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 10th Asia and Oceania Thyroid Association Congress, Bali 23rd October 2012

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

Thyroid cancer subtypes DTC 85% cured with treatment 7% 15% 25% 35% 100% “Unmet need” ~1/3 controlled by I-131, T4 and/or local Rx Thyroid carcinoma has 3 main histologic types: differentiated (including papillary, follicular, and Hürthle cell), medullary, and anaplastic (aggressive undifferentiated tumor). Of 53,856 patients treated for thyroid carcinoma between 1985 and 1995, 80% had papillary carcinoma, 11% had follicular carcinoma, 3% had Hürthle cell carcinoma, 4% had medullary carcinoma, and 2% had anaplastic thyroid carcinoma.12 The 10-year relative survival rates for patients with papillary, follicular, and Hürthle cell carcinomas were 93%, 85%, and 76%, respectively.12 Almost 10% of patients with papillary carcinoma and up to 25% of those with follicular carcinoma develop distant metastases. Approximately 50% of these metastases are present at diagnosis.48 Distant metastases occur even more often in patients with Hürthle cell cancer (35%) and those diagnosed after age 40 years.82,84 The sites of reported distant metastases among 1231 patients in 13 studies were lung (49%), bone (25%), both lung and bone (15%), and the central nervous system (CNS) or other soft tissues (10%) Although some patients, especially younger ones, with distant metastases survive for decades, approximately 50% die within 5 years regardless of tumor histology.48 …10-year mortality 15% recurrent/metastatic disease Tuttle et al J Natl Compr Canc Netw 2010;8:1228-1274

Metastatic Disease: existing therapies Regional LNs -surgery Brain -Surgery -XRT -RAI Lung Bone -Bisphosphonates Of all mets: Brain 10%, lung 65%, bone 40%

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

Growth signalling: targets for new drugs Somatic mutations in papillary thyroid cancer: BRAF 30-70% RAS 0-20% RET/PTC 20-50% PI3-kinase pathway also involved (PIK3CA copy number gain and mutation; PTEN): FTC 55% PTC 24% ATC 58% BRAF RAS RET RET/PTC PI3K PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation 25 of 81 (31%) benign thyroid adenoma (BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and 29 of 50 (58%) anaplastic thyroid cancer (ATC) Cell proliferation Differentiation Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13:1161-70.

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 Adapted from Brose et al BMC Cancer 2011;11:349

Rationale for targeting growth factor signalling cascades in thyroid cancer - Preclinical studies conditional expression of BRAFV600E in adult mice causes PTC Treatment with MEK inhibitor resulted in partial tumor regression Charles et al Cancer Res 2011;71:3863-71

Rationale for targeting growth factor signalling cascades in thyroid cancer - Clinical data Cote et al., 2003 N Engl J Med 2003;349: 1566-1569 Medullary thyroid cancer in MEN2: RET genotype/activity determines biological aggressiveness Papillary thyroid cancer: BRAFV600E connotes risk of death

BRAFV600E and immunohistochemistry mouse monoclonal antibody, clone VE1 (Capper and von Deimling) BRAFV600E positive by IHC positive by sequencing BRAFV600E positive by IHC negative by sequencing 10% (32% negative for both IHC and sequencing) 58% Bullock et al Endocr Rel Cancer 2012

Kinase inhibitors mimicking ATP within catalytic sites pseudosubstrate Wan et al Cell 2004;116:855-867 mimicking ATP within catalytic sites pseudosubstrate alteration of kinase stability sorafenib BRAF kinase

Phase Drug n CR(%) PR(%) SD(%) Medullary thyroid cancer Cohen et al 2 Axitinib 11 0 18 27 Schlumberger et al 2 Motesanib 91 0 2 48 Wells et al 2 Vandetanib 30 0 20 53 Robinson et al 2 Vandetanib 19 0 16 53 Kuzrock et al 1 Cabozantinib 37 0 29 41 Ahmed et al 2 Sorafenib 15 0 25 na Lam et al 2 Sorafenib 16 0 6 50 Hong et al 1 Sor’+tipifarnib 13 0 38 31 Carr et al 2 Sunitinib 7 0 50 na Differentiated thyroid cancer Cohen et al 2 Axitinib 45 0 31 42 Sherman et al 2 Motesanib 93 0 14 35 Gupta-Abramson et al 2 Sorafenib 30 0 23 53 Kloos et al 2 Sorafenib 41 0 15 56 Ahmed et al 2 Sorafenib 19 0 18 73 Carr et al 2 Sunitinib 28 3 28 37 Hong et al 1 Sor’+tipifarnib 22 0 4.5 36 Bible et al 2 Pazopanib 39 0 49 nr

Data from randomized, placebo-controlled studies

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)

Medullary Thyroid Cancer Vandetanib Cabozantinib

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

Vandetanib in MTC: phase III Placebo n = 100 HR/OR p value 1°endpoint Progression free survival 30.5 mo 19.3 mo 0.46 (0.31-0.69) 0.0001 2°endpoints Objective response rate 45% 13% 5.48 (2.99-10.79) <0.001 Disease control rate 87% 71% 2.64 (1.48-4.69) 0.001 Calcitonin response rate 69% 3% 72.9 (26.2-303.2) CEA response rate 52% 2% 52.0 (16.0-320.3) Wells et al J Clin Oncol 2012;30:134-141

Vandetanib in MTC: phase III- PFS Wells et al J Clin Oncol 2012;30:134-141

Vandetanib in MTC: phase III- OS Overall survival data immature (HR 0.89; 0.48-1.65) A final survival analysis planned when 50% pts dead Wells et al J Clin Oncol 2012;30:134-141

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;30:134-141

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: Cabo Placebo 11.2 mo 4.0 mo (HR 0.28, 0.19-0.4, p < 0.0001) ORR: 28% 0% (p, ns) Documented RECIST progression at baseline Schoffski et al J Clin Oncol 2012;30: suppl abstr 5508

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

Differentiated thyroid cancer Vandetanib (Lenvatinib) (Sorafenib)

Vandetanib in DTC: phase II 16 medical centres in Belgium, Denmark, France, Norway, Spain, Sweden, and Switzerland Vandetanib n = 72 Placebo n = 73 HR/OR p value 1°endpoint Progression free survival 11.1 mo 5.9 mo 0.63 (0.54-0.74) 0.008 2°endpoints Objective response rate 8% 5% 1.57 (0.42-5.81) 0.501 Disease control rate 57% 42% 1.79 (0.93-3.46) 0.082 one-sided p Leboulleux et al Lancet Oncol 2012;13:897–905

Vandetanib in DTC: phase II - PFS Progression-free survival numerical improvement in PFS benefit for patients with papillary thyroid cancer who were treated with vandetanib compared with other histological subtypes, although this difference was not significant (papillary thyroid cancer HR 0・52, 95% CI 0・26–1・02, two-sided p=0・056; follicular thyroid cancer or poorly differentiated carcinoma 0・83, 0・51–1・36, p=0・461; figure 3). Leboulleux et al Lancet Oncol 2012;13:897–905

Vandetanib in DTC: phase II - OS (crossover from placebo to vandetanib allowed, confouding assessment of the effects of treatment on overall survival) Almost half of patients treated with vandetanib (30 [41%] of 73 patients) had a dose reduction=(16 [22%]) and/or dose interruption (28 [38%]), mainly because of adverse events- diarrhoea, QT prolongation etc Leboulleux et al Lancet Oncol 2012;13:897–905

Vandetanib in DTC: phase II - OS 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) Leboulleux et al Lancet Oncol 2012;13:897–905

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 35% of pts required dose reduction for management of toxicity, and 23% were withdrawn from therapy due to toxicity. The most common adverse events were hypertension 64% (Gr 3: 4%), fatigue 55% (Gr3: 7%), diarrhea 45% (Gr3: 5%), decreased appetite 44% (Gr3: 2%), weight loss 43% (Gr3: 4%), and proteinuria 39% (Gr3: 7%). 5 pts (8.6%) experienced Gr 4 events. Sherman et al, J Clin Oncol 29: 2011 (suppl; abstr 5503)

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 58-84 weeks Partial responses in up to 25% Disease control rates (SD+PR) 59-100% Dose reductions due to AEs (mostly grade I-II) in 62% Brose et al BMC Cancer 2011;11:349

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.

Other kinase inhibitors Dabrafenib selective for mutant BRAF Motesanib Axitinib Pazopanib Sunitinib Targeted inhibition of Src kinase with dasantinib blocks thyroid cancer growth and metastasis

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

Kinase inhibitors in other malignancies

Kinase inhibitors: haematologic malignancies CML: BCR-ABL Imatinib Nilotinib Dasatinib complete response for up to 8 years in 85% of patients Hairy cell leukaemia: BRAFV600E Vemurafenib

Kinase inhibitors: melanoma Chapman et al N Engl J Med 2011;364:2507-16 Flaherty et al N Engl J Med 2012;367:107-114 BRAF inhibitor MEK inhibitor

Kinase inhibitor combinations to overcome resistance: melanoma dabrafenib+trametinib dabrafenib Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Flaherty et al N Engl J Med 2012;doi: 10.1056

Pharmacogenomics

BRAFV600E mutation: pharmacogenomics Clear evidence from hairy cell leukemia and melanoma that response to BRAF-targeted therapy is strongly associated with tumor genotype 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) MEK inhibitors preferentially inhibit cells lines containing mutant BRAF; Leboeuf et al JCEM 2008;93:2194 Sorafenib preferentially inhibits PTCs with RET/PTC1; Henderson et al Clin Cancer Res 2008;14:4908 ns Leboeuf et al JCEM 2008;93:2194 Sherman et al N Engl J Med 2008;359:31

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;30:134-141

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

Thyroid Group at RNSH, Sydney Endocrine Surgeons Endocrinologists Pathologist Scientists Bruce Robinson Stan Sihdu Mark Sywak Diana Learoyd Dindy Benn Anne-Louise Richardson Anthony Gill Leigh Delbridge Martyn Bullock Rory Clifton-Bligh Julian Ip Jimmy Lee Justin Gundara PhD students and Matti Gild