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New Approaches in the Treatment for the Advanced Thyroid Cancer Sun Wook Kim, MD PhD Division of Endocrinology and Metabolism, Sungkyunkwan University.

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Presentation on theme: "New Approaches in the Treatment for the Advanced Thyroid Cancer Sun Wook Kim, MD PhD Division of Endocrinology and Metabolism, Sungkyunkwan University."— Presentation transcript:

1 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 1

2 Objectives Conventional treatment in advanced thyroid cancers (differentiated thyroid cancers, DTCs) Genetic alterations in DTCs RECIST Newer molecular targeted therapies 2

3 Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosis 3

4 Classification of Thyroid Cancers Parafollicular cells Follicular cells Differentiated Medullary Follicular Anaplastic (Undifferentiated) Papillary Hürthle Sporadic (80%) Hereditary (20%) 4

5 Classification of Thyroid Cancers Cancer typeClinical 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 5

6 Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosis 6

7 Initial disease stage predicts overall survival in patients with DTC 01084621214 100 80 60 40 20 0 Survival (%) Years 75% of all tumours 25% of all tumours Jonklaas J, et al. Thyroid 2006;16:1229–42 Stage II Stage III Stage IV Stage I p<0.001 7

8 18 FDG 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 8

9 FDG Uptake Is a Marker of Resistance to 131 I 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 Robbins RJ, et al. J Clin Endocrinol Metab. 2006 RAI + FDG - RAI- FDG - RAI + FDG + RAI - FDG + - - - 9

10 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies 10

11 Therapeutic modalities for RAI refractory recurrent DTCs IndicationProsCons SurgerySurgically resectable local recurrences or metastatectomy Potential for curePotential 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 RFALocally 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 Busaidy and Cabanillas et al. J Thy Res 2012 11

12 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 Thus, patients with progressive DTC have had an unmet clinical need for over three decades 12

13 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies 13

14 Thyroid cancer is associated with aberrant cell signaling MAP kinase PI3K/AKT Genetic alteration Papillary thyroid cancer (%) Follicular thyroid cancer (%) B-Raf V600E44─45%0 B-Raf copy gain335 RET/PTC (1 and 3)~200 RAS~1040–50 PI3KCA mutations3<10 PI3KCA copy gain1228 PTEN2<10 Pax8/PPARγ035 Total>70>65 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 14

15 Cell signalling in differentiated thyroid cancer Graphic adapted from Keefe 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 15

16 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies 16

17 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 17

18 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 18

19 19

20 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCs RECIST Newer molecular targeted therapies 20

21 Kinase inhibitor activities relevant to advanced thyroid carcinomas IC50(nm) DrugVEGFR1VEGFR2VEGFR3RETBRAFOther targets Sorafenib9020496 Sunitinib291741 Motesanib23659PDGFR, C-KIT Vandetanib40110100EGFR Lenvatinib(E7080)224535PDGFR, FGFR-1 Axitinib1.20.250.29 Pazopanib103047PDGFR, C-KIT Schlumberger and Sherman, 2012 Eur J Endocrinology 21

22 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 22

23 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 23

24 Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial Leboulleux S et al, 2012 Lancet Oncol 11.1 (vandetabnib) vs 5.8 (placebo) mos. (HR=0.63, 95% CI 0.43-0.92) (P=0.008) 24

25 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% 25

26 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. 26

27 Axitinib Phase II (5mg twice daily) in 45 DTCs - PR: 14 - SD: 19 2 nd phase II is ongoing (NCT00389441) 27

28 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% 28

29 Sorafenib Reported in four phase II trials (400mg bid) DrugsYearnPR(%)SD>6 mo.(%) PFS, median Dose reduction for toxicity (%) Sorafenib20083023532047 Sorafenib200941 PTC15561552 Sorafenib200932253413.566 Sorafenib2011191882>2479 Better in PTCs, on lung than on bone metastses and among PTCs, with BRAF mutation Also, active in children with PTC 29

30 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 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 th erapy, chemotherap y or thalidomide Eligibility Criteria: Locally advanced or metastatic DTC Progression within 14 months RAI refractory No prior targeted th erapy, chemotherap y or thalidomide Placebo Randomisation (1:1)(n=380) Sorafenib 400 mg PO BID www.clinicaltrials.gov. NCT00984282 30

31 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) 31

32 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 32

33 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. 33

34 Thank you Greetings from South Korea 34


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