Management Advances for Differentiated and Medullary Thyroid Carcinoma

Management Advances for Differentiated and Medullary Thyroid Carcinoma

Marcia S. Brose MD PhDAbramson 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

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

Thyroid cancer: clinical pathology

Parafollicular cells

Follicular cells Differentiated

Medullary (2%)

Anaplastic (1%)

Follicular (6%)

Papillary (87%)

Hürthle cell (3%)

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. 2005.

Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.

Radioactive Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)

• It is estimated1 that in the USA in 2013 there will be: – >60 000 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; http://seer.cancer.gov/statfacts/html/thyro.html; 2. 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;91:2892–99. 5. Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505.

FDG-PET Predicts Survival in Patients With Metastatic Thyroid Cancer

Robbins et al. J Clin Endocrinol Metab. 2006;91:498-505.

0 10 20 30 40 50 60 70 80 90

1.00

0.75

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0Surv

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Months

FDG-negative176/179 alive

FDG-positive156/223 alive

Median survival = 53 months

Genetics of Differentiated Thyroid Cancer: aberrant intracellular signaling

PapillaryMutations identified in ~70%BRAFa (40–50%)RASb (7–20%)• RET/PTC (clonal; 10–20%)• EGFR (5%)• TRK (<5%)• PIK3CA (2%)

FollicularMutations in 70–75%• RAS (40–50%;

lower in oncocytic)• PAX8/PPARg (30–35%;

lower in oncocytic)• TP53 (21%)• PTEN (8%)• PIK3CA (7%) BRAF (2%)

Poorly differentiated RAS (25–30%)• TP53 (20–30%)• CTNNB1 (10–20%) BRAF (10–15%)

AnaplasticMedullary

DTCPapillary

Conventional

Oncocytic

aBRAF mutations are mostly V600E; 1–2% are K601E and othersbRAS 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) http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/

Targeting Cell Signaling in Thyroid Cancer

• HIF1a• Inhibition of apoptosis• Migration

• Growth• Survival• Proliferation

• Growth• Survival• Proliferation

MotesanibSorafenibSunitinibVandetanibCabozantinibLenvatinib

Axitinib MotesanibSorafenibSunitinibVandetanibLenvatinibCabozantinib

Vandetanib

Sorafenib Sorafenib

RET/PTC 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

EverolimusSirolimus

EverolimusSirolimus

EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor.Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-783.

Targets of Kinase Inhibitors

Compound Name VEGFR BRAF PDGFR KIT RET Other

Sorafenib + + + + + FLT-3

Sunitinib + + + FLT-3

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;6:257-265. 2. Pacini F. Expert Rev Endocrinol Metab. 2012;7:541-554.

Targeted Agents: Phase 2 Clinical Data

Drug Key Baseline Characteristics n

PFS(months

) PR SD PDSorafenib(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/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(Sherman) 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.

• Locally advanced or

metastatic, RAI-refractory DTC

• Progression (RECIST) within the previous 14 months

• No prior chemotherapy, targeted therapy, or thalidomide

417 patients randomized from Oct 2009 to July 2011

DECISION study design1

• 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

Sorafenib400 mg orally twice daily

Placebo orally twice daily

Randomization 1:1 Primary endpoint

Secondary endpointsOverall survival Response rateSafetyTime to progression Disease control rate Duration of responseSorafenib exposure (AUC0–12)

• Progression-free survival

1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

Key inclusion and exclusion criteria (1)

Inclusion• 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)


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


Baseline disease characteristics

Sorafenib(n=207)

Placebo(n=210)

Histology, investigator assessed, % Papillary FollicularHürthle cell Missing

66.221.311.61.0

67.126.26.70

Metastases Locally advancedDistant

3.496.6

3.896.2

Most common target/non-target lesion sites, %

LungLymph nodes (any)BonePleuraHead and neckLiver

86.054.627.519.315.913.5

86.248.126.711.416.214.3

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


nMedian PFS,

days (months)Sorafenib 207 329 (10.8)

Placebo 210 175 (5.8)

Progression-free survival(by independent central review)

PFS

pro

babi

lity

(%)

Days from randomization0 100 200 300 400 500 600 700 800

0

10

20

40

60

80

100

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 4CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

Overall survivalS

urvi

val p

roba

bilit

y (%

)

Days from randomization

0

10

20

40

60

80

100

30

50

70

90

0 100 200 300 400 500 600 700 800 900 1000

At progression:• 150 patients on placebo (71%) received open-label sorafenib• 55 patients on sorafenib (27%) received open-label sorafenib

Median OS

Sorafenib Not reached

Placebo Not reached

HR: 0.802; 95% CI: 0.539–1.194p=0.138, one-sided


Other secondary efficacy endpoints

Sorafenibn (%)

Placebon (%) p value

Total evaluable patients 196 201

Response rate 24 (12.2) 1 (0.5) <0.0001

Complete response 0 0 –

Partial response 24 (12.2) 1 (0.5) –

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) <0.0001

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

Maximum reduction in target lesion size(by independent central review)

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.

Max

imum

redu

ctio

n in

targ

et le

sion

siz

e (%

)

–70

–50

–40

–20

0

20

60

–30

–10

10

30

50

40

–60

Sorafenib Placebo

27% of patients73% of patients

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 reductionDose interruption

77.864.366.2

30.19.125.8

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

Most common treatment-emergent AEs (double-blind period)

AE*, % Sorafenib (n=207) Placebo (n=209)Any grade Grade 3/4 Any grade Grade 3/4

Hand–foot skin reaction 76.3 20.3 9.6 0Diarrhea 68.6 5.8 15.3 1.0Alopecia 67.1 0 7.7 0Rash/desquamation 50.2 4.8 11.5 0Fatigue 49.8 5.8 25.4 1.4Weight loss 46.9 5.8 13.9 1.0Hypertension 40.6 9.7 12.4 2.4Metabolic – lab (other) 35.7 0 16.7 0Anorexia 31.9 2.4 4.8 0Oral mucositis 23.2 1.0 3.3 0Pruritus 21.3 1.0 10.5 0Nausea 20.8 0 11.5 0Hypocalcemia 18.8 9.2 4.8 1.4

*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0


Serious adverse events and deaths(double-blind period)

Sorafenib n=207

Placebon=209

Serious AEs, n (%) 77 (37.2) 55 (26.3)

Most frequent serious AEs*, n (%)Secondary malignancy

• Squamous cell carcinoma of the skinDyspneaPleural 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)1 (0.5)

* Occurring in ≥2.0% of sorafenib-treated patients** Myocardial infarction (sorafenib); subdural hematoma (placebo)

Sorafenib benefit by BRAF status (PFS)– Papillary histology only

BRAF mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.393)

0

20

40

60

80

100

0 200 400 600 800

PFS

pro

babi

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(%)

Days from randomization Days from randomization

0

20

40

60

80

100

0 200 400 600 800

BRAF wild-type BRAF mutationMedian PFS, days (months)

Sorafenib (n=42) 278 (9.1)

Placebo (n=42) 170 (5.6)

HR: 0.58, 95% CI: 0.34–1.00, p=0.049

Median PFS, days (months)

Sorafenib (n=32) 623 (20.5)

Placebo (n=40) 286 (9.4)

HR: 0.40, 95% CI: 0.20–0.80, p=0.008

Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

0

20

40

60

80

100

0 200 400 600 800


Sorafenib (n=24) 167 (5.5)

Placebo (n=26) 105 (3.4)

Sorafenib benefit by RAS status (PFS)

RAS mutation was not an independent prognostic factor for PFSUnivariate (placebo arm only): mutant vs wild type RAS, HR=1.80; p=0.022Multivariate (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)

HR: 0.49, 95% CI: 0.24–1.00, p=0.045


Sorafenib (n=102) 329 (10.8)

Placebo (n=104) 175 (5.7)

HR: 0.60, 95% CI: 0.42–0.85, p=0.004

PFS

pro

babi

lity

(%)

Days from randomization Days from randomization

0

20

40

60

80

100

0 200 400 600 800

RAS wild-type RAS mutation

Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

UPCC 18310: Vemurafenib in patients with Progressive PTC with BRAF V600E

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

Cohort 1: VEGFR2i-naive (n = 26)

Cohort 2:VEGFR2i-pretreated (n = 25)

Vemurafenib960 mg biduntil disease progression or unacceptable toxicity

Key Eligibility Criteria• Recurrent, unresectable or

metastatic PTC• BRAFV600 mutation positive by

cobas• RAI refractory• Evidence of progression

within 14 months• Prior chemotherapy allowed

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

Cohort 1: VEGFR2i-Naive Best Objective Response

25.0

0.0

–25.0

–50.0

–75.0

–100.0

–30.0

No confirmed objective responseConfirmed objective response

Cohort 1, N = 26

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%) [0.37-0.77]

Each bar represents one cohort 1 patientAE, 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

Max

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in s

um o

f dia

met

ers

REC

IST

(%)

Cohort 1: VEGFR2i-NaiveSurvival Kaplan-Meier Curves

Brose et al. ECCO-ESMO 201325

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

0 5 10 15 20

Surv

ival

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Months

Censored

bMedian follow-up time: 11.4 mo.

Median OS: Not reachedb

1.0

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0.6

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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.

Thyroid cancer: clinical pathology

Parafollicular cells

Follicular cells Differentiated

Medullary (2%)

Anaplastic (1%)

Follicular (6%)

Papillary (87%)

Hürthle cell (3%)

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. 2005.

Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.

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

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

Roman et al. 2005.

Patients With Distant Metastasis at Diagnosis Have a Poor Prognosis

• 10-year overall survival: 40%• Median overall survival: 3.2 years

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

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!!!

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)

Barbet. JCEM. 2005.

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

Neck ultrasound

Chest CT

Liver protocol MRI

MRI spine and pelvis

MTC: Sites of Recurrent or Persistent Disease Optimal Imaging Strategies

• Cervical nodes and thyroid bed• Lungs and mediastinum• Liver and abdominal lymph nodes• Bone

CT, computed tomography; MRI, magnetic resonance imaging.Giraudet. JCEM. 2007.

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

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

ZETA Study: VandetanibSignificantly Prolonged PFSa vs Placebo

CI=confidence interval; HR=hazard ratio.

1. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2. Wells SA Jr et al. J Clin Oncol. 2012;30(2):134-141. 38

0 6 12 18 24 30 36

Months

Prog

ress

ion-

free

Surv

ival Median PFS not reached

(95% CI: 22.6 months, nonestimable)

16.4 months median PFS(95% CI: 8.3-19.7)

HR=0.35 (95% CI: 0.24-0.53)P<0.0001

▬▬ CAPRELSA 300 mg ▬▬ PlaceboEvents/Patients 59/231 41/1001.0

0.75

0.50

0.25

0.0

PFS: 65% Relative Reduction in Risk of Progression1

Number at RiskCAPRELSA 300 mg 231 173 145 118 33 1 0Placebo 100 47 30 24 6 0 0

FDA Approves vandetanib in MTC 4/6/2011• 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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Months

Prob

abili

ty

219 121 78 55 31 12 2 1111 35 11 6 3 2 0 0

CabozantinibPlacebo

p<0.0001

Cabozantinib Phase III in MTCProgression Free Survival by IRC

COMETRIQTM (cabozantinib) Capsules [package insert]. Exelixis, Inc: San Francisco, CA.

P< 0.0001

• Significant difference in tumor response rate – 27% in cabozantinib vs 0% placebo; P<0.0001

• Median duration of response: 14.7 months

FDA Approves cabozantinib in MTC 11/29/2011

• Approved for progressive or symptomatic disease only

• Warnings about gastrointestinal perforations and fistula formations

• Starting dose 140 mg/d

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

University of PennsylvaniaThyroid 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

Documents

Management Advances for Differentiated and Medullary Thyroid Carcinoma