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Advances in the management of iodine-refractory thyroid cancers

Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870. Advances in the management of iodine-refractory thyroid cancers. Marcia Brose MD PhD Department of Otorhinolaryngology: Head and Neck Surgery

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Advances in the management of iodine-refractory thyroid cancers

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  1. Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 Advances in the management of iodine-refractory thyroid cancers 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

  2. Disclosure Elements • My goal is to present information on several agents currently under investigation for the treatment of advanced thyroid. As none of the agents other than doxorubicin and vandetanib and cabozantinib are FDA approved for the use in thyroid cancer, the rest of the new agents that will be discussed here are in clinical trials (not FDA approved) at this time. • Marcia S. Brose MD PhD

  3. DISCLOSURE: In the last three years I have financial interest/arrangement or affiliation with: Name of Organization Relationship Bayer Healthcare research funding, honorarium Onyx research funding, honorarium Novartis research funding, Exelixis research funding honorarium Astrazeneca consulting Bristol-Myers Squibb consulting Genentech/Roche research funding

  4. Thyroid Cancer: Clinical Pathology Papillary Follicular Hurtle Cell Differentiated Anaplastic Follicular cells Sporadic Familial Medullary Parafollicular cells American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins. 2005. MSB 05/30/09

  5. 2.1-5.0cm >5.0cm Thyroid cancer in the United States 0-1.0cm 1.1-2.0cm Davies, JAMA 2006 295:2164

  6. Differentiated Thyroid Cancer

  7. Thyroid Cancer: Treatment Strategy • High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm) • Total Thyroidectomy • RAI (131I) 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

  8. RAI-Refractory Disease • 25-50% of Metastatic Thyroid Cancers loose ability to take up Iodine • This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism • In other words, the cancer cells “forget” how to take up iodine and so they are immune to the treatment.

  9. RAI-refractory disease • Standard Chemotherapy has minimal efficacy. 1974 Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer. • No longer used because recent data shows response is 5% • High toxicity in patient with otherwise good QOL Cooper DS, et al. Thyroid. 2009;9:1176-214. Hodak SP, Carty SE. Oncology. 2009;23:775-6. Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.

  10. Thyroid Cancer is associated with aberrant cell signaling MAP Kinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

  11. 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.

  12. Targeting cell signaling in thyroid cancer Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Motesanib Sorafenib Sunitinib Vandetanib XL-184 Vandetanib Ras Ras PI3K B-Raf PI3K Raf AKT Sorafenib Sorafenib MEK AKT MEK mTOR mTOR Everolimus Sirolimus ERK ERK Everolimus Sirolimus 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.

  13. UPCC 03305: Sorafenib in Advanced Thyroid Cancer February 2006-February 2011 Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • Evidence of PD within 6 months of study entry • ECOG 0–2 • Good organ and bone marrow function Primary endpoints • RECIST • PFS • Response rate n=55 Sorafenib400mg b.i.d. b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9

  14. Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory 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) Sorafenib400mg orallyb.i.d. Progression n=190 Investigator’s decision Placebo Crossover or continue sorafenib 400mg orally b.i.d. Offstudy n=190 Disease progression Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory Biomarkers Primary Endpoint: PFS (RECIST) Independent review Met primary endpoint January 2013 www.clinicaltrials.gov. NCT00984282

  15. Targets of Kinase Inhibitors

  16. Summary DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways Iodine-refractory patients have an average survival of 3 years Phase III study of sorafenib in this patient population is positive. Results are expected at ASCO 2013. Results of phase II trials with lenvatinibhave led to the initiation of a phase III trials for patients with RAI-refractory DTC Additional MKIs are also now in development many of which target VEGFR2, but also mTOR, MEK, and BRAF

  17. Advanced Thyroid Cancer’s New Unmet Need: Progression on Sorafenib/VEGFR2 inhibitor • Patients progress but maintain good performance status • Most patients respond then progress in a new lesion or a subset of lesions What to do? • We need additional treatment options

  18. Targeting cell signalling in thyroid cancer Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Motesanib Sorafenib Sunitinib Vandetanib XL-184 Vandetanib Ras Ras PI3K B-Raf PI3K Raf AKT Sorafenib Sorafenib MEK AKT MEK mTOR mTOR Everolimus Sirolimus ERK ERK Everolimus Sirolimus 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.

  19. UPCC 19309: Everolimus + Sorafenib for DTC patients who progress on Sorafenib alone Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • PD on sorafenib • ECOG 0–2 • Good organ and bone marrow function Sorafenib + Everolimus Intra-patient Dose escalation Primary endpoints • RECIST • PFS • Response rate n=35 22 patients accrued so far b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal

  20. NO25530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor RO5185426 in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive forthe BRAF V600 Mutation and Resistant to Radioactive Iodine First Line Sorafenib Naïve (n=25) Eligibility criteria: • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory RO5185426BID + Informed Consent BRAF V600E testing Second Line Prior Sorafenib (n=15+) + • Secondary Endpoints: • PFS, TTP, OS, TTP, in sorafenib naïve pts • BORR, CB, TTP, PFS and OS, in soraefnib exposed patients Status: Accrual Complete Primary Endpoint: Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve pts Independent review

  21. Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced DTC

  22. ASCO 2012: Selumetinib: MEK inhibition to increase RAI uptake (Ho et al) Going forward as an earlier treatment: Use for patients with high risk disease to increase uptake, Unclear where in the treatment paradigm this will end up.

  23. Summary Second Line Agents • Due to tumor heterogeneity, a patient with progression on a multikinase inhibitor may continue to derive benefit from that inhibitor • Combination or Sequential treatments with MKIs (sorafenib + everolimus, or sorafenib + vemurafenib) are likely to aid patients with progression • New agents in development that specifically target mutations (BRAF V600E) may also play a role in the treatment of thyroid cancer in the first or second line settings and carry the most promise

  24. Medullary Thyroid Cancer

  25. Signaling pathways in MTC X C-MET EGFR VEGFR VEGFR PLC-g RET -P PKC Endothelial cell RAS Y1062 BRAF VEGF MEK PI3K Tumor cell AKT ERK

  26. Multikinase inhibitor activities relevant to MTC Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494

  27. ZETA Study: VandetanibSignificantly Prolonged PFSa vs Placebo PFS: 65% Relative Reduction in Risk of Progression1 ▬▬ CAPRELSA 300 mg ▬▬Placebo Events/Patients 59/231 41/100 1.0 0.75 0.50 0.25 HR=0.35 (95% CI: 0.24-0.53)P<0.0001 0.0 CI=confidence interval; HR=hazard ratio. aPFS is defined as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria In Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.2 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.11. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2. Wells SA Jr et al. J Clin Oncol. 2012;30(2):134-141.

  28. Cabozantinib Ph III in MTCProgression Free Survival by IRC p < 0.0001 • Significant difference in tumor response rate • 28% in cabozantinib vs. 0% placebo; p<0.0001 • Median duration of response: 14.6 months ASCO 2012 oral presentation

  29. Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced MTC

  30. Summary: Agents for MTC • Phase II data shows that several multikinase inhibitors are clinically active in patients with advanced Differentiated and Medullary thyroid cancer. • Vandetanib was approved last year and Cabozantinib just received FDA approval for MTC • Response in these patients result in prolonged disease control • Additional agents are needed as these agents last only 10-12 months, there is a great unmet need to identify additional agents for this disease.

  31. Summary: Targeted therapy for Advanced Thyroid Cancer • Where do we go from here? • Completion of large randomized trials: • Phase III of sorafenib is positive. Phase III of lenvatinib is underway. • More data on the activity of the targeted agents used sequentially: • Sopatients are to benefit from the number of agents available • Novel strategies for treatment bear investigating: • including novel targets and the use of combination therapies to improve outcome.(Sor+Ev, Sor+ Vem) • Further subgroup analysis to identify subpopulations: • use of clinical and molecular markers to identify patients that may benefit better with some therapies over others. Pts with Ras mutations, Poorly differentiated TC • Registration trial for sorafenib in MTC!!!

  32. Agents currently available in our Thyroid Cancer Therapeutics Program

  33. Thyroid Cancer Interest Group Susan Mandel MD Ara Chalian MD Kelly Malloy MD Douglas Fraker MD Robert Lustig MD Virginia LiVolsi MD ZubairBaloch MD MSB is a Damon Runyon-Siemens Clinical Investigator Many Community Endocrinologists that have referred their patients, and the patients that have agreed to participate in our trials. Brose Group Carolyn Grande RN, CRNP Steve Keefe MD Thelma McClosky Tatyana Kuznetsova, PhD Waixing Tang MD Stephen Stopenski Thyroid Cancer Clinical Trials Unit Larisa Zifchak RN Parna Prajapati RamkrishnaMakani Jillilan Stanley Experimental Therapeutics Program Andrea Troxel PhD Peter O’Dwyer MD Pathology/Imaging Michael Feldman MD PhD Laurie Loevner MD University of PennsylvaniaThyroid Cancer Therapeutics Program

  34. Questions? Marcia S. Brose MD PhD Email: Marcia.Brose@uphs.upenn.edu Telephone: 215-615-6519 Thank you for your courage and attention!

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