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Management Advances for Differentiated and Medullary Thyroid Carcinoma

Management Advances for Differentiated and Medullary Thyroid Carcinoma. Marcia S. Brose MD PhD Abramson Cancer Center of the University of Pennsylvania Philadelphia, PA

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Management Advances for Differentiated and Medullary Thyroid Carcinoma

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  1. Management Advances for Differentiated and Medullary Thyroid Carcinoma Marcia S. Brose MD PhD Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, PA On behalf of: Christopher Nutting, Barbara Jarzab, RossellaElisei, Salvatore Siena, Lars Bastholt, Christelle de la Fouchardiere, FurioPacini, Ralf Paschke, Young KeeShong, Steven I. Sherman, Johannes WA Smit, John Woojune Chung, HaraldSiedentop, Istvan Molnar and Martin Schlumberger

  2. Disclosures • Companies: AstraZeneca, Bayer/Onyx, Eisai, Exelixis, Novartis, Oxigene, Plexxikon, Roche • Relationships: Advisory board consultant, honoraria, research grants, and primary investigator • As there are currently no FDA approved agents for progressive DTC, all agents I will discuss will be off label use or in the context of a clinical trial 2

  3. Thyroid cancer: clinical pathology Papillary (87%) Differentiated Follicular cells Follicular (6%) Hürthle cell (3%) Anaplastic (1%) Medullary (2%) Parafollicular cells • Treatment of Differentiated Thyroid Cancer includes: • Surgery – thyroidectomy • Radioactive iodine • Thyroid stimulating hormone (TSH) suppression • Recurrent progressive RAI refractory disease treated with sorafenib 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. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.

  4. Radioactive Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC) • It is estimated1 that in the USA in 2013 there will be: • >60 000 new cases of thyroid cancer, and • 1850 deaths due to thyroid cancer • In approximately 5–15% of patients with thyroid cancer, the disease becomes refractory to RAI2,3 • Median survival for patients with RAI-refractory DTC and distant metastases is estimated to be 2.5–3.5 years4,5 • Patients often suffer multiple complications associated with disease progression 1. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html; 2. Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev EndocrinolMetab 2012;7:541–54; 4. Durante C et al. J ClinEndocrinolMetab 2006;91:2892–99. 5. Robbins RJ et al. J ClinEndocrinolMetab 2006;91:498–505.

  5. 1.00 0.75 0.50 0.25 0 FDG-negative 176/179 alive FDG-positive 156/223 alive Survival Distribution Function Median survival = 53 months 0 10 20 30 40 50 60 70 80 90 Months FDG-PET Predicts Survival in Patients With Metastatic Thyroid Cancer Robbins et al. J Clin Endocrinol Metab. 2006;91:498-505.

  6. Genetics of Differentiated Thyroid Cancer: aberrant intracellular signaling • Poorly differentiated • RAS (25–30%) • TP53 (20–30%) • CTNNB1 (10–20%) • BRAF (10–15%) Anaplastic Medullary Oncocytic Conventional • Papillary • Mutations identified in ~70% • BRAFa (40–50%) • RASb(7–20%) • RET/PTC (clonal; 10–20%) • EGFR (5%) • TRK (<5%) • PIK3CA (2%) • Follicular • Mutations in 70–75% • RAS (40–50%;lower in oncocytic) • PAX8/PPARg(30–35%; lower in oncocytic) • TP53 (21%) • PTEN (8%) • PIK3CA (7%) • BRAF (2%) Papillary DTC aBRAFmutations are mostly V600E; 1–2% are K601E and othersbRASincludes N-, H-, and K-RAS (predominantly NRAS and HRAS codon 61)Nikiforov YE et al. Arch Pathol Lab Med 2011;135:569–77; COSMIC database – Catalog of Somatic Mutations in Cancer (as of February 22, 2013) http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/

  7. Targeting Cell Signaling in Thyroid Cancer Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Motesanib Sorafenib Sunitinib Vandetanib Cabozantinib Lenvatinib Vandetanib Axitinib Motesanib Sorafenib Sunitinib Vandetanib Lenvatinib Cabozantinib Ras Ras PI3K B-Raf PI3K Raf AKT Sorafenib AKT MEK Sorafenib MEK mTOR mTOR ERK ERK Everolimus Sirolimus Everolimus Sirolimus S6K S6K • Growth • Survival • Proliferation • HIF1a • Inhibition of apoptosis • Migration • Growth • Survival • Proliferation • Migration •Angiogenesis EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-783.

  8. Targets of Kinase Inhibitors • DTC, differentiated thyroid cancer; EGFR, endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. • 1. Perez CA , et al. Biologics. 2012;6:257-265. 2. Pacini F. Expert Rev Endocrinol Metab. 2012;7:541-554.

  9. Targeted Agents: Phase 2 Clinical Data • DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; PD, progressive disease; PDTC, poorly-differentiated thyroid cancer; PFS, progression-free survival; PR, partial response; SD, stable disease.

  10. DECISION study design1 417 patients randomized from Oct 2009 to July 2011 • Locally advanced or metastatic, RAI-refractory DTC • Progression (RECIST) within the previous 14 months • No prior chemotherapy, targeted therapy, or thalidomide Sorafenib400 mg orally twice daily Primary endpoint • Progression-free survival Randomization 1:1 Placebo orally twice daily Secondary endpoints Overall survival Response rate Safety Time to progression Disease control rate Duration of response Sorafenib exposure (AUC0–12) Stratified by: geographical region (North America or Europe or Asia) age (<60 or ≥60 years) Progression assessed by independent central review every 8 weeks At progression: patients on placebo allowed to cross over at the investigator’s discretion patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion 1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

  11. Key inclusion and exclusion criteria (1) Inclusion Locally advanced or metastatic DTC (papillary, follicular including Hürthle cell or poorly differentiated) RAI-refractory DTC At least one target lesion without iodine uptake, or Progression following treatment dose of RAI, or Cumulative RAI treatment ≥600 mCi Progressive disease within the last 14 months (RECIST) Adequate TSH suppression (<0.5 mU/l) 1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

  12. Key inclusion and exclusion criteria (2) Inclusion (cont.) Not a candidate for surgery or radiotherapy with curative intent Adequate bone marrow, liver and renal function Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2 Exclusion Prior anti-cancer treatment with targeted therapy or chemotherapy 1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

  13. Baseline disease characteristics EBRT, external beam radiation therapy 1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

  14. Progression-free survival(by independent central review) 100 90 80 HR: 0.587; 95% CI: 0.454–0.758; p<0.0001 70 PFS probability (%) 60 50 40 30 20 0 100 200 300 400 500 600 700 800 10 Days from randomization 0 Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

  15. Overall survival 100 Survival probability (%) 90 80 70 HR: 0.802; 95% CI: 0.539–1.194 p=0.138, one-sided 60 50 40 30 Days from randomization 20 • At progression: • 150 patients on placebo (71%) received open-label sorafenib • 55 patients on sorafenib (27%) received open-label sorafenib 10 0 100 200 300 400 500 600 700 800 900 1000 0 Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

  16. Other secondary efficacy endpoints CR, complete response; PR, partial response; SD, stable disease; NA, not assessed

  17. Maximum reduction in target lesion size(by independent central review) 60 50 40 30 73% of patients 27% of patients 20 10 0 Maximum reduction in target lesion size (%) –10 –20 –30 –40 –50 –60 Sorafenib Placebo –70 Maximum reduction is defined as the difference in the sum of the longest diameter of target lesions from baseline. Negative values refer to maximal reduction and positive values to the minimal increase.

  18. Treatment and dose modifications(double-blind period) AE, adverse event Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4

  19. Most common treatment-emergent AEs (double-blind period) *National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

  20. Serious adverse events and deaths(double-blind period) * Occurring in ≥2.0% of sorafenib-treated patients ** Myocardial infarction (sorafenib); subdural hematoma (placebo)

  21. Sorafenib benefit by BRAF status (PFS)– Papillary histology only BRAF wild-type BRAF mutation 100 100 80 80 HR: 0.40, 95% CI: 0.20–0.80, p=0.008 60 60 HR: 0.58, 95% CI: 0.34–1.00, p=0.049 40 40 PFS probability (%) 20 20 0 0 0 200 400 600 800 0 200 400 600 800 Days from randomization Days from randomization BRAF mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.393) Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

  22. Sorafenib benefit by RAS status (PFS) RAS wild-type RAS mutation 100 100 80 80 HR: 0.60, 95% CI: 0.42–0.85, p=0.004 HR: 0.49, 95% CI: 0.24–1.00, p=0.045 60 60 PFS probability (%) 40 40 20 20 0 0 0 200 400 600 800 0 200 400 600 800 Days from randomization Days from randomization RAS mutation was not an independent prognostic factor for PFS Univariate (placebo arm only): mutant vs wild type RAS, HR=1.80; p=0.022 Multivariate (placebo arm only): mutant vs wild type RAS, HR=1.56; p=0.154 RASmutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.422) Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013

  23. UPCC 18310: Vemurafenib in patients with Progressive PTC with BRAF V600E • Key Eligibility Criteria • Recurrent, unresectable or metastatic PTC • BRAFV600 mutation positive by cobas • RAI refractory • Evidence of progression within 14 months • Prior chemotherapy allowed Cohort 1: VEGFR2i-naive (n = 26) Vemurafenib960 mg biduntil disease progression or unacceptable toxicity Cohort 2: VEGFR2i-pretreated (n = 25) bid, 2 times a day; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; VEGFR, vascular endothelial growth factor receptor; VEGFR2i, vascular endothelial growth factor receptor 2 inhibitor. Brose et al. ECCO-ESMO 2013 Primary end point: response rate per investigator in VEGFR2i-naive patients. Secondary end points: safety, duration of response, PFS, OS, PK, response rate in VEGFR2 inhibitor–pretreated patients

  24. Cohort 1: VEGFR2i-Naive Best Objective Response Cohort 1, N = 26 25.0 No confirmed objective response Confirmed objective response 0.0 –25.0 –30.0 Max change in sum of diameters RECIST (%) –50.0 –75.0 –100.0 Each bar represents one cohort 1 patient AE, adverse event; CR, complete response; PR, partial response; SD, stable disease. aPatients with at least 2 postbaseline tumor scans or progressive disease/withdrawal because of death or AE within first 2 cycles. 24

  25. Cohort 1: VEGFR2i-NaiveSurvival Kaplan-Meier Curves Censored OS PFS 1.0 1.0 Censored 0.8 0.8 0.6 0.6 Survival Probability Survival Probability 0.4 0.4 Median OS: Not reachedb Median PFS 15.6 mo (95% CI: 11.2–NR)a 0.2 0.2 0.0 0.0 5 0 10 15 20 0 5 10 15 20 Months Months bMedian follow-up time: 11.4 mo. a13 patients continue therapy. Brose et al. ECCO-ESMO 2013 25

  26. Summary: RAI-Refractory DTC • DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways, and iodine-refractory patients have an average survival of 3 years • Results of phase 3 trials with sorafenib (DECISION) were positive, This agent was the FDA approved November 2013, and is first agent to be approved since doxorubicin in 1974. • Two additional phase 3 trials of lenvatinib (SELECT) and vandetanib (VERIFY) are ongoing • Additional MKIs have also shown activity in the Phase II setting, many of which target VEGFR-2, but also mTOR, MEK, MET and BRAF and BRAF V600E and will be needed in the second- and third-line setting DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; mTOR, mammalian target of rapamycin; RAI, radioactive iodine; VEGFR, vascular endothelial growth factor.

  27. Thyroid cancer: clinical pathology Papillary (87%) Differentiated Follicular cells Follicular (6%) Hürthle cell (3%) Anaplastic (1%) Medullary (2%) Parafollicular cells • Treatment of Medullary Thyroid Cancer includes: • Surgery – thyroidectomy • Thyroid stimulating hormone (TSH) replacement • Recurrent non surgical and metastatic disease treated with Cabozantinib and Vandetanib 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. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.

  28. Medullary Thyroid Cancer • From calcitonin-producing parafollicular C cells • Accounts for 2%-5% of thyroid cancers • ~1400 cases per year in US • Disproportionate number of thyroid cancer deaths • 350,000 Americans living with thyroid cancer • Heritable in 25% of cases • Mutations in the RET gene cause familial MTC–multiple endocrine neoplasia 2 (MEN2) • 30%-40% of sporadic MTC bear somatic RET mutations

  29. Plasma Markers in MTC • Calcitonin • Synthesized and excreted by C cells of the thyroid and by some medullary thyroid tumors • Diarrhea and flushing at high levels • Calcitonin levels can be affected by RET inhibition • Carcinoembryonic antigen (CEA) • Synthesized and excreted by some medullary thyroid tumors • Synthesized by other types of tumors as well

  30. Patients With Distant Metastasis at Diagnosis Have a Poor Prognosis • 10-year overall survival: 40% • Median overall survival: 3.2 years Roman et al. 2005.

  31. MTC: Initial Treatment • Complete surgical resection is the only curative treatment for MTC • Metastasis (lymph node or systemic) is present at diagnosis in 40%-50% of sporadic cases of MTC • Surgery : • Total thyroidectomy • Extent of surgery depends on stage of disease • Curable vs noncurable • Central neck dissection +/- Ipsilateral neck dissection or Contralateral neck dissection • Goal • Early disease: removal of all neoplastic disease • Advanced disease: airway protection

  32. MTC: Treatment • Radiation therapy • Adjunctive and palliative treatment for extensive neck or mediastinal disease • Palliative treatment for bony metastasis • May be effective in controlling complications associated with MTC activity in the neck and mediastinum • No evidence that radiation therapy improves survival • Radioactive Iodine is ineffective in the treatment of MTC!!!

  33. MTC: Treatment • Follow-up postsurgery • High level of calcitonin 2-3 months postsurgery indicates persistent disease • Most important prognostically is total calcitonin and the doubling time (DT) • Reoperation may allow removal of at least some neoplastic tissue, but less likely to prevent recurrence • Calcitonin levels normalize in 5%-35% of cases after re-operation • Radiation to the neck and mediastinum in cases of persistent elevated calcitonin levels can decrease the risk of recurrence (unlikely to affect survival)

  34. Risk Stratification Using Serum Calcitonin DT • Calcitonin DT highly predictive of mortality • Independent predictor in multivariate analysis, controlled for TNM stage • Rapid DT could identify stage II and III patients at higher risk for death Barbet. JCEM. 2005.

  35. MTC: Sites of Recurrent or Persistent Disease Optimal Imaging Strategies • Cervical nodes and thyroid bed • Lungs and mediastinum • Liver and abdominal lymph nodes • Bone Neck ultrasound Chest CT Liver protocol MRI MRI spine and pelvis CT, computed tomography; MRI, magnetic resonance imaging. Giraudet. JCEM. 2007.

  36. MTC: Treatment of Metastatic Disease • No standard of care • Rate or progression is variable • Some patients survive for years with metastatic disease • Traditional chemotherapy • Prior to 4/6/2011, doxorubicin was the only FDA-approved agent; relative risk (RR) <40%; poorly tolerated, short duration response • Dacarbazine-based regimens RR< 40% and generally short-lived • NCCN practice guidelines (2008) • Disseminated symptomatic disease • Clinical trial (preferred) • Radiation therapy for focal symptoms • Sorafenib • Dacarbazine-based chemotherapy • Consider bisphosphonate therapy for bone metastases • Best supportive care

  37. Rationale for RET as a Therapeutic Target • Activated by mutations in ~50% of cases (>60% of progressive cases presenting for clinical trials) • Somatic mutation of RET associated with poor prognosis • Limited expression outside the thyroid, potentially high therapeutic index

  38. 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. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. Wells SA Jr et al. J Clin Oncol. 2012;30(2):134-141.

  39. FDA Approves vandetanib in MTC 4/6/2011 • Approved for progressive or symptomatic disease only • MDs required to undergo Risk Evaluation and Mitigation Strategy (REMS) training for QTc prolongation detection • REMS program lays out a plan for EKG monitoring throughout therapy for all patients treated with vandetanib • Training itself takes approximately 2 hours • Starting dose 300 mg/d

  40. Cabozantinib Phase III in MTCProgression Free Survival by IRC P< 0.0001 • Significant difference in tumor response rate • 27% in cabozantinib vs 0% placebo; P<0.0001 • Median duration of response: 14.7 months COMETRIQTM (cabozantinib) Capsules [package insert]. Exelixis, Inc: San Francisco, CA.

  41. FDA Approves cabozantinibin MTC 11/29/2011 • Approved for progressive or symptomatic disease only • Warnings about gastrointestinal perforations and fistula formations • Starting dose 140 mg/d

  42. Key Points: MTC for Oncologists • MTC has a distinct clinical presentation, genetics, and molecular targets compared with differentiated thyroid cancer • Importance of distinguishing progressive vs indolent disease (imaging and CEA DT) • Success of treatment will be strongly dependent on attention to kinase-related symptom management • REMS is required for vandetanib; oncologists are required to follow EKGs closely • Cabozantinib has black box warning about risk of fistula formation in regions of prior invasive disease and radiation • Either can be used in first or second line setting

  43. University of PennsylvaniaThyroid Cancer Therapeutics Program • Brose Translational Research Lab • Raya Terry, MD • Tatyana Kuznetsova, PhD • Waixing Tang, MD • Zakkiyya Posey • Thyroid Cancer Clinical Trials Unit • Yvette Cruz, RN • Carolyn Grande, RN, CRNP • Thelma McCloskey • Parna Prajapati • Ramkrishna Makani • Jillian Stanley • Experimental Therapeutics Program • Andrea Troxel, PhD • Peter O’Dwyer, MD • Pathology/Imaging • Michael Feldman, MD, PhD • Laurie Loevner, MD • Thyroid Cancer Interest Group • Susan Mandel, MD • Ara Chalian, MD • Douglas Fraker, MD • Robert Lustig, MD • Virginia LiVolsi, MD • Zubair Baloch, MD • Steve Keefe, MD • Daniel Pryma MD • Marcia Simpson Brose is a Damon Runyon-Siemens Clinical Investigator • Many community endocrinologists who have referred their patients, and the patients who have agreed to participate in our trials

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