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Recent progress of targeted kinase inhibitors in thyroid cancer A/Prof Rory Clifton-Bligh Kolling Institute of Medical Research, University of Sydney Department.

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Presentation on theme: "Recent progress of targeted kinase inhibitors in thyroid cancer A/Prof Rory Clifton-Bligh Kolling Institute of Medical Research, University of Sydney Department."— Presentation transcript:

1 Recent progress of targeted kinase inhibitors in thyroid cancer A/Prof Rory Clifton-Bligh Kolling Institute of Medical Research, University of Sydney Department of Endocrinology Royal North Shore Hospital, St Leonards, NSW Royal North Shore Hospital 10 th Asia and Oceania Thyroid Association Congress, Bali 23 rd October 2012

2 Overview  Scope of problem for thyroid cancer  Molecular targets for thyroid cancer  Data  Success of kinase inhibitors in other cancers  Pharmacogenomics  Conclusions

3 Thyroid cancer subtypes …10-year mortality DTC 85% cured with treatment 15% recurrent/metastatic disease 7% 15% 25% 35% 100% ~ 1/3 controlled by I-131, T4 and/or local Rx Tuttle et al J Natl Compr Canc Netw 2010;8: “Unmet need”

4 Metastatic Disease: existing therapies Regional LNs -surgery Brain -Surgery -XRT -RAI Lung -RAI Bone -RAI -XRT -Bisphosphonates

5 Challenge in designing clinical trials in DTC: (sometimes) indolent natural history Leboulleux et al Lancet Oncol 2012;13:897–905 Waterfall plot of best percentage change in target lesion size from baseline, placebo group from Vandetanib trial in DTC, phase II !

6 Growth signalling: targets for new drugs  Somatic mutations in papillary thyroid cancer: BRAF30-70% RAS0-20% RET/PTC 20-50%  PI3-kinase pathway also involved (PIK3CA copy number gain and mutation; PTEN): FTC55% PTC24% ATC58% Cell proliferation Differentiation Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13: PI3K BRAF RAS RET RET/PTC

7 Adapted from Brose et al BMC Cancer 2011;11:349 Growth signalling: targets for new drugs Tumor endothelial cell DTC tumor cell PDGF-β VEGF VEGFR-2 PDGFR-β PI3K BRAF RAS RET RET/PTC

8 Rationale for targeting growth factor signalling cascades in thyroid cancer - Preclinical studies  conditional expression of BRAF V600E in adult mice causes PTC  Treatment with MEK inhibitor resulted in partial tumor regression Charles et al Cancer Res 2011;71:

9 Rationale for targeting growth factor signalling cascades in thyroid cancer - Clinical data  Medullary thyroid cancer in MEN2: RET genotype/activity determines biological aggressiveness  Papillary thyroid cancer: BRAF V600E connotes risk of death Cote et al., 2003 N Engl J Med 2003;349:

10 BRAF V600E and immunohistochemistry mouse monoclonal antibody, clone VE1 (Capper and von Deimling) Bullock et al Endocr Rel Cancer % BRAF V600E positive by IHC positive by sequencing BRAF V600E positive by IHC negative by sequencing 10% (32% negative for both IHC and sequencing)

11 Kinase inhibitors  mimicking ATP within catalytic sites  pseudosubstrate  alteration of kinase stability Wan et al Cell 2004;116: sorafenib BRAF kinase

12 PhaseDrugnCR(%)PR(%)SD(%) Medullary thyroid cancer Cohen et al 2Axitinib Schlumberger et al2Motesanib Wells et al 2Vandetanib Robinson et al 2Vandetanib Kuzrock et al 1Cabozantinib Ahmed et al2Sorafenib15025na Lam et al 2Sorafenib Hong et al 1Sor’+tipifarnib Carr et al 2Sunitinib7050na Differentiated thyroid cancer Cohen et al2Axitinib Sherman et al 2Motesanib Gupta-Abramson et al2Sorafenib Kloos et al 2Sorafenib Ahmed et al 2Sorafenib Carr et al 2Sunitinib Hong et al 1Sor’+tipifarnib Bible et al 2Pazopanib39049nr

13 Data from randomized, placebo- controlled studies

14 Typical inclusion criteria  Measurable disease at least one measurable lesion as measured by CT or MRI  Disease progression (RECIST)  (RAI-refractory disease: for DTC trials)

15 Medullary Thyroid Cancer  Vandetanib  Cabozantinib

16 Vandetanib  RET, VEGF receptor, and EGFR tyrosine kinases  MTC: approved for patients with unresectable locally advanced or metastatic disease (US, Canada, Europe)

17 Vandetanib in MTC: phase III Vandetanib n = 231 Placebo n = 100 HR/ORp value 1°endpoint Progression free survival 30.5 mo19.3 mo0.46 ( ) °endpoints Objective response rate 45%13%5.48 ( ) <0.001 Disease control rate 87%71%2.64 ( ) Calcitonin response rate 69%3%72.9 ( ) <0.001 CEA response rate 52%2%52.0 ( ) <0.001 Wells et al J Clin Oncol 2012;30:

18 Vandetanib in MTC: phase III- PFS Wells et al J Clin Oncol 2012;30:

19 Vandetanib in MTC: phase III- OS Wells et al J Clin Oncol 2012;30: Overall survival data immature (HR 0.89; ) A final survival analysis planned when 50% pts dead

20 Side-effects: vandetanib  Diarrhoea (16%)  Palmar-plantar erythrodysethesia (13%)  Hypertension (8%)  Prolonged QT  Headache  Nausea  Leukopenia  Discontinued therapy because of AE: Vandetanib 12% Placebo 3% Wells et al J Clin Oncol 2012;30:

21 Cabozantinib (XL184) in MTC: phase III  MET, VEGFR2, RET  EXAM trial, international multicentre  330 pts, median age 55 y Cabozantinib n = 219 Placebo n = 111  PFS: CaboPlacebo 11.2 mo4.0 mo (HR 0.28, , p < )  ORR:28%0% (p, ns) Schoffski et al J Clin Oncol 2012;30: suppl abstr 5508

22 Side-effects: cabozantinib  Diarrhoea (16%)  Palmar-plantar erythrodysethesia (13%)  Hypertension (8%)

23 Differentiated thyroid cancer  Vandetanib  (Lenvatinib)  (Sorafenib)

24 Vandetanib in DTC: phase II  16 medical centres in Belgium, Denmark, France, Norway, Spain, Sweden, and Switzerland Vandetanib n = 72 Placebo n = 73 HR/ORp value 1°endpoint Progression free survival 11.1 mo5.9 mo0.63 ( ) °endpoints Objective response rate 8%5%1.57 ( ) Disease control rate 57%42%1.79 ( ) Leboulleux et al Lancet Oncol 2012;13:897–905

25 Vandetanib in DTC: phase II - PFS Leboulleux et al Lancet Oncol 2012;13:897–905 Progression-free survival

26 Vandetanib in DTC: phase II - OS Leboulleux et al Lancet Oncol 2012;13:897–905 (crossover from placebo to vandetanib allowed, confouding assessment of the effects of treatment on overall survival)

27 Two patients in the vandetanib group and one in the placebo group died from “treatment- related” serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group) Vandetanib in DTC: phase II - OS Leboulleux et al Lancet Oncol 2012;13:897–905

28 Lenvatinib (E7080)  VEGFR1-3, FGFR1-4, RET, KIT, PDGFRβ  Phase II RAI-refractory DTC (papillary, follicular or Hurthle Cell) and disease progression demonstrated by RECIST during the prior 12 months  58 pts: PR 50% (CI, 37-63%)  35% required dose reduction for management of toxicity, and 23% were withdrawn Sherman et al, J Clin Oncol 29: 2011 (suppl; abstr 5503)

29 Sorafenib  Phase III trial ongoing (DECISION)  Phase II: four trials including 168 patients with thyroid cancer treated with sorafenib Median progression-free survival (PFS) ranged from weeks Partial responses in up to 25% Disease control rates (SD+PR) % Dose reductions due to AEs (mostly grade I- II) in 62% Brose et al BMC Cancer 2011;11:349

30 Thyroid dysfunction in patients on kinase inhibitors  Elevated TSH/requirement for higher Thyroxine dose in Thyroid cancer patients: 49-78% of patients receiving vandetanib  Hypothyroidism in patients with intact thyroid (eg renal cell cancer) In 36-85% pts treated with sunitinib In 18-68% pts treated with sorafenib Torino et al Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219–28.

31 Other kinase inhibitors  Dabrafenib selective for mutant BRAF  Motesanib  Axitinib  Pazopanib  Sunitinib

32 Combinations  Receptor tyrosine kinase + MEK inhibitor dabrafenib + MEKi  RAI + MEK inhibitor Selumetinib (AZD6244)*  TKI + mTOR inhibitor Temsirolimus + sorafenib* BRAF mTOR *Ho et al J Clin Oncol 2012;30:suppl abstr 5509 Sherman E et al J Clin Oncol 2012;30:suppl abstract 5514 MEK I-131

33 Kinase inhibitors in other malignancies

34 Kinase inhibitors: haematologic malignancies  CML: BCR-ABL Imatinib Nilotinib Dasatinib  complete response for up to 8 years in 85% of patients  Hairy cell leukaemia: BRAF V600E Vemurafenib

35 Kinase inhibitors: melanoma Chapman et al N Engl J Med 2011;364: Flaherty et al N Engl J Med 2012;367: BRAF inhibitorMEK inhibitor

36 Kinase inhibitor combinations to overcome resistance: melanoma Flaherty et al N Engl J Med 2012;doi: dabrafenib dabrafenib+trametinib

37 Pharmacogenomics

38 BRAF V600E mutation: pharmacogenomics  In vitro experience suggests that thyroid cell lines containing mutant BRAF cell lines are more sensitive to BRAF or MEK inhibitors  ?no clinical evidence for pharmacogenomic effects in thyroid cancer: Motesanib ( Phase 2, 93 pts) DCR BRAF+60% (6/10) BRAF-33% (5/15)  Clear evidence from hairy cell leukemia and melanoma that response to BRAF-targeted therapy is strongly associated with tumor genotype Leboeuf et al JCEM 2008;93:2194 Sherman et al N Engl J Med 2008;359:31 ns

39 RET mutation: pharmacogenomics  In subgroup analysis, suggestion of higher response rate to vandetanib in sporadic tumors with M918T mutation  in vitro, Vandetanib does not inhibit the V804 mutations in RET Wells et al J Clin Oncol 2012;30:

40 Conclusions  Thyroid cancer mortality is related to: Well-defined activation of growth factor signalling pathways Loss of iodine uptake (DTC)  These signalling pathways are targets for several drugs in clinical use or development Many pts require dose reduction or drug withdrawal to manage toxicity Some treatment-related deaths reported  Vandetanib has FDA approval for use in MTC  Balance of risks vs benefits needs to be carefully addressed in phase III trials Need greater definition of those pts who will have survival benefit from treatment

41 Thyroid Group at RNSH, Sydney Endocrine Surgeons Endocrinologists PathologistScientists Bruce RobinsonStan Sihdu Mark Sywak Diana Learoyd Dindy BennAnne-Louise Richardson Anthony Gill Leigh Delbridge Martyn Bullock Rory Clifton-Bligh Julian Ip Jimmy Lee Justin Gundara PhD students and Matti Gild

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