required for vandetanib; oncologists are required to follow EKGs closely
Cabozantinib has black box warning about risk of fistula formation in regions of prior invasive disease and radiation
Either can be used in first or second line setting

43. University of Pennsylvania Thyroid Cancer Therapeutics Program
Brose Translational Research Lab
Raya Terry, MD
Tatyana Kuznetsova, PhD
Waixing Tang, MD
Zakkiyya Posey
Thyroid Cancer Clinical Trials Unit
Yvette Cruz, RN
Carolyn Grande, RN, CRNP
Thelma McCloskey
Parna Prajapati
Ramkrishna Makani
Jillian 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
Douglas Fraker, MD
Robert Lustig, MD
Virginia LiVolsi, MD
Zubair Baloch, MD
Steve Keefe, MD
Daniel Pryma MD
Marcia Simpson Brose is a Damon Runyon-Siemens Clinical Investigator
Many community endocrinologists who have referred their patients, and the patients who have agreed to participate in our trials