8/20/2017. Disclosures. Systemic Therapy for Thyroid Cancer: Who, When, and Why? Objectives. Thyroid cancer epidemiology

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1 Disclosures Systemic Therapy for Thyroid Cancer: Who, When, and Why? Steven P. Weitzman, MD, FACE, ECNU The University of Texas MD Anderson Cancer Center Department of Endocrine Neoplasia and Hormonal Disorders I have no relevant financial or nonfinancial relationship(s) with the products or services described, reviewed, evaluated or compared in this presentation. This presentation includes discussion of investigational agents not approved by the US Food and Drug Administration (FDA) for use in the United States or off label use of FDA approved drugs. Objectives Thyroid cancer epidemiology Briefly review Epidemiology of thyroid cancer TSH suppressive therapy RAI use Discuss supportive treatment options which are not chemotherapy Describe the rationale behind use of multi-kinase inhibitors Present the data supporting treatment with FDA approved agents Estimated new cases 56,800 Estimated deaths 2,010 Lifetime risk of developing cancer: Approximately 1.2% of men and women will be diagnosed with thyroid cancer at some point during their lifetime Prevalence: In 2014, there were an estimated 726,646 people living with thyroid cancer in the United States SEER Cancer Stat Facts: Thyroid Cancer. National Cancer Institute. Bethesda, MD, This audience knows what is common Well diff DIFFERENTIATION Undiff All races, Differentiated thyroid cancer (DTC) Papillary thyroid cancer (PTC) 89.4% Follicular thyroid cancer (FTC) 4.6% Hürthle cell thyroid cancer (HCC) 2.0% Poorly differentiated thyroid cancer Medullary thyroid cancer (MTC) 1.7% Anaplastic thyroid cancer (ATC) 0.8% NOS 1.3% Thyroid Cancer PTC FTC HCT MTC ATC NOS FTC Minimally invasive PTC Classical Follicular FTC Widely invasive PTC Aggressive variants TISC = Trabecular-insular-solid carcinomas = PDTC TISC Necrosis absent Few mitoses Age 65 TISC Necrosis present Many mitoses Age > 65 ATC DTC makes up ~ 97% of all thyroid cancers Good PROGNOSIS Poor SEER Cancer Stat Facts: Thyroid Cancer, based on November 2016 SEER data submission, posted to the SEER web site, April National Cancer Institute. Bethesda, MD, Adapted from: Bongiovanni M, Sadow PM, Faquin WC 2009 Poorly differentiated thyroid carcinoma: a cytologic-histologic review. Adv Anat Pathol 16:

2 Standard therapies for DTC TSH Suppressive therapy Surgery Radioactive iodine (select pts) TSH suppression McGriff NJ, Csako G, Gourgiotis L, Guthrie LC, Pucino F, Sarlis NJ 2002 Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Annals of medicine 34: Haugen BR, Alexander EK, Bible KC, et al American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26: Radioiodine How radioiodine works Used since the 1940s Takes advantage of the NIS I-131 causes cell death by emission of short path-length (1 to 2 mm) beta particles The uptake of I-131 by thyroid tissue can be detected by scanning for the gamma radiation that is also emitted by the isotope Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC 2001 The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy. The Journal of Clinical Endocrinology & Metabolism 86: RAI - Uses When is RAI no longer an option? Remnant ablation Reduce risk of recurrence Treat microscopic disease Treat distant disease Reduce risk of death Does not definitively treat bulky disease Does not definitively treat skeletal metastases RAI refractory disease Disease does not take up radioiodine at known sites of disease Continued growth within months after RAI Total cumulative dose 600 mci Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ 2017 Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch Endocrinol Metab 61:

3 When is RAI no longer an option? When is RAI no longer an option? RAI refractory disease Disease does not take up radioiodine at known sites of disease Continued growth within months after RAI Total cumulative dose 600 mci RAI refractory disease Disease does not take up radioiodine at known sites of disease Continued growth within months after RAI Total cumulative dose 600 mci Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ 2017 Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch Endocrinol Metab 61: Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ 2017 Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch Endocrinol Metab 61: RAIR disease What s next? RAI refractory disease Watchful waiting Localized therapies Systemic or targeted therapies Watchful waiting Watchful waiting Haugen BR, Alexander EK, Bible KC, et al American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26: Haugen BR, Alexander EK, Bible KC, et al American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:

4 Distant disease or locally advanced disease Stage at diagnosis and survival rates Weitzman SP, Cabanillas ME 2015 The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res 7: SEER Cancer Stat Facts: Thyroid Cancer. National Cancer Institute. Bethesda, MD, When are distant mets discovered in DTC? Localized treatments 1-4% at the time of diagnosis 7-23% develop distant metastases during their disease course Sites of metastasis: Lung > Bone < 45 yo 45 yo Surgery Radiation EtOH ablation Cryoablation Embolization Shoup M, Stojadinovic A, Nissan A, et al Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. Journal of the American College of Surgeons 197: Zolendronic acid - DTC Zolendronic acid - DTC Orita Y, Sugitani I, Toda K, Manabe J, Fujimoto Y 2011 Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma. Thyroid 21:31-35 Orita Y, Sugitani I, Toda K, Manabe J, Fujimoto Y 2011 Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma. Thyroid 21:

5 Anti-resorptive therapy - MTC Criteria for starting systemics Fewer patients in the AR+ group developed 1 SREs when compared with patients in the ARgroup (25% vs 42%, P=0.026) The beneficial effect of ARs on SREs development remained significant after adjusting for age, gender, and distant non-bone metastases (P=0.047) In addition, fewer patients in the AR+ group developed a subsequent BM compared with the AR- group (59% vs 84%, P=0.005) All other options have been exhausted and good PS ECOG = Eastern Cooperative Oncology Group Xu JY, Murphy WA, Jr., Milton DR, et al Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma. J Clin Endocrinol Metab 101: Xu J, Murphy Jr WA, Milton DR, et al. Medullary Thyroid Cancer with Bone Metastases and the Effect of Antiresorptive Agents on Skeletal Related Events: Experience at MD Anderson Cancer Center [abstract LB-OR02-3]. Endocrine Reviews Volume 37, Issue 2 Supplement, April Criteria for starting systemics Considering systemics? All other options have been exhausted and good PS Clinically significant rapidly progressive disease Disease threatening critical structures Symptomatic disease which cannot be managed with local therapies You have assessed: Cross sectional imaging (CT/MRI/PET) Rate of progression Risks versus benefits of systemic therapy Considering systemics? Is it rapidly progressing? Haugen BR, Alexander EK, Bible KC, et al American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:

6 RECIST v 1.1 Target lesion response Considering systemic therapy? Receptor tyrosine kinase Development of thyroid cancer RAS tipifarnib BRAF dabrafenib vemurafenib sorafenib MEK selumetinib trametinib cobimetinib mtor everolimus temsirolimus Xing M 2013 Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13: Cabanillas ME, Habra MA 2016 : Role in thyroid cancer and other solid tumors. Cancer Treatment Reviews 42: Multi-kinase inhibitors Anti-angiogenic kinase inhibitors The specific kinase targets vary The drug IC 50 varies between drugs and between different kinases Formation of new blood vessels Vascular Endothelial Growth Factor (VEGF) Weitzman SP, Cabanillas ME 2015 The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res 7: Angiogenesis, nd. Retrieved from 6

7 2 approved drugs for RAIR DTC Sorafenib Sorafenib Approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment DECISION trial (sorafenib versus placebo) DECISION trial (sorafenib versus placebo) DECISION (study of sorafenib in locally advanced or metastatic patients with radioactive Iodine refractory thyroid cancer) Multicenter, randomized, double-blind, placebocontrolled phase 3 trial RAIR DTC with progression in 14 months Placebo pts could cross over if progress Enrolled and randomized 419 pts (2 randomized twice and excluded) Brose MS, Nutting CM, Jarzab B, et al Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384: Sorafenib Sorafenib NO difference in OS (overall survival) Complicated by cross-over Objective response rate all PRs 12.2% vs 0.5% (p<0.0001) Disease control rate PR + SD x 6 mo 54.1% vs 33.8% (p<0.0001) 7

8 Sorafenib Approved by the FDA in 2015 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment Serious AEs 37.2% sorafenib 26.3% placebo SELECT trial (lenvatinib versus placebo) Study of (E7080) in Differentiated Cancer of the Thyroid Multicenter, international, randomized, doubleblind, placebo-controlled phase 3 trial RAIR DTC with progression in 12 months Allowed 1 prior TKI Placebo pts could cross over if progressed 392 pts were randomized and all included in intention to treat analysis Figure 2. Kaplan Meier Estimate of Progression-free Survival in the Intention-to-Treat Population. Schlumberger M, Tahara M, Wirth LJ, et al versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372: NO difference in OS (overall survival) Complicated by cross-over LEN PLAC OR DCR = CR+PR+SD Clinical benefit rate = CR+PR+durable SD 8

9 There were 118 deaths (about 75% due to progression in both arms) In the lenvatinib arm, there were 20 pts (7.7%) who died as a result of an drug AE 6 deaths (2.3%) were thought to be drug related. In placebo arm there were 6 pts (4.6%) who died as a result of drug AE. None were considered treatment related. Brose MS, Worden FP, Newbold KL, Guo M, Hurria A. Effect of Age on the Efficacy and Safety of in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial. Journal of Clinical Oncology.0(0):JCO Brose MS, Worden FP, Newbold KL, Guo M, Hurria A. Effect of Age on the Efficacy and Safety of in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial. Journal of Clinical Oncology.0(0):JCO approved drugs for MTC Vandetanib Vandetanib Cabozantinib Approved by the FDA in 2011 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment 9

10 Vandetanib ZETA study Approved by the FDA in 2013 for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Only prescribers and pharmacies certified through the Vandetanib Risk Evaluation Mitigation Strategy Program, a restricted distribution program, are able to prescribe and dispense vandetanib. Vandetanib (ZD6474) Zactima Efficacy in Thyroid Cancer Assessment Multicenter, international, randomized, doubleblind, placebo-controlled phase 3 trial Measurable, unresectable locally advanced or metastatic, hereditary or sporadic MTC Placebo pts could cross over if progressed Wells SA, Jr., Robinson BG, Gagel RF, et al Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30: Vandetanib Vandetanib Median PFS Vandetanib Weibull model predicted 30.5 months HR 0.46; p<0.001 Placebo = 19.3 months Cabozantinib Approved by the FDA in 2012 for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 10

11 EXAM trial Cabozantinib Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer Multicenter, international, randomized, double-blind, placebo-controlled phase 3 trial Unresectable, locally advanced, or metastatic MTC Patients were required to have radiographic disease progression per modified Response Evaluation Criteria in Solid Tumors (mrecist) within the prior 14 months. Placebo pts could NOT cross over if progressed Elisei R, Schlumberger MJ, Müller SP, et al Cabozantinib in Progressive Medullary Thyroid Cancer. Journal of Clinical Oncology 31: Compared to Vandetanib 30.5 months and Placebo 19.3 months Cabo or Vande?? Weitzman SP, Cabanillas ME 2015 The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res 7: Systemic Therapy for Thyroid Cancer Summary Reviewed the epidemiology of thyroid cancer Discussed use of RAI and TSH suppressive therapy Clarified the role of localized therapies Explained the use of systemic therapies 4 FDA approved drugs Data supporting their use Side-effect profile If you cannot use one of the approved treatments, it is recommended to refer the patient to a clinical trial In a separate talk I will present: Patient cases Alternative therapies Off label and novel therapies 11