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Targeted therapy in thyroid cancer

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  1. TARGETED THERAPY IN THYROID CANCER DR. R. RAJKUMAR M.D., D.M. MEDICAL ONCOLOGIST GURU HOSPITAL
  2. THYROID CANCER CLINICAL PATHOLOGY 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. Parafollicular cells Follicular cells Differentiated Anaplastic Medullary Papillary Follicular Hurtle Cell Sporadic Familial
  3. US EU Japan Estimated Thyroid Cancer Incidence in 2008 0 5000 10000 15000 20000 25000 30000 35000 40000 AnnualIncidence LA/C ~37,000 ~33,000 ~18,000 ~6,000 GLOBAL INCIDENCE OF THYROID CANCR LA/C = Latin America and Caribbean. 1. GLOBOCAN 2008, International Agency for Research on Cancer. http://globocan.iarc.fr/. 2. Sherman. Lancet. 2003;361:501-511. 3. Eustatia-Rutten et al. J Clin Endocrinol Metab. 2006;91:313-319. • Thyroid cancer is the most common form of endocrine malignancy1 • DTC represents > 90% of all thyroid carcinomas2 • The prognosis of patients with DTC is generally good due to tumor biology and efficacy of the initial surgery and 131I therapy3
  4. DIMENSIONS OF THE PROBLEM • Increasing in incidence – 95% sporadic or RT-induced, 5% familial • 3.5 to 4:1 female to male gender distribution • > 95% of carcinomas arise from thyroid follicular cells and are well-differentiated • Surgery +/- I-131 remains the standard of care – Vast majority treated in this manner are cured • Emergence of Multiple TKIs in Iodine-Refractory TC and MTC that can affect response and likely prolong PFS and OS
  5. THYROID CANCER IN THE UNITED STATES New Diagnosis Cancer Deaths Pfister, D. Treatment of Radioactive Thyroid Cancer. Presentation. ASCO, 2007.
  6. >5.0cm 2.1-5.0cm THYROID CANCER IN THE UNITED STATES 0-1.0cm 1.1-2.0cm Davies, JAMA 2006 295:2164
  7. 0 1084 62 12 14 0% 20% 40% 60% 80% 100% Survival Stage I Stage II Stage III Stage IV DTC: INITIAL DISEASE STAGE PREDICTS OVERALL SURVIVAL Years 75% of all tumors 25% of all tumors p<0.001 Jonklaas J et al. Thyroid. 2006, 16(12): 1229-1242.
  8. Principles of High Risk Patients Treatment • • Total Thyroidectomy Radioiodine – – – Gross Extrathyroidal > 4cm primary Distant metastases Extension • Neck Dissection – Clinical or US-detected disease – Locoregional recurrence TSH Suppression – <0.1 for those at high risk or with disease • known residual ATA Guidelines. Cooper et al. Thyroid 2009. 19(11). NCCN Guidelines. Thyroid Carcinoma v2.2013.
  9. 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
  10. TSH SUPPRESSION IMPROVES SURVIVAL FOR DTC PATIENTS WITH METASTASES 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 Survival,% Years All > 45 yr TSH suppressed 15 yr 10 yr TSH unsuppressed 11 yr 6 yr p < 0.01 p < 0.005 Median n = 450 Jonklaas et al. Thyroid. 2006;16:1299-1242.
  11. Survival(%) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years after the discovery of metastases 0 5 10 15 20 25 30 35 40 1 2 3 127 patients 4 cancer related deaths 168 patients 149 patients SURVIVAL AND RESPONSE TO TREATMENT • Group 1: initial 131I uptake and CR – Age < 40 years – Well-differentiated cancer – Small size of metastases • Group 2: initial 131I uptake and persistent disease • Group 3: no initial 131I uptake Durante et al. J Clin Endocrinol Metab. 2006;91:2892-2899.
  12. Radioiodine Refractory Prognosis Outcome1 – Median Survival 3-6 years – 10-year survival less than 15% Prognostic Factors2,3 – – – Age BRAF Mutation PET positivity Durante et al. J Clin Endocrinol Metab 2006;91(8):2892–2899. Elisei et. al, J Clin Endocrinol Metab 2008;93(10):3943-9 Robbins and Weil. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047-59
  13. Radioiodine Refractory Criteria A. One or more (measurable) lesions that do 131Inot demonstrate radioiodine scan uptake on diagnostic B. One or more lesions that has progressed 131Iwithin 12 months of therapy. 131IC. Cumulative activity of of > 600 mCi
  14. RAI-REFRACTORY DISEASE • 25–50% of metastatic thyroid cancers lose ability to take up iodine • RAI refractory means that there are progressing lesions that do not take up RAI (Note: there may still be some that do) • Loss of iodine uptake inversely correlates with survival 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.
  15. RAI-REFRACTORY THYROID CANCER • L-T4 treatment: serum TSH < 0.1 mU/L • Local treatments when needed: surgery, radiation, radiofrequency or cryoablation • Imaging follow-up every 6 months • Stable disease: follow-up • Progression: – > 20% (RECIST) in 6-15 months – Inclusion in a trial • Chemotherapy: low efficacy, significant toxicity (eg, doxorubicin: 5% PR, 47% SD, median PFS 7 months) • Targeted therapy as first line (ATA, 2009) Cooper et al. Thyroid. 2009;9:1167-1214.
  16. NCCN AND ATA GUIDELINES FOR THE TREATMENT OF DIFFERENTIATED THYROID CANCER (DTC) Initial treatment • Total thyroidectomy, except in patients with unifocal microcarcinoma (individualized to patient and extent of disease)1,2 Postoperative treatment • Radioactive iodine (131I) (RAI) therapy1,2 Follow-up treatment • Levothyroxine to suppress TSH levels to < 0.1mU/L1,2 Recurrent or metastatic disease treatment • Local therapy (re-operation, external radiation) • Systemic therapy – RAI therapy – patients with refractory advanced disease • chemotherapy (limited efficacy and considerable toxicity)1,2 • participation in clinical trials with small molecule tyrosine kinase inhibitors is recommended1,2 1. NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V.1.2010. 2. Cooper DS, et al. Thyroid .2009;9:1167-214. NCCN = National Comprehensive Cancer Network. ATA = American Thyroid Association .
  17. CYTOTOXIC AGENTS IN DTC • ADRIAMYCIN IS THE MOST STUDIED AGENT. • Others include- Bleomycin, platinums, etoposide, and Pemetrexed. • <20% Response Rate.
  18. THYROID CANCER IS ASSOCIATED WITH ABERRANT CELL SIGNALING Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35% Total >70% >65% MAPKinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
  19. RAS/BRAF MUTATIONS ARE MORE PREVALENT IN RAI REFRACTORY THYROID CANCER Ricarte-Filho JC, Cancer Research 2009 Jun 1;69(11):4885-93
  20. 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
  21. WHO IS APPROPRIATE FOR KINASE INHIBITOR THERAPY? 1. Patients whose tumors no longer take up radioactive iodine or who have exceeded their lifetime dose 2. Patients with disease measurable by exam or CT scan 3. Patients with >1 lesion which is >1 cm in size and who are symptomatic 4. Patients with progressive disease
  22. KINASE INHIBITORS KIATP KI PY Y ATP Activated pathway Cancer Activated Pathway Cancer VEGFR inhibition Tumor angiogenesis Tumor growth RET, BRAF….. inhibition
  23. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib TARGETING CELL SIGNALLING IN THYROID CANCER 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 Everolimus Sirolimus Everolimus Sirolimus
  24. UPCC 03305: SORAFENIB IN ADVANCED THYROID CANCER Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9 n=55 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 Sorafenib 400mg b.i.d. Primary endpoints • RECIST • PFS • Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
  25. Update UPCC O3305: May 2009 Results: • Response for all 50 evaluable patients – PR 36% (18 patients) – SD 46% (23 patients) – clinical benefit 82% (41 patients) • Exact binomial confidence interval excludes the null hypothesis (p<0.0001) • PFS is 63 weeks for all patients, and 84 weeks in patients with DTC Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)
  26. UPCC 03305: BEST RESPONSE IN 46 EVALUABLE PATIENTS Papillary Follicular/Hürthle Cell Medullary Poorly Differentiated/Anaplastic 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –10 ChangeinsumoftargetlesionbyRECIST comparedtobaseline(%) PD SD PR Best response of advanced thyroid cancer patients to sorafenib Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)
  27. CUTANEOUS ADVERSE EVENTS WITH SORAFENIB IN THYROID CARCINOMA PATIENTS 1. Cutaneous toxicity peaks in the second cycle 2. Brief dose holidays and dose reductions are reasonable. Rash usually improves with continued sorafenib treatment 3. Rash is more common in patients with extensive sun exposure in the past 4. Skin creams may be used as well as NSAIDs for control of the pain from the rash
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  29. Eligibility criteria • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory • No prior targeted therapy, chemotherapy or thalidomide PHASE III STUDY OF SORAFENIB IN LOCALLY ADVANCED OR METASTATIC PATIENTS WITH RADIOACTIVE IODINE REFRACTORY THYROID CANCER (DECISION) TRIAL – PRIMARY ENDPOINT POSITIVE • An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC www.clinicaltrials.gov. NCT00984282 Off study Disease progression Crossover or continue sorafenib 400mg orally b.i.d. Randomisation(1:1) (n=380) Progression Sorafenib 400mg orally b.i.d. Placebo Investigator’s decision n=190 n=190 Primary Endpoint: PFS (RECIST) Independent review Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory Biomarkers
  30. PHASE III DECISION Trial • Over 400 patients enrolled in the trial world wide • January 3, 2013 press release revealed that the primary endpoint of Progression Free Survival significantly favored the Sorafenib arm
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  39. RAI-refractory DTC 2013 DECISION establishes sorafenib as a standard therapy Multiple Questions Raised  Who to treat?  With what agent?  Can we identify alternative targets? • Will selective BRAF V600E inhibitors be effective?  Sorafenib resistance?  Is this the right strategy?
  40. THERAPEUTIC OPTIONS BEYOND FRONTLINE TKI THERAPY 1. Single progressive lesions can be resected or irradiated and the frontline TKI continued 2. Minimally progressive lesions can often be observed on the original TKI as this disease frequently progresses very slowly 3. For patients progressing on a frontline TKI, an m-TOR inhibitor can be added to block the PI3K escape pathway 4. For disease progressing in multiple areas one might switch to another available TKI or a clinical trial with an investigational agent
  41. ADVANCED THYROID CANCER’S NEW UNMET NEED: PROGRESSION ON SORAFENIB/VEGFR2 INHIBITOR • What to do with patients who progress but maintain good performance status • Most patients respond to frontline TKI therapy but then progress in a new lesion or a subset of lesions
  42. TARGETS OF KINASE INHIBITORS Compound Name VEGFR BRAF PDGFR KIT RET Other Sorafenib (Nexavar) + + + + + FLT-3 Sunitinib (Sutent) + + + FLT-3 Axitinib (AG-013736) + + + Motesanib (AMG- 706) + + + + Pazopanib (GW786034) + + + Vandetanib (Zactima) + + EGFR Cabozotanib (XL184) + + C-MET Lenvatinib (E7080) + + + + FGFR
  43. MSB 05/30/09 TARGETED AGENTS PHASE II CLINICAL DATA Drug Key Baseline Characteristics n PFS Months PR SD PD Sorafenib (Brose) •DTC+ PDTC(90%), 47 20 38% 47% 2% Sunitinib (Cohen) • DTC (74%); MTC (26%) 51 - 17% DTC 74% DTC 9% DTC Axitinib (Cohen) •Papillary (50%); Medullary (18%); Follicular/Hurthle (25%/18%); Anaplastic (3%) 60 18.1 30% 48% 7% Motesanib (Sherman) •Papillary (61%); Follicular/Hurthle (34%) 93 10 14% 67% 8% Pazopanib (Bible) PD and DTC (Progression <6months) 37 12 49% - - Lenvatinib (E7080, Sherman) •DTC 100% 58 13.3 45% 46% 5%
  44. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib TARGETING CELL SIGNALLING IN THYROID CANCER 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 Everolimus Sirolimus Everolimus Sirolimus
  45. UPCC 19309: EVEROLIMUS + SORAFENIB FOR DTC PATIENTS WHO PROGRESS ON SORAFENIB ALONE n=35 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 b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal 22 patients accrued so far
  46. Eligibility criteria: • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory UPCC 18310: NO25530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor Vemurafenib in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine Vemurafenib 960mg BID Primary Endpoint: Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve pts Independent review Secondary Endpoints: •PFS, TTP, OS, TTP, in sorafenib naïve pts •BORR, CB, TTP, PFS and OS, in soraefnib exposed patients InformedConsent BRAFV600Etesting + First Line Sorafenib Naïve (n=25) Second Line Prior Sorafenib (n=25) +
  47. E7080 (lenvatinib) phase II results Sherman et al.ASCO 2011, abstr 5503 Overall (n=58) CR 0 PR 26 (45%) SD 27 (46%) PD 3 (5%) DCR 53 (91%)
  48. Overcoming sorafenib resistance Targeting alternative pathways J Clin Oncol 31, 2013 (suppl; abstr 6024)
  49. MSB 10/16/10 CLINICAL TRIALS ONGOING FOR METASTATIC DIFFERENTIATED THYROID CANCER Compound Name DTC/MTC Status Sorafenib (Nexavar) DTC First Line – International Phase III – Positive Study Lenvatinib (E7080) DTC First and Second Line – Phase III Vemurafenib (BRAF V600E inhibitor) DTC (PTC) First and Second Line Phase II – (Phase III?) Everolimus+Sorafenib DTC Second Line – Phase II Cabozantinib DTC First Line – Phase I complete First Line and Second Line Phase II– Pending Pioglitazone (PPARγ) DTC (FTC*) First and Second Line - Phase II Pazopanib (GW786034) DTC First and Second line – Phase II Done Sunitinib (Sutent) DTC First line Phase II – Done.
  50. Are there better strategies? Restoration of Radioiodine Sensitivity Ho et al. N Engl J Med 2013;368:623-32.
  51. TAKE HOME MESSAGES-I • Multiple VEGFR agents in DTC have activity that affect the vast majority of patients with advanced RAI-refractory thyroid cancer needing therapy • Results of phase III trial with sorafenib (DECISION) showing that patients treated with sorafenib have a longer progression free survival than those on placebo. We look forward to a future major oncology meeting for these results. Results from the Phase III trial of lenvatinib (SELECT ) are likely to follow in another year. • Molecular markers (eg. BRAF V600E mutation) are newer targets being tested in Phase II clinical trials. If positive, patients will need routine molecular testing for these mutations • Many studies for second line treatment of DTC are underway and now a primary focus of our research program at the Abramson Cancer Center and at other sites. These trials target new molecular mechanisms and hope to add to the success of the VEGFR inhibitors in this disease.
  52. Take Home Messages-II 1. Patients with progressive RAI-refractory TC should be referred to an oncologist with access to all the available and investigational kinase inhibitors. 2. Treatment with a kinase inhibitor should be initiated in patients with progressive, measurable disease. 3. The physician managing these patients should be comfortable with and skilled in managing the adverse events related to kinase inhibitors. 4. Many clinical trials are now available for patients progressing on frontline kinase inhibitor therapy.
  53. Take Home Message Who To Treat? Who Not To Treat? • Radioiodine Refractory • No radiographic disease (TG only) RAI Sensitive No progression Very slow progression without threatened symptoms – – Negative RAI Scan Progression Despite Recent RAI >600 mCi prior RAI • • • – • • Non-surgical candidates Established Progression – Threatened Symptoms
  54. REFERENCES 1. Giuffrida D, Prestifilippo A, et al; Journal of Oncology Volume 2012, Article ID-391629, “New Treatment in Advanced Thyroid Cancer” 2. Brose M, Nutting C, et al; BMC Cancer 2011, 11:349 “Rationale and design of DECISION: a double blind, randomized, placebo controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic, RAI- refractory, differentiated thyroid cancer” 3. Harris P, Bible K; Expert Opinion Investigational Drugs; October 2011 20(10): 1357-1375; “Emerging Therapeutics for Advanced Thyroid Malignancies: Rationale and Targeted Approaches” 4. Gupta-Abramson V, Troxel A, et al; JCO 2008 Vol. 26: 4714 “Phase II Trial of Sorafenib in Advanced Thyroid Cancer” 5. Kojic K, Kojic S & Wiseman S; Expert Reviews in Anticancer Therapy 2012 Vol.12(3):345; “Differentiated thyroid cancers: a comprehensive review of novel targeted therapies

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