MSB 05/30/09

Promising New Treatments for Metastatic Differentiated and

Medullary Thyroid Cancer

Marcia Brose MD PhD

Department of Otorhinolaryngology: Head and Neck SurgeryDepartment of Medicine, Division of Hematology/Oncology

Abramson Cancer CenterThe University of Pennsylvania

Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870

Disclosure Elements– My goal is to present information on a several agents

currently under investigation for the treatment of advanced thyroid cancer including our clinical trial of sorafenib for metastatic thyroid cancer. As no agent other than doxorubicin is FDA approved, none of the new agents discussed here are FDA approved at this time.

– Research Funding: Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals , Bayer Schering Pharma, Exelixis, Daichi-Sanyo

– Honoraria/Consultant: Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals , Bayer Schering Pharma,

– Marcia S. Brose MD PhD

MSB 05/30/09

Thyroid Cancer in the United States

Thyroid cancer is the most commonendocrine neoplasm..

Thyroid cancer was diagnosed in 38,000 individuals in 2008 (74% women).

From 1997-2004 incidence of thyroid cancer increased by 6.2% mostly due to increased detection.

From 1985 to 2004 mortality rate increased by 0.3% a year.

MSB 05/30/09

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

MSB 05/30/09

Thyroid Cancer: Clinical Pathology

Cancer Type Clinical Characteristics

Papillary • ~80% of thyroid cancers•10 year survival : 74-93%

Follicular •Constitute ~10% of thyroid cancers•10 year survival 43-94%

Hürthle Cell •Constitute ~4% of thyroid cancers•10 year survival: ~76%

Anaplastic •Constitute ~2% of thyroid cancers•Aggressive, rapidly invasive•Median survival: 4-12 months from diagnosis

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. Are C and Sasha A. Annals of Surgical Oncology. 2006; 13(4):453-464.NCCN Practice Guidelines. v2.2007. Al-Rawi M. Ann R Coll Surg Engl. 2006; 88:433-438.

Diff

eren

tiate

d

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0 1084 62 12 14

0%

20%

40%

60%

80%

100%

Surv

ival

Stage IStage I

Stage IIStage II

Stage IIIStage III

Stage IVStage IV

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.

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0 1084 62 12 14

0%

20%

40%

60%

80%

100%

Surv

ival

Surv

ival

Stage IStage I

Stage IIStage II

Stage IIIStage III

Stage IVStage IV

Jonklass, Thyroid 2006

Initial disease stage predicts Initial disease stage predicts OVERALL SURVIVALOVERALL SURVIVAL

YearsYears

75% of all

tumors

25% of all

tumors

p<0.001

MSB 05/30/09

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

MSB 05/30/09

RAI-Refractory Disease• 25-50% of Metastatic Thyroid Cancers loose

ability to take up Iodine• Loss of Iodine Uptake inversely correlates with

decrease in survival• This is attributed to down regulation of the Na+/I-

Symporter (NIS) and other genes of NaImetabolism– Promoter methylation of genes required for NaI

metabolism lead to decreased expression– Associated with increased signaling through MAPK

pathway• Standard Chemotherapy has minimal efficacy

MSB 05/30/09

FDG-PET Predicts for survival in patients with metastatic thyroid cancer

Robbins et al. JCEM. 2006, 91:498

Thyroid Cancer is associated with aberrant cell signaling

>65%>70%Total35%0%Pax8/PPARγ7%2%PTEN28%12%PI3KCA copy gain6%3%PI3KCA mutations

17-45%8-10%RAS0%20%RET/PTC (1 and 3)35%3%BRAF copy gain0%44%BRAF V600EFTCPTCGenetic Alteration

MA

P K

inas

ePI

3K/A

KT

Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

Targets of Kinase Inhibitors for Metastatic Thyroid Cancer

++++Motesanib (AMG-706)

EGFR

+

RET

+

BRAF

+++Pazopanib(GW786034)

+++Axitinib (AG-013736)

FLT-3+++Sunitinib (Sutent)

BCR-ABL++

Imatinib (Gleevec)

FLT-3+++Sorafenib (Nexavar)

OtherKITPDGFRVEGFRCompound Name

MSB 05/30/09

Targeted Agents: Phase II Clinical DataDrug Key Baseline Characteristics n PFS PR SD PD

Sorafenib

(Brose)

•DTC(90%), MTC, ATC 30 18.4 23% 54% 7%

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

Mo

30% 48% 7%

Motesanib

(Sherman)

•Papillary (61%); Follicular/Hurthle (34%)

93 10

Mo

14% 67% 8%

Lenalidomide

(Ain)

•Papillary (50%); Follicular (17%), Hurthle (17%)

21 - 39% 50% 11%

Note: Ain Data NOT RECIST criteria

Sorafenib in Advanced Thyroid Cancer

• 1º endpoints: RECIST, PFS, RR

Eligibility Criteria• Metastatic, iodine

refractory thyroid cancer• Life expectancy > 3

months• Evidence of progressive

disease within 6 months of study entry

• ECOG 0-2• Good organ and bone

marrow function*

Eligibility Criteria• Metastatic, iodine

refractory thyroid cancer• Life expectancy > 3

months• Evidence of progressive

disease within 6 months of study entry

• ECOG 0-2• Good organ and bone

marrow function*

Sorafenib

400 mg BID

Sorafenib

400 mg BID

Gupta-Abramson, et al. J Clin Oncol. 2008 (epub ahead of print)

n=55

* Leukocyte count ≥3,000/L, absolute neutrophil count≥1,500/L, platelets more than 100,000/L, hemoglobin ≥ 9 g/dL, serum creatinine ≤ 1.5 upper limit of normal (ULN) or 24-hour creatinine clearance ≥ 75 mL/min, serum bilirubin ≤ 1.5 ULN, serum AST ≤ 2.5 ULN, alkaline phosphatase ≤2.5 ULN, and prothrombin time-international normalized ratio/partial thromboplastin time ≤ 1.5 ULN.

MSB 05/30/09

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

Medullary Thyroid Cancer

• Sporadic– 75% of cases

• Inherited– 25% of cases– Multiple Endocrine Neoplasia 2A (MEN2A)

• MTC, Pheochromocytoma, Hyperparathyroidism– Multiple Endocrine Neoplasia 2B (MEN2B)

• MTC, Pheochromocytoma, Neuromas, Marfanoid habitus– Familial MTC

• Mutations in the RET gene – 95% of MEN2A and MEN 2B cases have germline mutations– 88% of familial MTC cases have germline mutations– 25% (up to 50%) of sporadic MTC cases have somatic mutations– 20% of papillary thyroid cancer cases

The RET Proto-oncogene

RET gene expression:•During embryogenesis•Multiple adult tissues

•Including thyroid•In some solid tumors

•MTC•Pheochromocytoma

Differentiation Proliferation Survival Motility

Binding of GDNF to RET activates cell proliferation, survival, and motility

Plasma Markers in MTC

• Calcitonin– Synthesized and excreted by the C cells of the thyroid

and by some medullary thyroid tumors– Diarrhea and flushing– Calcitonin levels can be affected by Ret inhibition

• CEA– Synthesized and excreted by some medullary thyroid

tumors. – Synthesized by other types of tumors as well

Medullary Thyroid Cancer-Treatment

• Complete surgical resection is the only curative treatment for MTC

• There is no standard treatment for metastatic disease

• Metastasis (LN or systemic) are present at diagnosis in 40-50% of sporadic cases of MTC

Patients with distant metastasis at diagnosis have a poor prognosis

Roman et al 2005

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

Medullary Thyroid Cancer-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

Medullary Thyroid Cancer- TreatmentMetastatic Disease

• No standard of care

• Rate or progression is variable– Some patients survive for years with metastatic disease

• Chemotherapy – Doxorubicin- The only FDA-approved agent; RR < 40%; Poorly

tolerated, short duration response– DTIC-based regimens RR < 40% and generally short-lived– NCCN Practice Guidelines (2008)

• Disseminated symptomatic disease– Clinical trial (preferred) or– RT for focal symptoms or– Sorafenib or– DTIC-based chemotherapy– Consider bisphosphonate therapy for bone metastases– Best Supportive Care

Signaling pathways in MTC

C-MET

BRAF

MEK

ERK

RAS

AKT

VEGF

VEGFR

Tumorcell

Endothelialcell

Y1062

-P

X

RET

PI3K

EGFR

VEGFRPLC-γ

PKC

Multikinase inhibitor activities relevant to MTC

Drug In vitro IC50 (nm)

VEGFR1 VEGFR2 VEGFR3 RET RET/PTC3 RAF Other

Axitinib 1.2 0.25 0.29 - - - PDGFR 1.7

E7080 22 4 5.2 35 - - FGFR 46

Motesanib 2 3 6 59 - - PDGFR 84

Pazopanib 10 30 47 2800 - - PDGFR 74

Sorafenib - 90 20 49 50 6 PDGFR 58

Sunitinib 2 9 17 41 224 - -

Vandetanib 1600 40 110 100 50-100 - EGFR 500

XL 184 - 0.035 - 4.5 - - C-MET 1.8

Sherman, J Clin Endocrinol Metab, 2009, p 1494

Motesanib: Phase II trial in MTC

Schlumberger, et al., J Clin Oncol, 2009, p 3798

24 wk clinical benefit rate: 51%RET negative 69%RET positive 10%

SD PR 81% 2%

Sorafenib: Phase II trials for advanced MTC

• N = 19– PR 11% SD 84% 6 mo CBR 68%

• N = 5– CR 1 pt PR 1 pt– Symptom control 4 pts

Lam, et al., AACR 2009, abstract 4513

Kober, et al., ASCO 2007, abstract 14065

Sunitinib: Phase II trials for advanced MTC

• N = 6 with progressive disease– 0% PR, 83% SD after 12 wks

• N = 8 with progressive disease– 37.5% clinical benefit rate (PR + SD ≥ 12

wks) Ravaud, et al., ASCO 2008, abstract 6058

Cohen, et al., ASCO 2008, abstract 6025

Vandetanib: Phase II trial for metastaticinherited MTC

Adapted from Wells, ATA Symposium, 2009

300 mg daily starting dose

SD cPR63% 33%

N = 30 pts

Cohen, et al., J Clin Oncol, 2008, p 4710

Axitinib: Phase II trial for advanced thyroid cancers

SD PR 38% 30%

MTC (n=11): SD PR27% 18%

*Response is per investigator report ^Patient was on randomized vandetanib trial. # MTC patient with G469A BRAF mutation. Kurzrock, et al., ATA 2009

-60-50-40-30-20-10

010203040

XL 184: Phase I trial enriched for MTC

• Scan data available for 33 patients with measurable disease (RECIST)• 1 patient discontinued prior to having post baseline scan• 44% (15/34) experienced a tumor shrinkage of > 30% on at least one post-baseline

scan• 29% (10/34) of patients with measurable disease had confirmed PR• Median time to response is 49.5 days (range of 22-365 days)• Five patients responded at the first (Day 28) radiographic evaluation

% T

umor

Cha

nge

V S#

S T M TV V T TV^M S

T, prior non-RET TKI therapy; Prior RET TKIs (V, vandetanib, M, motesanib, S, sorafenib)

Response was observed after failure of other therapies

Toxicities of TKI therapies• Mucocutaneous

– Hand-foot syndrome– Photosensitivity (esp. vandetanib)– Stomatitis– Squamous cell carcinoma (sorafenib)

• Gastrointestinal– Diarrhea– Nausea– Perforation (rare)

• Cardiovascular– Hypertension– Thromboembolism– Cardiomyopathy

• Fatigue• Hypothyroidism

Sherman, J Clin Endocrinol Metab, 2009, p 1494-6

Summary• Phase II data shows that several

multikinase inhibitors are clinically active in patients with advanced Differentiated and Medullary thyroid cancer.

• Response in these patients results in prolonged disease control

• The clinical activity of of several of these agents is being pursued in ongoing Phase III clinical trials.

Thank you!