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New Approaches in the Treatment for the Advanced Thyroid Cancer

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

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New Approaches in the Treatment for the Advanced Thyroid Cancer

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  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

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

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

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

  5. Classification of Thyroid Cancers Differentiated

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

  7. 0 2 4 6 8 10 12 14 Initial disease stage predicts overall survival in patients with DTC Stage I 100 80 60 40 20 0 75% of all tumours Stage II Stage III Survival (%) 25% of all tumours Stage IV p<0.001 Years Jonklaas J, et al. Thyroid 2006;16:1229–42

  8. 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

  9. 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 + Robbins RJ, et al. J ClinEndocrinolMetab. 2006

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

  11. Therapeutic modalities for RAI refractory recurrent DTCs Busaidy and Cabanillas et al. J Thy Res 2012

  12. FDA approval of doxorubicin for treatment of metastatic thyroid cancer (1974) Epithelial origin, 5% PR Thus, patients with progressive DTC have had an unmet clinical need for over three decades FDA = Food and Drug Administration; PR = partial response Matuszczyk A, et al. HormMetab Res 2008

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

  14. Thyroid cancer is associated with aberrant cell signaling MAP kinase PI3K/AKT Nikiforov YE. Mod Path 2008;21 Suppl 2:S37–43Xing M. EndocrRelat Cancer 2005;12:245–62Wang HM, et al. Ann SurgOncol 2007;14:3011–8

  15. Cell signalling in differentiated thyroid cancer Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Ras Ras PI3K B-Raf PI3K Raf AKT MEK AKT MEK mTOR mTOR ERK ERK 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.

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

  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

  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

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

  20. Kinase inhibitor activities relevant to advanced thyroid carcinomas Schlumberger and Sherman, 2012 Eur J Endocrinology

  21. 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. 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. 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

  24. 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. 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 lenvatinibvs placebo on PFS in progressive refractory DTC is on-going.

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

  27. 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. Sorafenib • Reported in four phase II trials (400mg bid) • Better in PTCs, on lung than on bone metastses and among PTCs, with BRAF mutation • Also, active in children with PTC

  29. Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial • Comparing the effect of sorafenibvs placebo on PFS in treatment of naïve patients with RAI refractory, progressive metastatic DTC Eligibility Criteria: • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory • No prior targeted therapy, chemotherapy or thalidomide Randomisation (1:1)(n=380) Progression Sorafenib400 mg PO BID Doctor’s Decision Crossover or Continue Sorafenib 400 mg PO BID OffStudy Placebo Disease Progression www.clinicaltrials.gov. NCT00984282

  30. 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. 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. 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. Thank you Greetings from South Korea

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