New systemic treatment options for radioiodinerefractory. medullary thyroid cancers

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1 New systemic treatment options for radioiodinerefractory differentiated and medullary thyroid cancers Prof. Dr. Patrick Schöffski, MPH, Department of General Medical Oncology University Hospitals Leuven, Leuven Cancer Institute, and Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven (Belgium)

2 Thyroid carcinoma Common abbreviations used in the field of thyroid cancer and in this presentation Differentiated thyroid carcinoma Papillary thyroid carcinoma Follicular thyroid carcinoma Anaplastic thyroid carcinoma Medullary thyroid carcinoma TC DTC PTC FTC ATC MTC Radioactive iodine RAI, 131-I Thyreoglobulin Multiple endocrine malignancy TG MEN

3 Magnitude of the TC problem TC accounts for >90% of all endocrine malignancies Represents <1% of all human cancers Often considered rare, but number of cases exceeds incidence of stomach, liver, ovary, brain, myeloma, pharynx, larynx, bone or testicular cancer in the US Almost new cases in US in 2008 More than deaths in US in 2008 One in about 130 men and women will be diagnosed with TC during their lifetime

4 Thyroid Cancer: 2008 Estimates European Age-Standardised Incidence Rates per 100,000, EU-27 Countries In 2008 there were an estimated 33,600 new cases of thyroid cancer diagnosed in the European Union (EU-27). The highest incidence rate was estimated to be in France, where the female rate was five times higher than the rate of the lowest ranking country, Greece (18.6 versus 3.3 per 100,000 females). Cancer Research UK, November 2013

5 Thyroid Cancer: 2008 Estimates World Age-Standardised Incidence Rates per 100,000 Population, World Regions The highest rates for thyroid cancer in the world occur in Northern America, where the female age-standardised rate is 15.1 per 100,000 females, compared with 1.2 per 100,000 females in Middle Africa. Incidence is low in all parts of Africa. Worldwide more cases occur in females aged than in any other age group. Cancer Research UK, November 2013

6 TC: age, mortality and survival Mortality stable over the past 25 years 30-year survival rates in DTC exceed 90 % 10-year survival rate FDG-PET/CT of differentiated thyroid carcinoma with lymph node metastasis PTC 92% FTC 89% MTC 80% ATC 13% Howlader N et al. SEER Cancer Statistics Review 2008

7 Etiology Radiation exposure as best known risk factor Poorly studied Occupational exposures Dietary habits Lifestyle Parity Genetic disposition DTC: Cowden, Gardner and FAP syndromes MTC: MEN 2A and 2B

8 Multistage carcinogenesis and molecular relationship of TC subtypes Molecular studies have identified a number of abnormalities in TC associated with cell transformation, progression and dedifferentiation Distinct molecular events are linked with specific stages and phenotypes of TC Thyrocyte-derived TCs constitute a biological continuum progressing from DTC to ATC Gradual loss of papillary and follicular growth patterns, increase in solid growth pattern with more mitosis, necrosis and nuclear pleomorphism Majority of aggressive TC have residual foci of DTC, supporting the relationship of various subtypes

9 Pathogenesis and cells of origin Thyroid follicular cells (90-95% of all cases) PTC (>90%) FTC (5-8%) ATC (1-2%) Neuroendocrine C cells MTC

10 Differential diagnosis Benign thyroid diseases Lymphoma Sarcoma Metastasis Renal cell carcinoma Lung cancer Breast cancer Melanoma Courtesy of Schöffski P. Patient with renal cell carcinoma and thyroid metastasis

11 Natural course and outcome Variable presentation from clinically insignificant cases to very aggressive disease with 5-year disease-specific mortality of up to 50% Majority of patients with DTC have excellent disease-specific survival, resulting in low number of deaths as compared to other solid tumours Important: most patients with TC do well or do not require specific systemic treatment However, the majority of patients with poorly differentiated TC or ATC succumb to their disease despite aggressive treatment

12 Differentiated thyroid carcinoma (DTC)

13 DTC Accounts for 90-95% of all cases of TC and is highly curable Includes the most common entities PTC (>90%) FTC (<10%) Excellent disease-specific survival Low number of deaths as compared to other cancers Primary curative treatment involves surgery, RAI Treatment is followed by life-long thyroxine administration to suppress TSH to undetectable level Impact of TSH suppression on survival Jonklaas J et al. Thyroid 2006;16(12): The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers

14 Relapse of DTC after surgery and RAI Despite low disease-specific mortality, global risk of recurrence is 20-30% over years Most frequent sites of recurrence Lymph nodes Thyroid bed Neck muscles Trachea Outside of neck area Around 8% of patients with local relapse and 50% of patients with metastasis will die of TC

15 Higher risk of death from DTC Age >45 years Tumour size >4 cm (classic PTC) Specific papillary subtypes (tall cell, columnar or insular variant) or poorly differentiated TC Incomplete resection Lymph node involvement in older patients Presence of distant metastasis Failure of initial RAI therapy Disease-specific death predominantly seen in patients with distant metastasis

16 Distant metastasis in DTC Distant metastasis occurs in 5-25% of cases Metastatic differentiated thyroid carcinoma Half of them have synchronous metastasis, the other half developing metastasis during follow-up Usually involves lung and bone Two third of metastatic patients show uptake of 131-I Treatment of metastasis based on repeated doses of RAI Courtesy of Schöffski P.

17 Role of RAI therapy in metastatic DTC RAI is the mainstay of treatment of metastatic DTC Significant proportion of patients can be cured or at least durable palliation is achieved At least one study confirmed impact of RAI on survival Younger patients with limited disease volume and lung metastases have 15 year-survival of around 90 % Residual lung lesions may persist for years after RAI Bone lesions respond poorly Courtesy of Schöffski P. Typical lung metastasis in DTC

18 RAI-treatment of distant metastasis Two third of metastatic patients initially present with uptake of 131-I Repeated doses of RAI of GBq given at 3-9 month intervals No defined maximum limit of cumulative 131-I! Individual dose should not exceed 2 Gy total body exposure to avoid bone marrow damage Risk of marrow failure, myelodysplastic syndrome, leukaemia After RAI treatment, 40-50% have no residual 131-I uptake One third of patients achieve normalization of chest X ray in case of lung metastases Recurrence rates after 10 years <10 %

19 The RAI-refractory patient Roughly 25 % of RAI-treated patients become iodine-negative (=resistant) following repeated 131-I therapy These patients potentially qualify for Best supportive care Tyrosine kinase inhibitors (TKI) Chemotherapy Experimental therapy

20 RAI-refractory patient as defined in recent trials (<5% of all DTC patients) Patients who never showed 131-I uptake on diagnostic scan in at least one lesion and have progressive lesion (RECIST) within the last 14 months Patients who received a cumulative RAI dose of >600 mci and have at least one target lesion which progressed (RECIST) within the last 14 months (the dose of 600 mci is not based on scientific evidence) Patients who previously showed 131-I uptake on diagnostic scan, were treated with RAI of at least >100 mci but progressed (RECIST) within 14 months

21 Chemotherapy in RAI-refractory DTC 10-15% of DTCs result in recurrent or refractory disease Disease course for these patients is highly variable Doxorubicin is the only FDA-approved chemotherapeutic option for such patients, with highly variable response rate Doxorubicin never studied in adequately powered randomized trial Patient benefit 5% PR, 47% SD, median PFS 7 months according to the literature Limited efficacy and significant morbidity Possible indications: inoperable, progressive, symptomatic disease, failure of tyrosine kinase inhibitors Combination chemotherapy doxorubicin/cisplatinum not better than doxorubicin alone

22 DTC is becoming a role model for targeted therapy Presence of constitutively activated tyrosine kinases makes DTC a logical candidate for targeted treatment PTC RET/PTC C-MET FTC EGFR VEGF-A 165 VEGFR-2 Endothelial cell Ras Ras B-Raf PI3K Raf PI3K MEK AKT MEK AKT ERK mtor ERK mtor S6K S6K Growth HIF1a Survival Inhibition of apoptosis Proliferation Migration Adapted from Keefe SM et al. Clin Cancer Res 2010;16(3): Growth Survival Proliferation Migration Angiogenesis

23 B-RAF Cyclin D1 DNA-methylation Epigenetic alterations Growth factors MET P53 PI3K/AKT/PTEN RAS RET VEGF Oncogene addication and druggable molecular targets in TC

24 Molecular epidemiology of cell signaling abberations in DTC MAP kinase PI3K/AKT Genetic alteration Papillary TC (%) Follicular TC (%) Poorly diff. TC (%) B-Raf V600E 44 0 <5 B-Raf copy gain 3 35? RET/PTC (1 and 3) ~ RAS ~ PI3KCA mutations 3 <10? PI3KCA copy gain 12 28? PTEN 2 <10? Pax8/PPARγ Total >70 >65 Adapted from Schlumberger M; Nikiforov YE. Mod Pathol 2008;21(Suppl 2):S37-S43; Xing M. Endocr Relat Cancer 2005;12(2): ; Wang HM et al. Ann Surg Oncol 2007;14(10):

25 1st line recommendation for RAIrefractory DTC (American Thyroid Association) Treatment with a targeted agent Only one completed and reported Phase III trial ( DECISION, 2013) Off label use of targeted agents common practice Increasing trial activity in this field but very small niche for development of new drugs Limited interest of pharmaceutical industry in this indication Brose MS et al. J Clin Oncol ASCO 2013;31(18_suppl):4

26 Selected targeted agents in advanced stages of clinical testing in TC Axitinib Phase II Carbozantinib Phase III MTC completed/reported 1 Lenvatinib Motesanib Pazopanib Phase III DTC on-going Phase II Phase II Sorafenib Phase III DTC completed/reported 2 Sunitinib Phase II Vandetanib Phase III MTC completed/reported 3 Important: all tested agents showed activity 1 Schöffski P et al. J Clin Oncol ASCO 2012;30(15_suppl):5508; 2 Brose MS et al. J Clin Oncol ASCO 2013;31(18_suppl):4; 3 Wells SA et al. J Clin Oncol 2012;30(2):

27 Vascular endothelial growth factor (VEGF) in advanced DTC Elevated VEGF expression associated with high tumorigenic potential in human TC cell lines 1 Association between increasing tumour size and VEGF expression 2 Increased levels of VEGF correlate with lymph node metastasis in PTC 3 Association with VEGF expression and development of distant metastasis 4 VEGF staining associated with increased risk of recurrence and decrease disease-free survival 5 1 Viglietto G et al. Oncogene 1995;11(8): ; 2 Bunone G et al. Am J Pathol 155(6): ; 3 Yu XM et al. Clin Cancer Res 2005;11(22): ; 4 Klein M et al. J Endocrinol 1999;161(1):41-49; 5 Lennard CM et al. Surgery 2001;129(5):

28 All tested VEGF-R inhibitors (VEGFRi) are active in thyroid cancer in Phase 2 Agent ORR (RECIST) mpfs (months) Axitinib 35-38% 15 not reached Levantinib 50% 13 Motesanib 14% 9 Pazopanib 49% 12 Sorafenib 15-23% 15 not reached Sunitinib 18-31% 13 not reached By permission of Cohen EEW. WCTC Toronto 2013

29 VEGFRi (here: pazopanib) induce durable radiological and biochemical responses Reprinted from Bible KC et al. Lancet Oncology 2010;11(10): , with permission from Elsevier

30 Sorafenib in DTC Oral kinase inhibitor against VEGFR-2, PDGF-R, B-RAF Inhibits B-RAF-stimulated DNA-synthesis and cell proliferation and induces apoptosis in TC cells Anti-angiogenic effects through VEGFR-2 and PDGF-R Inhibits B-RAF signaling and growth of all tested thyroid cell lines carrying B-RAF mutation Retards growth of ATC cell line xenografts in nude mice Studied in Phase 2 and Phase 3 DTC trials Was reimbursed in many countries even before results of Phase 3 became available in 2013

31 Phase 3 trial sorafenib vs. placebo in DTC ( DECISION ): design Locally advanced or metastatic radioactive iodine (RAI)- refractory DTC (N=380) R a n d o m i z e 1:1 Sorafenib 400 mg po bid Placebo Unblind Progression of disease (primary endpoint) Investigator's decision Sorafenib (cross over or continue) Follow-up until disease progression Off treatment Brose MS et al. BMC Cancer 2011;11:349

32 Phase 3 trial sorafenib vs. placebo in DTC ( DECISION ): key results Sorafenib significantly extended PFS, the primary endpoint of the study, compared to placebo PFS was evaluated by an independent radiological committee using RECIST Median PFS was 10.8 vs. 5.8 months (HR=0.587 [95% CI, ]; p<0.0001) Safety and tolerability in the study were consistent with the known profile of sorafenib At time of progression, 71% of patients in placebo arm crossed over to open-label sorafenib No statistically significant difference in overall survival, and median overall survival not yet reached in either arm Brose MS et al. J Clin Oncol ASCO 2013;31(18_suppl):4

33 Mode of action of VEGFRi in DTC? Mutations? Refractory DTC harbour mutations in BRAF, RAS of Pi3K Presence of these mutations not a prerequisite for activity No evidence of VEGF-R mutations or amplifications Angiogenesis? DTC are high vascular cancers with high expression of VEGF/VEGF-R However, ligand-directed therapies (aflibercept, bevacizumab) seem to be inactive

34 VEGF-Ri is to be regarded as the new standard? Efficacy All agents tested so far found to be active Clear extension of PFS over placebo for sorafenib (Phase 3) and vandetanib (Phase 2) Responses can be very durable Complete responses are uncommon Overall survival benefit unlikely ever to be demonstrated due to poststudy treatments Long term safety and subjective patient benefit Key concerns in a disease with relatively slow natural evolution is long term safety Still an important field for clinical research

35 Re-sensitizing refractory DTC to RAI by MEK1/2 inhibitor selumetinib From Ho AL et al. New Engl J Med J 2013;368(7): Copyright (2013) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

36 Re-sensitizing refractory DTC to RAI by MEK1/2 inhibitor selumetinib From Ho AL et al. New Engl J Med J 2013;368(7): Copyright (2013) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

37 Growing evidence for B-RAF inhibition in PTC: vemurafenib V600E mutation much more common in TC than in melanoma Early experience in V600E mutated PTC very promising Kim KB et al. Thyroid 2013 [Epub ahead of print]

38 Medullary thyroid carcinoma (MTC)

39 MTC biology MTC accounts for 5% of thyroid cancers Distant metastasis carries a poor prognosis with median OS in historical series in the range of 2 years 75% sporadic 65% RET mutated 25% hereditary Almost universally RET mutated RET protooncogene is located on 10q11.2 Signals through multiple pathways and regulates cell survival, growth and differentiation

40 MTC is a distinct entity Arise from the parafollicular or c-cells of the thyroid Non-thyrocyte cancer, does not take up iodine MTC has worse prognosis than DTC, still many patients with metastatic disease survive for years with limited symptoms Associated with paraneoplastic symptoms related to the hormone producing capacity of the C-cells Apart from medication against diarrhea many patients do not require any specific treatment Presence of nodal metastasis does have prognostic impact, in contrast to DTC

41 Treatment of MTC Total thyroidectomy and node dissection Postoperative calcitonin should fall to undetectable levels Life-long substitution with physiological doses of thyroxine Most frequent sites of metastasis lymph nodes, liver, lung, bone Chemotherapy in inoperable, progressive, symptomatic disease Symptomatic response to doxorubicin or 5-FU/DTIC 5-20% Limited symptomatic benefit of IFN or somatostatin analogs Limited efficacy of radionuclides (anti CEA mab, 90Yttrium- DOTATOC, ) Multiple kinase inhibitors tested and active Two drugs FDA-approved

42 Vandetanib Oral tyrosine kinase inhibitor blocking activity of RET-derived oncoproteins Inhibits tumour growth of RET-transformed TC cells in nude mice Additional activity against EGF-receptor and VEGF-signaling pathways, both involved in TC pathogenesis Phase II and III studies in MTC completed and reported ( ZETA ) Wells SA et al. J Clin Oncol 2010;28(5): ; Wells SA et al. J Clin Oncol 2012;30(2):

43 Phase II vandetanib in patients with hereditary MTC Wells SA et al. J Clin Oncol 2010;28(5): Reprinted with permission. (2010) American Society of Clinical Oncology. All rights reserved

44 Phase 3 ZETA trial: progression-free survival by central review Wells SA et al. J Clin Oncol 2010;28(5): Reprinted with permission. (2010) American Society of Clinical Oncology. All rights reserved

45 Phase 3 ZETA trial: other notable features Significantly higher objective response rate Biochemical responses Calcitonin (69% vs. 3%, p<0.0001) CEA (52% vs. 2%, p<0.0001) Significant delay in time to worsening of pain (hazard ratio 0.61, p= 0.006) Unlikely to see an overall survival difference (cross-over allowed) Wells SA et al. J Clin Oncol 2010;28(15_suppl):5503

46 Phase 3 ZETA trial: response rate per mutational subtype Objective response rate: Summary of subgroup analyses (randomized phase) Patient subgroup and randomized treatment Hereditary MTC Vandetanib, 300 mg Placebo Sporadic RET mutation positive Vandetanib, 300 mg Placebo Sporadic RET mutation negative Vandetanib, 300 mg Placebo Sporadic RET mutation unknown Vandetanib, 300 mg Placebo Sporadic M918T mutation positive Vandetanib, 300 mg Placebo Sporadic M918T mutation negative Vandetanib, 300 mg Placebo Sporadic M918T mutation unknown Vandetanib, 300 mg Placebo Wells SA et al. J Clin Oncol 2010;28(15_suppl):5503 No. of patients Responses No. %

47 Cabozantinib Oral tyrosine kinase inhibitor targeting MET, VEGFR-2, RET, including common mutants of MET and RET Inhibits angiogenesis, tumour proliferation, migration and tumour cell survival Phase I and III studies in MTC completed and reported ( EXAM ) Schöffski P et al. J Clin Oncol ASCO 2012;30(15_suppl):5508

48 Kurzrock R et al. J Clin Oncol 2011;29(19): MTC patients in cabozantinib Phase I trial

49 Phase 3 EXAM trial: progression-free survival by central review Probability of Survival Cabozantinib Placebo Median PFS (months) year PFS 47.3% 7.2% HR (95% CI) 0.28 (0.19, 0.40) p< Months Schöffski P et al. J Clin Oncol ASCO 2012;30(15_suppl):5508

50 Different patient selection in Phase 3 explains variable efficacy outcomes Disease Characteristics RECIST progression EXAM N=330 ZETA N=331 Inoperable, locally advanced or metastatic MTC Required within 14 months of study entry Not required Patients in placebo arm, n PFS (placebo arm) 4 months 19 months 1 year PFS rate (placebo arm) 7% 63% a Schöffski P et al. WCTC 2013; Schöffski P et al. J Clin Oncol ASCO 2012;30(15_suppl):5508; Wells SA et al. J Clin Oncol 2012;30(2):

51 Systemic therapy in thyroid cancer DTC VEGFR TKI have consistently shown efficacy in RAI-refractory patients Responses are seen in all histological subtypes and molecular phenotypes Phase 3 data show improved PFS of sorafenib over placebo No head-to-head comparison of VEGFR TKI performed BRAF/MEK inhibition currently evaluated in Phase 2 New strategies include combinations of different antiangiogenic agents, VEGRFi/mTORi, Pi3K/MAPKi

52 Systemic therapy in thyroid cancer MTC Tyrosine kinase inhibitors targeting RET are effective Vandetanib showed improved PFS over placebo and was approved in 2011 Cabozantinib showed improved PFS over placebo and was approved by FDA in 2012 No head-to-head comparison available or planned Tumours harbouring M918T mutation appear to demonstrate greater benefit RET mutation alone cannot explain all the efficacy observed Few options for TKI-refractory patients and limited trial activity

53 Financial implications Drug Dose (mg) Frequency Estimated monthly cost (US$) Estimated annual cost (US$) Sunitinib 50 qd Vemurafenib 960 bid Vandetanib 300 qd Cabozantinib 140 qd Sorafenib 400 bid Axitinib 5 bid Everolimus 10 qd Pazopanib 800 qd Cohen EEW. WCTC Toronto Data from de Souza JA. 2013

54 New network for trials: EORTC Endocrine Tumours Task Force (EnTF) Contact: Schlumberger M. Villejuif (F)

55 THANK YOU!