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. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7 th edition. Lippincott Williams and Wilkins Parafollicular cells Follicular cells Differentiated Anaplastic Medullary Papillary Follicular Hurtle Cell Sporadic Familial

US EU Japan Estimated Thyroid Cancer Incidence in Annual Incidence LA/C ~37,000 ~33,000 ~18,000 ~6,000 Global Incidence of Thyroid Cancer was > 212,000 in LA/C = Latin America and Caribbean. 1. GLOBOCAN 2008, International Agency for Research on Cancer Sherman. Lancet. 2003;361: Eustatia-Rutten et al. J Clin Endocrinol Metab. 2006;91: Thyroid cancer is the most common form of endocrine malignancy 1 DTC represents > 90% of all thyroid carcinomas 2 The prognosis of patients with DTC is generally good due to tumor biology and efficacy of the initial surgery and 131 I therapy 3

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

>5.0cm cm Thyroid cancer in the United States 0-1.0cm cm Davies, JAMA :2164

MSB 05/30/ % 20% 40% 60% 80% 100% Survival 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):

MSB 05/30/09 Thyroid Cancer: Treatment Strategy High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm) –Total Thyroidectomy –RAI ( 131 I) 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 Survival, % Years All> 45 yr TSH suppressed 15 yr10 yr TSH unsuppressed 11 yr6 yr p < 0.01 p < Median n = 450 Jonklaas et al. Thyroid. 2006;16:

Survival and Response to Treatment Group 1: initial 131 I uptake and CR –Age < 40 years –Well-differentiated cancer –Small size of metastases Group 2: initial 131 I uptake and persistent disease Group 3: no initial 131 I uptake Durante et al. J Clin Endocrinol Metab. 2006;91:

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: Hodak SP, Carty SE. Oncology. 2009;23: Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22: ,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 every 6 months Stable disease: follow-up Progression: –> 20% (RECIST) in 6-15 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:

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 ( 131 I) (RAI) therapy 1,2 Follow-up treatment Levothyroxine to suppress TSH levels to < 0.1mU/L 1,2 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 recommended 1,2 1. NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V Cooper DS, et al. Thyroid.2009;9: NCCN = National Comprehensive Cancer Network. ATA = American Thyroid Association.

Thyroid Cancer is associated with aberrant cell signaling Genetic AlterationPTCFTC BRAF V600E44%0% BRAF copy gain3%35% RET/PTC (1 and 3)20%0% RAS8-10%17-45% PI3KCA mutations3%6% PI3KCA copy gain12%28% PTEN2%7% Pax8/PPARγ0%35% Total>70%>65% MAP Kinase PI3K/AKT 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 JCRicarte-Filho JC, Cancer Research 2009 Jun 1;69(11):

Cell signalling in differentiated thyroid cancer Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16: 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 KI ATP KI P Y Y ATP Activated pathway Cancer Activated Pathway Cancer VEGFR inhibition Tumor angiogenesis Tumor growth RET, BRAF….. inhibition

Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16: Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib 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 Everolimus Sirolimus Everolimus Sirolimus

Thyroid Cancer is associated with aberrant cell signaling Genetic AlterationPTCFTC BRAF V600E44%0% BRAF copy gain3%35% RET/PTC (1 and 3)20%0% RAS8-10%17-45% PI3KCA mutations3%6% PI3KCA copy gain12%28% PTEN2%7% Pax8/PPARγ0%35% Total>70%>65% MAP Kinase PI3K/AKT 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 Sorafenib 400mg 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 2009 Results: 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 Papillary Follicular/Hürthle Cell Medullary Poorly Differentiated/Anaplastic –10 –20 –30 –40 –50 –60 –70 –80 –90 –10 Change in sum of target lesion by RECIST compared to baseline (%) PDSDPR 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 NCT Off study Disease progression Crossover or continue sorafenib 400mg orally b.i.d. Randomisation (1:1) (n=380) Progression Sorafenib 400mg orally b.i.d. Placebo Investigator’s decision n=190 Primary Endpoint: PFS (RECIST) Independent review Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory 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 VEGFRBRAF PDGFRKITRETOther Sorafenib (Nexavar) FLT-3 Sunitinib (Sutent) FLT-3 Axitinib (AG ) + ++ Motesanib (AMG- 706) Pazopanib (GW786034) +++ Vandetanib (Zactima) ++ EGFR Cabozotanib (XL184) ++ C-MET Lenvatinib (E7080) ++++ FGFR

MSB 05/30/09 Targeted Agents: Phase II Clinical Data DrugKey Baseline Characteristics nPFS Months PRSDPD Sorafenib (Brose) DTC+ PDTC(90%),472038%47%2% Sunitinib (Cohen) DTC (74%); MTC (26%) % DTC 74% DTC 9% DTC Axitinib (Cohen) Papillary (50%); Medullary (18%); Follicular/Hurthle (25%/18%); Anaplastic (3%) %48%7% Motesanib (Sherman) Papillary (61%); Follicular/Hurthle (34%) %67%8% Pazopanib (Bible) PD and DTC (Progression <6months) %-- Lenvatinib (E7080, Sherman) DTC 100% %46%5%

Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16: Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib 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 Everolimus Sirolimus Everolimus Sirolimus

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-patient Dose 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 Vemurafenib 960mg BID Primary Endpoint: Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve pts Independent review Secondary Endpoints: PFS, TTP, OS, TTP, in sorafenib naïve pts BORR, CB, TTP, PFS and OS, in soraefnib exposed patients Informed Consent BRAF V600E testing + 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 NameDTC/MTCStatus Sorafenib (Nexavar)DTC First Line – International Phase III – Positive Study, Awaiting Data Presentation Lenvatinib (E7080)DTCFirst and Second Line – Phase III Vemurafenib (BRAF V600E inhibitor)DTC (PTC)First and Second Line Phase II – (Phase III?) Everolimus+SorafenibDTCSecond Line – Phase II CabozantinibDTC First Line – Phase I complete First Line and Second Line Phase II– Pending Pioglitazone (PPARγ)DTC (FTC*)First and Second Line - Phase II Pazopanib (GW786034)DTCFirst and Second line – Phase II Done Sunitinib (Sutent)DTCFirst 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

References 1.Giuffrida D, Prestifilippo A, et al; Journal of Oncology Volume 2012, Article ID , “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 (10): ; “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