MSB 05/30/09

Advances in the management of iodine-refractory thyroid cancers

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 several agents currently under investigation for the treatment of advanced thyroid. As none of the agents other than doxorubicin and vandetanib and cabozantinib are FDA approved for the use in thyroid cancer, the rest of the new agents that will be discussed here are in clinical trials (not FDA approved) at this time.

– Marcia S. Brose MD PhD

DISCLOSURE:In the last three years I have financial interest/arrangement

or affiliation with:Name of Organization RelationshipBayer Healthcare research funding,

honorariumOnyx research funding,

honorariumNovartis research funding, Exelixis research funding

honorariumAstrazeneca consultingBristol-Myers Squibb consultingGenentech/Roche research funding

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

>5.0cm2.1-5.0cm

Thyroid cancer in the United States

0-1.0cm1.1-2.0cm

Davies, JAMA 2006295:2164

Differentiated Thyroid Cancer

MSB 09/21/09

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

• This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism

–In other words, the cancer cells “forget” how to take up iodine and so they are immune to the treatment.

RAI-refractory disease• Standard Chemotherapy has minimal

efficacy. 1974 Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer. –No longer used because recent data

shows response is 5%–High toxicity in patient with otherwise

good QOL

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.

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

ePI

3K/A

KT

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

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

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

MotesanibSorafenibSunitinibVandetanibXL-184

Axitinib MotesanibSorafenibSunitinibVandetanib

Vandetanib

Sorafenib Sorafenib

Targeting cell signaling 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 03305: Sorafenib in Advanced Thyroid Cancer

February 2006-February 2011

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

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

• 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

dom

isat

ion

(1:1

)(n

=380

)Progression

Sorafenib400mg orally

b.i.d.

Placebo

Investigator’s decisionn=190

n=190

Primary Endpoint:PFS (RECIST)Independent reviewMet primary endpointJanuary 2013

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

Targets of Kinase InhibitorsCompound Name VEGFR BRAF

PDGFR KIT RET Other

Sorafenib + + + + + FLT-3

Sunitinib + + + FLT-3

Axitinib (AG-013736) + + +

Motesanib (AMG-706) + + + +Pazopanib(GW786034) + + +

Vandetanib + + EGFR

Cabozantinib (XL184) + + C-MET

Lenvatinib(E7080) + + + + FGFR

Summary• DTC is a vascular tumor that has been associated with

increased activity of the MAPK pathways• Iodine-refractory patients have an average survival of 3

years• Phase III study of sorafenib in this patient population is

positive. Results are expected at ASCO 2013.• Results of phase II trials with lenvatinib have led to the

initiation of a phase III trials for patients with RAI-refractory DTC

• Additional MKIs are also now in development many of which target VEGFR2, but also mTOR, MEK, and BRAF

Advanced Thyroid Cancer’s New Unmet Need: Progression on Sorafenib/VEGFR2 inhibitor

• Patients progress but maintain good performance status

• Most patients respond then progress in a new lesion or a subset of lesions

What to do?• We need additional treatment options

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

NO25530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor RO5185426 in Patients with Metastatic

or Unresectable Papillary Thyroid Cancer (PTC) positive forthe BRAF V600 Mutation and Resistant to

Radioactive Iodine

RO5185426 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

Con

sent

BR

AF

V600

E te

stin

g + First Line Sorafenib Naïve

(n=25)

Second Line Prior Sorafenib

(n=15+)

+

Status:Accrual Complete

Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced DTC

ASCO 2012: Selumetinib: MEK inhibition to increase RAI uptake

(Ho et al)

Going forward as an earlier treatment:1. Use for patients with high risk disease to increase uptake, 2. Unclear where in the treatment paradigm this will end up.

Summary Second Line Agents• Due to tumor heterogeneity, a patient with

progression on a multikinase inhibitor may continue to derive benefit from that inhibitor

• Combination or Sequential treatments with MKIs (sorafenib + everolimus, or sorafenib + vemurafenib) are likely to aid patients with progression

• New agents in development that specifically target mutations (BRAF V600E) may also play a role in the treatment of thyroid cancer in the first or second line settings and carry the most promise

Medullary Thyroid Cancer

MSB 09/21/09

Signaling pathways in MTC

C-MET

BRAF

MEK

ERK

RAS

AKT

VEGF

VEGFR

Tumorcell

EndothelialcellY1062

-P

X

RET

PI3K

EGFR

VEGFRPLC-g

PKC

Multikinase inhibitor activities relevant to MTC

Drug In vitro IC50 (nm)

VEGFR1

VEGFR2 VEGFR3 RET RET/PTC3 RAF Other

Sorafenib - 90 20 49 50 6 PDGFR 58

Vandetanib 1600 40 110 100 50-100 - EGFR 500Cabozantinib (XL 184) - 0.035 - 4.5 - - C-MET

1.8

Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494

27

ZETA Study: VandetanibSignificantly Prolonged PFSa vs Placebo

CI=confidence interval; HR=hazard ratio.aPFS is defined as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria In Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.2 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.1

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.

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

Cabozantinib Ph III in MTCProgression Free Survival by IRC

Cabozantinib Placebo

Median PFS(months) 11.2 4.0

1 year PFS 47.3% 7.2%

HR (95% CI) 0.28 (0.19, 0.40)

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<0.0001p < 0.0001

• Significant difference in tumor response rate – 28% in cabozantinib vs. 0% placebo; p<0.0001

• Median duration of response: 14.6 monthsASCO 2012 oral presentation

Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced MTC

Summary: Agents for MTC• Phase II data shows that several multikinase

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

• Vandetanib was approved last year and Cabozantinib just received FDA approval for MTC

• Response in these patients result in prolonged disease control

• Additional agents are needed as these agents last only 10-12 months, there is a great unmet need to identify additional agents for this disease.

Summary: Targeted therapy for Advanced Thyroid Cancer

• Where do we go from here?– Completion of large randomized trials:

• Phase III of sorafenib is positive. Phase III of lenvatinib is underway.

– More data on the activity of the targeted agents used sequentially:• So patients are to benefit from the number of agents

available– Novel strategies for treatment bear investigating:

• including novel targets and the use of combination therapies to improve outcome.(Sor+Ev, Sor + Vem)

– Further subgroup analysis to identify subpopulations:• use of clinical and molecular markers to identify patients that

may benefit better with some therapies over others. Pts with Ras mutations, Poorly differentiated TC

– Registration trial for sorafenib in MTC!!!

Agents currently available in our Thyroid Cancer Therapeutics Program

Agent Sub-types

Vandetanib MTC, (DTC)

Sorafenib DTC, MTC, ATC

Everolimus DTC

Pazopanib DTC

Lenvatinib (E7080) DTC

Cabozantinib (XL184) MTC, DTC

Vemurafenib (PLX4322 – BRAF V600Ei) PTC

Combretastatin ATC

PLX3397 ATC

MSB 10/16/10

• Thyroid Cancer Interest Group – Susan Mandel MD– Ara Chalian MD– Kelly Malloy MD– Douglas Fraker MD– Robert Lustig MD– Virginia LiVolsi MD– Zubair Baloch MD

• MSB is a Damon Runyon-Siemens Clinical Investigator

• Many Community Endocrinologists that have referred their patients, and the patients that have agreed to participate in our trials.

University of PennsylvaniaThyroid Cancer Therapeutics Program

• Brose Group– Carolyn Grande RN, CRNP– Steve Keefe MD– Thelma McClosky– Tatyana Kuznetsova, PhD– Waixing Tang MD– Stephen Stopenski

• Thyroid Cancer Clinical Trials Unit– Larisa Zifchak RN– Parna Prajapati– Ramkrishna Makani– Jillilan Stanley

• Experimental Therapeutics Program– Andrea Troxel PhD– Peter O’Dwyer MD

• Pathology/Imaging– Michael Feldman MD PhD– Laurie Loevner MD

MSB 10/16/10

Questions?

Marcia S. Brose MD PhDEmail: Marcia.Brose@uphs.upenn.edu

Telephone: 215-615-6519

Thank you for your courage and attention!