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Recent progress of targeted kinase inhibitors in thyroid cancer

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.

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Recent progress of targeted kinase inhibitors in thyroid cancer

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  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 10th Asia and Oceania Thyroid Association Congress, Bali 23rd 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. 85% cured with treatment 35% 100% 25% 15% “Unmet need” 7% ~1/3 controlled by I-131, T4 and/or local Rx Thyroid cancer subtypes DTC 15% recurrent/metastatic disease …10-year mortality Tuttle et al J Natl Compr Canc Netw 2010;8:1228-1274

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

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

  6. 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% RET RET/PTC RAS BRAF Growth signalling: targets for new drugs PI3K Cell proliferation Differentiation Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13:1161-70.

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

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

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

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

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

  12. 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

  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 Wells et al J Clin Oncol 2012;30:134-141

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

  19. 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

  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;30:134-141

  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: Cabo Placebo 11.2 mo 4.0 mo (HR 0.28, 0.19-0.4, p < 0.0001) • 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 Leboulleux et al Lancet Oncol 2012;13:897–905

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

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

  27. 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

  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 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

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

  33. Kinase inhibitors in other malignancies

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

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

  36. Kinase inhibitor combinations to overcome resistance: melanoma dabrafenib+trametinib dabrafenib Flaherty et al N Engl J Med 2012;doi: 10.1056

  37. Pharmacogenomics

  38. 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 ns BRAFV600E mutation: pharmacogenomics Leboeuf et al JCEM 2008;93:2194 Sherman et al N Engl J Med 2008;359:31

  39. 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 RET mutation: pharmacogenomics Wells et al J Clin Oncol 2012;30:134-141

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

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