Promising New Treatments for Metastatic Differentiated and Medullary Thyroid Cancer. Marcia Brose MD PhD

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1 Promising New Treatments for Metastatic Differentiated and Medullary Thyroid Cancer Marcia Brose MD PhD Department of Otorhinolaryngology: Head and Neck Surgery Department of Medicine, Division of Hematology/Oncology Abramson Cancer Center The 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

2 Thyroid Cancer in the United States Thyroid cancer is the most common endocrine neoplasm.. Thyroid cancer was diagnosed in 38,000 individuals in 2008 (74% women). From 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. Thyroid Cancer: Clinical Pathology Follicular cells Differentiated Anaplastic Papillary Follicular Hurtle Cell Medullary Parafollicular cells Sporadic Familial 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

3 Differentiated Thyroid Cancer: Clinical Pathology Cancer Type Papillary Follicular Hürthle Cell Anaplastic Clinical Characteristics ~80% of thyroid cancers 10 year survival : 74-93% Constitute ~10% of thyroid cancers 10 year survival 43-94% Constitute ~4% of thyroid cancers 10 year survival: ~76% Constitute ~2% of thyroid cancers Aggressive, rapidly invasive Median survival: 4-12 months from diagnosis 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 Are C and Sasha A. Annals of Surgical Oncology. 2006; 13(4): NCCN Practice Guidelines. v Al-Rawi M. Ann R Coll Surg Engl. 2006; 88: % 80% Initial Disease Stage Predicts OVERALL SURVIVAL Stage I Stage II 75% of all tumors Survival 60% 40% 20% 0% p<0.001 Stage III Stage IV Years Jonklaas J et al. Thyroid. 2006, 16(12): % of all tumors

4 100% 80% Initial disease stage predicts OVERALL SURVIVAL Stage I Stage II 75% of all tumors Survival 60% 40% 20% 0% p<0.001 Stage III Stage IV Years Jonklass, Thyroid % of all tumors 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

5 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 NaI metabolism Promoter methylation of genes required for NaI metabolism lead to decreased expression Associated with increased signaling through MAPK pathway Standard Chemotherapy has minimal efficacy FDG-PET Predicts for survival in patients with metastatic thyroid cancer Robbins et al. JCEM. 2006, 91:498

6 Thyroid Cancer is associated with aberrant cell signaling MAP Kinase PI3K/AKT Genetic Alteration BRAF V600E BRAF copy gain RET/PTC (1 and 3) RAS PI3KCA mutations PI3KCA copy gain PTEN Pax8/PPARγ Total PTC 44% 3% 20% 8-10% 3% 12% 2% 0% >70% FTC 0% 35% 0% 17-45% 6% 28% 7% 35% >65% Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007 Targets of Kinase Inhibitors for Metastatic Thyroid Cancer Compound Name VEGFR BRAF PDGFR KIT RET EGF R Other Sorafenib (Nexavar) Imatinib (Gleevec) Sunitinib (Sutent) FLT-3 BCR- ABL FLT-3 Axitinib (AG ) Motesanib (AMG-706) Pazopanib (GW786034)

7 Targeted Agents: Phase II Clinical Data Drug Key Baseline Characteristics n PFS PR SD PD Sorafenib (Brose) Sunitinib (Cohen) Axitinib (Cohen) DTC(90%), MTC, ATC % 54% 7% DTC (74%); MTC (26%) 51-17% DTC Papillary (50%); Medullary (18%); Follicular/Hurthle (25%/18%); Anaplastic (3%) Mo 74% DTC 9% DTC 30% 48% 7% Motesanib (Sherman) Papillary (61%); Follicular/Hurthle (34%) 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 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* n=55 Gupta-Abramson, et al. J Clin Oncol (epub ahead of print) Sorafenib 400 mg BID 1º endpoints: RECIST, PFS, RR * 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.

8 Thyroid Cancer: Clinical Pathology Follicular cells Differentiated Anaplastic Papillary Follicular Hurtle Cell Medullary Parafollicular cells Sporadic Familial 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 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

9 The RET Proto-oncogene Binding of GDNF to RET activates cell proliferation, survival, and motility RET gene expression: During embryogenesis Multiple adult tissues Including thyroid In some solid tumors MTC Pheochromocytoma Differentiation Proliferation Survival 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

10 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 10-year overall survival 40% Median overall survival 3.2 years Roman et al 2005

11 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- Treatment Metastatic 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

12 Signaling pathways in MTC EGFR C-MET RET X Y1062 -P RAS BRAF PKC PLC-γ VEGF VEGFR Endothelial cell Tumor cell PI3K AKT MEK ERK Drug Multikinase inhibitor activities relevant to MTC In vitro IC 50 (nm) VEGFR1 VEGFR2 VEGFR3 RET RET/PTC3 RAF Other Axitinib PDGFR 1.7 E FGFR 46 Motesanib PDGFR 84 Pazopanib PDGFR 74 Sorafenib PDGFR 58 Sunitinib Vandetanib EGFR 500 XL C-MET 1.8 Sherman, J Clin Endocrinol Metab, 2009, p 1494

13 Motesanib: Phase II trial in MTC SD PR 81% 2% 24 wk clinical benefit rate: 51% RET negative 69% RET positive 10% Schlumberger, et al., J Clin Oncol, 2009, p 3798 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

14 Sunitinib: Phase II trials for advanced MTC N = 6 with progressive disease 0% PR, 83% SD after 12 wks Cohen, et al., ASCO 2008, abstract 6025 N = 8 with progressive disease 37.5% clinical benefit rate (PR SD 12 wks) Ravaud, et al., ASCO 2008, abstract 6058 Vandetanib: Phase II trial for metastatic inherited MTC SD cpr 63% 33% N = 30 pts 300 mg daily starting dose Adapted from Wells, ATA Symposium, 2009

15 Axitinib: Phase II trial for advanced thyroid cancers SD PR 38% 30% MTC (n=11): SD PR 27% 18% Cohen, et al., J Clin Oncol, 2008, p 4710 XL 184: Phase I trial enriched for MTC % Tumor Change # V S T, prior non-ret TKI therapy; Prior RET TKIs (V, vandetanib, M, motesanib, S, sorafenib) S T M M S V T V V^ T T Response was observed after failure of other therapies 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 days) Five patients responded at the first (Day 28) radiographic evaluation *Response is per investigator report ^Patient was on randomized vandetanib trial. # MTC patient with G469A BRAF mutation. Kurzrock, et al., ATA 2009

16 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 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.

17 Thank you!