New Approaches in the Treatment for the Advanced Thyroid Cancer Sun Wook Kim, MD PhD Division of Endocrinology and Metabolism, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Objectives Conventional treatment in advanced thyroid cancers (differentiated thyroid cancers, DTCs) Genetic alterations in DTCs RECIST Newer molecular targeted therapies

Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosis First, let me begin with short background story. DTC accounts more than 90% of all thyroid cancers and therapeutic approach will be quite different from DTC and other type of thyroid cancers. Today’s talk for newer therapies will be focused on advanced DTC.

Classification of Thyroid Cancers Parafollicular cells Follicular cells Differentiated Medullary Follicular Anaplastic (Undifferentiated) Papillary Hürthle Sporadic (80%) Hereditary (20%) As you know, Differentiated thyroid cancer is originated from follicular cells and it’s biologic behavior is different from anaplastic or undifferentiated carcinoma Or Medullary carcinoma which is derived from parafollicular C cells.

Classification of Thyroid Cancers 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: 4–5 months from diagnosis Differentiated DTC is comprised of papillary, follicular and hurthl cell cancers. It accounts for more than 90% of all thyroid cancers with variable prognosis with 50% to 95% 10 year survival rate.

Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosis Second background is that RAI refractory DTCs have poor prognosis.

Initial disease stage predicts overall survival in patients with DTC Stage I 100 80 60 40 20 75% of all tumours Stage II Stage III Survival (%) 25% of all tumours Although over 75% of DTCs do well after conventional treatment comprised of surgery, RAI and TSH suppression, 25% of DTC do not respond to conventional therapy and shows poor prognosis. Stage IV p<0.001 10 8 4 6 2 12 14 Years Jonklaas J, et al. Thyroid 2006;16:1229–42

18FDG PET-CT Approved for detection of occult thyroid cancer when serum thyroglobulin>10ng/ml and negative RAI scan (Sensitivity 60-95%, specificity 50-90% accuracy 75%) Flip-flop phenomenon between FDG and RAI uptake In these patients with advanced DTC, FDG-PET has a crucial role in the diagnosis and evaluation of prognosis. It is approved for detection of occult thyroid cancer when thyroglobulin is over 10ng/ml and RAI scan is negative. Its sensitivity is around 68%, specificity 82% and overall accuracy is around 75%. There is a flip – flop phenomenon between FDG and RAI uptake.

FDG Uptake Is a Marker of Resistance to 131I Treatment and of Poor Prognosis Estimated 60 months survival RAI +, FDG -: 95% RAI -, FDG +: 45% RAI +, FDG +: 45% Presence of FDG uptake is related to Age >40 years Large metastases Poorly differentiated or papillary/follicular disease with necrosis and mitosis RAI- FDG - - - - RAI + FDG - - - - RAI - FDG + - - - RAI + FDG + Thus FDG uptake in the metastatic lesion is a marker of resistance to RAI treatment and poor prognosis. You can see in this figure that if FDG uptake is positive, the overall prognosis is poor regardless of RAI uptake and it reached about 50% 5YSR compare to 95% when FDG uptake was negative. These patients with FDG positive will be the patients who needs novel therapeutic modalities. Robbins RJ, et al. J Clin Endocrinol Metab. 2006

Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies

Therapeutic modalities for RAI refractory recurrent DTCs Indication Pros Cons Surgery Surgically resectable local recurrences or metastatectomy Potential for cure Potential significant morbidity External beam radiation Adjuvant: neck Therapeutic and palliative: metastatic sites Decrease in recurrences, progression and pain May preclude future neck surgery; dysphagia and xerostomia; secondary malignancy PEIT and RFA Locally recurrent disease in patients at high risk for morbidity and mortality from surgery Potential for avoidance of surgery Local pain; injury to local structure; unknown effect on survival and recurrence Systemic chemotherapy Unresectable, RAI-refractory, metastatic disease May slow progression of disease; may alleviated disease symptom Significant adverse events; unknown effect on survival There are 4 conventional modalities which have each pros and cons. First, Surgical resection is indicated in resectable local recurrence and metastasis for cure but accompanies potential morbidity caused by surgery. External Beam radiation therapy is indicated as adjuvant setting after surgery or palliative to metastatic site. It may decrease recurrences, progression and pain but may preclude future surgery and associated with dysphagia, xerostomia and secondary malignancy. PEIT or RFA is for local treatment when the patients’ condition does not allow surgical approach. However, its effect on overall survival is unknown. Finally, systemic chemotherapy can be considered in unresectable , RAI refractory disease in the hope that it may slow progression and alleviate symptoms but accompanies significant side effects. Busaidy and Cabanillas et al. J Thy Res 2012

FDA approval of doxorubicin for treatment of metastatic thyroid cancer (1974) Matuszczyk A, et al. Horm Metab Res 2008 Epithelial origin, 5% PR FDA = Food and Drug Administration; PR = partial response For chemotherapeutic approach, FDA approved doxorubicin for treatment of DTC in 1974. However, it has very low response rate around 5%. Thus patients with progressive DTC have had unmet clinical need for over three decades. Thus, patients with progressive DTC have had an unmet clinical need for over three decades

Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies

Thyroid cancer is associated with aberrant cell signaling Genetic alteration Papillary thyroid cancer (%) Follicular thyroid cancer (%) B-Raf V600E 44─45% B-Raf copy gain 3 35 RET/PTC (1 and 3) ~20 RAS ~10 40–50 PI3KCA mutations <10 PI3KCA copy gain 12 28 PTEN 2 Pax8/PPARγ Total >70 >65 MAP kinase PI3K/AKT Most common genetic alterations in Papillary thyroid cancer are point mutations of BRAF and RAS and rearrangement of RET proto-oncogene. In follicular cancers, mutations in RAS and rearrangement of the PPARr and PAX8 genes are common changes. These genetic changes involves MAP Kinase pathway or PI3K/AKT pathways and gives us a basis for using molecular drugs targeting these pathways. Nikiforov YE. Mod Path 2008;21 Suppl 2:S37–43 Xing M. Endocr Relat Cancer 2005;12:245–62 Wang HM, et al. Ann Surg Oncol 2007;14:3011–8

Cell signalling in differentiated thyroid cancer Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Ras Ras B-Raf PI3K Raf PI3K AKT MEK AKT MEK mTOR ERK mTOR ERK Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer. S6K S6K • Growth • Survival • Proliferation • HIF1a • Inhibition of apoptosis • Migration • Growth • Survival • Proliferation • Migration • Angiogenesis Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.

Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies

RECIST (1) Response Evaluation Criteria In Solid Tumors Defines when cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progression") during treatments. Published in February, 2000 by an international collaboration EORTC, NCI of US and NCI of Canada Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progression") during treatments. The criteria were published in February, 2000 by an international collaboration including the European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group.

RECIST (2) Eligibility - Only patients with measurable disease at baseline (longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan) Response Criteria - CR: disappearance of target lesion - PR: >30% decrease in longest diameter of target - SD: neither PR nor PD - PD: >20% increase in longest diameter of target or appearance of one or more new lesions Frequency of tumor re-evaluation - usually every other cycle (6-8 weeks) is reasonable

사진작가들의 꿈의 장소: spirit island in Maligne lake

Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies Finally, let’s review about Newer molecular targeted therapies

Kinase inhibitor activities relevant to advanced thyroid carcinomas IC50(nm) Drug VEGFR1 VEGFR2 VEGFR3 RET BRAF Other targets Sorafenib 90 20 49 6 Sunitinib 2 9 17 41 Motesanib 3 59 PDGFR, C-KIT Vandetanib 40 110 100 EGFR Lenvatinib(E7080) 22 4 5 35 PDGFR, FGFR-1 Axitinib 1.2 0.25 0.29 Pazopanib 10 30 47 Sorafenib, sunitinib, motesanib, vandetanib and lenvatinib is multikinase inhibitors that share the ability of inhibiting RET and VEGFR along with other kinases. It have been used in advanced DTCs with the aim of inhibiting MAPK and angiogenesis. In contrast, the main role of axitinib and pazopanib see to act only in antiangiogenic effect. Schlumberger and Sherman, 2012 Eur J Endocrinology

Motesanib (AMG 706) First large, international trial for progressive DTC was a phase II study of motesanib (125mg/day) on 93 patients - PR: 13 (14%) - SD: 33 (35%) (>24 weeks) - PFS (Progression Free Survival) : 40 weeks

Vandetanib Randomized phase II in 145 patients with refractory DTC treated with vandetanib (300mg/day) vs placebo on PFS Objective tumor response rate: <5% in vandetanib group PFS: 11.1 mos (vandetabnib) vs 5.8 mos (placebo) (HR=0.63, 95% CI 0.43-0.92) Leboulleux S et al, 2012 Lancet Oncol

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial 11.1 (vandetabnib) vs 5.8 (placebo) mos. (HR=0.63, 95% CI 0.43-0.92) (P=0.008) Leboulleux S et al, 2012 Lancet Oncol

Sunitinib First phase II (37.5mg qd) in 28 DTC patients with FDG-avid disease on FDG-PET scan - One CR, 7 PR and 14 SD - Decrease in FDG uptake at 7 days of medication predicts better response to therapy Second phase II with 31 DTCs with progressive disease (50mg/day 4wks, 2wks off) - PR 13% - SD 68%

Lenvatinib (E7080) Phase II (24mg of lenvatinib) in 58 DTCs - PR 45% (53% of naïve patients and 42% of pretreated patients) - SD 46% - PFS (median) 13.3 mos - Dose reduction 39% - Withdrawal 29% Phase III comparing the effect of lenvatinib vs placebo on PFS in progressive refractory DTC is on-going.

Axitinib Phase II (5mg twice daily) in 45 DTCs - PR: 14 - SD: 19 2nd phase II is ongoing (NCT00389441)

Pazopanib Multi-targeted TKI (VEGFR, PDGFR and c-Kit) Approved for renal cell cancer and soft tissue sarcoma in USFDA Phase II (800mg daily) in 37 DTCs - PR 49%

Dose reduction for toxicity (%) Sorafenib Reported in four phase II trials (400mg bid) Drugs Year n PR(%) SD>6 mo.(%) PFS, median Dose reduction for toxicity (%) Sorafenib 2008 30 23 53 20 47 2009 41 PTC 15 56 52 32 25 34 13.5 66 2011 19 18 82 >24 79 Effect of sorafenib was reported in 4 phase II trials. First trial included 30 patients with advanced thyroid cancer. 75% showed Partial response or stable disease and progression free survival was 20 month. In another trial with 41 PTC patients, also about 70% showed partial response or stable disease. In a third trial in 32 patients, 25% PR and 34% SD was observed. In a fourth trial, 3 patients showed PR and the rest showed stable disease. However, half of the patients in all trial need to reduce the dose because of toxicity. Efficacy of sorafenib seems better on lung than bone metastases and with BRAF mutation. Sorafenib also proved to be active in children with DTC. Better in PTCs, on lung than on bone metastses and among PTCs, with BRAF mutation Also, active in children with PTC

Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial Comparing the effect of sorafenib vs placebo on PFS in treatment of naïve patients with RAI refractory, progressive metastatic DTC Crossover or Continue Sorafenib 400 mg PO BID Progression Off Study Doctor’s Decision Disease Progression Eligibility Criteria: Locally advanced or metastatic DTC Progression within 14 months RAI refractory No prior targeted therapy, chemotherapy or thalidomide Placebo Randomisation (1:1) (n=380) Sorafenib 400 mg PO BID There is on-going DECISION trial which finished enrollment. DECISION is phase III study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancers It is going to compare the effect of sorafenib vs placebo on PFS in the patients with RAI refractory progressive DTCs. It finished enrollment of 380 eligible patients and on-going. In case of progression in patients on placebo, they can be switched to sorafenib treatment according to physicians decision. www.clinicaltrials.gov. NCT00984282

Agents to restore RAI uptake 13 cis-retinoic acid Bexarotene (synthetic agonist of RXR) Rosiglitazone Selumetinib (AZD6244) - MEK ½ inhibitor - 11(65%) of 17 RAI refractory DTC restored RAI uptake - 6/7(86%) had PR to RAI (only in patients whose information on best response was available)

Side effects of molecular targeted therapies Fatigue, Hypertension, Anorexia, Diarrhea Cytopenia, Skin toxicities - Dose reduction in 11-73% - Withdrawal in 7-25% Serum TSH should be monitored - T4 dose increase is needed sometimes Cutaneous squamous cell cancers and keratoacanthomas in up-to 21% of patients treated with BRAF inhibitors

Take home messages Patients with advanced DTC require novel therapies and should be considered in prospective trials of molecular targeted agents when the disease burden is large and when progression has been documented. DECISION (sorafenib) and Phase III E7080 trial will provide evidence that kinase inhibitors are more effective in patients with DTC with metastatic disease refractory to RAI treatment.

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