Part I

Investigator Insights

Emerging Multikinase Inhibitors in Thyroid Carcinoma

Dr. Marcia Brose

Abramson Cancer Center

University of Pennsylvania

MSB 09/21/09

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

US EU Japan

Estimated Thyroid Cancer Incidence in 2008

0

5000

10000

15000

20000

25000

30000

35000

40000

An

nu

al I

nci

den

ce

LA/C

~37,000~33,000

~18,000

~6,000

Global Incidence of Thyroid Cancer was > 212,000 in 20081

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

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

Thyroid Cancer in the United States

New Diagnosis Cancer Deaths

Pfister, D. Treatment of Radioactive Thyroid Cancer. Presentation. ASCO, 2007.

>5.0cm

2.1-5.0cm

Thyroid cancer in the United States

0-1.0cm

1.1-2.0cm

Davies, JAMA 2006295:2164

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0 1084 62 12 14

0%

20%

40%

60%

80%

100%

Surv

ival

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.

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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

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

Su

rviv

al,

%

Years

All > 45 yr

TSH suppressed 15 yr 10 yrTSH unsuppressed 11 yr 6 yr

p < 0.01 p < 0.005

Mediann = 450

Jonklaas et al. Thyroid. 2006;16:1299-1242.

Su

rviv

al (

%)

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 patients4 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.

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.

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 every6 months

• Stable disease: follow-up

• Progression:

– > 20% (RECIST) in6-15 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.

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 .

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%

MA

P K

inas

eP

I3K

/AK

T

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

RAS/BRAF Mutations are More Prevalent in RAI Refractory Thyroid Cancer

MSB 09/21/09

Ricarte-Filho JC, Cancer Research 2009 Jun 1;69(11):4885-93

Cell signalling in differentiated thyroid cancer

Graphic adapted fromKeefe 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

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

MSB 09/21/09

Part II

Investigator Insights

Emerging Multikinase Inhibitors in Thyroid Carcinoma

Dr. Marcia Brose

Abramson Cancer Center

University of Pennsylvania

MSB 09/21/09

Kinase Inhibitors

KIATP KI

PY Y

ATP

Activated pathway

Cancer

Activated Pathway Cancer

VEGFR inhibition

Tumor

angiogenesisTumor

growth

RET, BRAF….. inhibition

Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.

MotesanibSorafenibSunitinibVandetanibXL-184

Axitinib MotesanibSorafenibSunitinibVandetanib

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

EverolimusSirolimus

EverolimusSirolimus

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%

MA

P K

inas

eP

I3K

/AK

T

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

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

Sorafenib400mg 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

Update UPCC O3305: May 2009Results:

• 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)

UPCC 03305: Best Response in

46 Evaluable Patients

PapillaryFollicular/Hürthle CellMedullaryPoorly Differentiated/Anaplastic

302010

0–10–20–30–40–50–60–70–80–90–10

Ch

ang

e in

su

m o

f ta

rget

lesi

on

by

RE

CIS

Tco

mp

ared

to

bas

elin

e (%

)

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)

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 MSB

09/21/09

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

Offstudy

Disease progression

Crossover or continue

sorafenib 400mg orally b.i.d.

Ran

do

mis

atio

n (

1:1)

(n=

380)

ProgressionSorafenib

400mg orallyb.i.d.

Placebo

Investigator’s decisionn=190

n=190

Primary Endpoint:PFS (RECIST)Independent review

Secondary Endpoints:OS, TTP, RR, DCR, PRO, PKSafetyExploratory Biomarkers

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

• The final results of the study to be presented at a major meeting in 2013

MSB 09/21/09

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

MSB 09/21/09

Part III

MSB 09/21/09

Investigator Insights

Emerging Multikinase Inhibitors in Thyroid Carcinoma

Dr. Marcia Brose

Abramson Cancer Center

University of Pennsylvania

MSB 09/21/09

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

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

MSB 05/30/09

Targeted Agents: Phase II Clinical DataDrug Key Baseline

Characteristicsn 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%

Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.

MotesanibSorafenibSunitinibVandetanibXL-184

Axitinib MotesanibSorafenibSunitinibVandetanib

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

EverolimusSirolimus

EverolimusSirolimus

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-patientDose 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

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

Vemurafenib960mg BID

Primary Endpoint:Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve ptsIndependent review

Secondary Endpoints:• PFS, TTP, OS, TTP, in

sorafenib naïve pts• BORR, CB, TTP, PFS and

OS, in soraefnib exposed patients

Info

rmed

Co

nse

nt

BR

AF

V60

0E t

esti

ng + First Line

Sorafenib Naïve (n=25)

Second Line Prior Sorafenib

(n=25)

+

MSB 10/16/10

Clinical Trials Ongoing for Metastatic Differentiated Thyroid Cancer

Compound Name DTC/MTC Status

Sorafenib (Nexavar) DTCFirst Line – International Phase III – Positive Study, Awaiting Data Presentation

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 DTCFirst 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.

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.

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.

MSB 09/21/09

References1. 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

MSB 09/21/09