Targeted Therapy for Thyroid Cancer

1. Targeted Therapy for Thyroid Cancer Management of Advanced Non-Medullary Thyroid Cancer R Michael Tuttle, MD Professor of Medicine , Endocrine Service Memorial Sloan Kettering Cancer Center New York, NY

2. Targeted TherapiesWhat are our options? Systemic Therapies Chemotherapy/Novel Therapies Radioactive Iodine Surgery External Beam Radiation Embolization Often, multiple “targeted therapies” are used over the life time of a patient with advanced thyroid cancer

3. 23 year old females/p total thyroidectomy3.5 cm PTC, 18/26 lymph nodes positiveHer first diagnostic WBS in preparation for RRA RAI CXR

4. 42 year old male Wide spread metastatic moderately differentiated papillary thyroid cancer

5. 38 year old female, metastatic papillary thyroid cancerdiagnosed age 15, multiple RAI therapies for RAI avid pulmonary mets, at age 36 developed bone mets

6. 73 year old male with poorly differentiated papillary thyroid cancer Positive on diagnostic RAI scan CT Scan T10 Lesion

7. 58 year old male with wide spread metastatic Hürthle Cell Carcinoma

8. 41 year old femaleLocally aggressive, poorly differentiatedWide spread progressive distant mets

9. 67 year old female5 cm tall cell variant PTC with extrathyroidal extension150 mCi RRA one year ago, neck uptake onlyNow with suppressed Tg 378 ng/mL CXR Post therapy FDG PET

10. Traditional chemotherapy • Overall response rates less than 0-20% • Doxorubicin (FDA approved for thyroid cancer), Cisplatin • Responses • Generally partial and short lived • Response rates not determined by RECIST criteria • Seldom used in clinical practice • NCCN & ATA guidelines specifically note that failure of traditional chemotherapy is not a requirement prior to entry into experimental trials

11. Molecular Abnormalities in the Primary Tumor RAS RAS GTP P GDP BRAF mSos Grb2 PI3K MEK AKT MTOR ERK c-jun c-fos Proliferation Growth MAP Kinase Pathway RET/PTC Tyr 70% of all PTC have mutations in either the RET/PTC, RAS or BRAF

12. Molecular Abnormalities in the Primary Tumor RAS RAS GTP P GDP BRAF mSos Grb2 PI3K MEK AKT MTOR ERK c-jun c-fos Proliferation Growth MAP Kinase Pathway RET/PTC VEGF RET PDGF EGF Insulin IGF HGF FGF Tyr

13. Specific Targets Differ Between Agents Adapted from Licitra, E Journal Cancer 2010

14. Specific Targets Differ Between Agents Adapted from Licitra, E Journal Cancer 2010

15. Clinical Trials in Non-Medullary Thyroid Cancer Modified from Tuttle RM. Clinical Thyroidology 2009; 21(1):3-7.

16. 1 Phase 2 Clinical Trials 2 3 4 5 6 7 8 9 10 11 1Ain 2000, 2Mrozek 2006, 3Ain 2007, 4Woyach 2008, 5Argiris 2008, 6Pennell 2008, 7Sherman 2008, 8Cohen 2008, 9Gupta-Abramson 2008, 10Kloos 2009, 11Bible 2010 Adapated from Tuttle RM. Clinical Thyroidology 2009

17. Clinical Implications of Trial Design As described in the published thyroid cancer clinical trials • Phase 2 Trials • Entry criteria • RAI refractory disease • Included all histology subtypes (PTC, FTC, ATC, HCC) • No placebo arm • Variable requirements for progression prior to entry • Variable definitions of progression prior to entry • Magnitude of the change in size • Time interval • Endpoint • Evaluation of change in size of lesions • RECIST criteria

18. Variations in Rate of Progression in Patients with Metastatic Disease Impact on Eligibility Criteria For Clinical Trials Goal Line Volume of Disease Anaplastic RAI Refractory RAI Responsive Normal Life Span

19. TKI therapy may alter rate of growth MD Anderson Experience: Sorafenib/Sunitinib Cabanillas et al. JCEM June 2010

20. TKI therapy may alter rate of growth Pazopanib therapy Percentage change in tumor size (%) Time Bible et al. Lancet Oncology 2010

21. Toxicity Profile • Dose related and usually reversible • Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension • About 1% risk of death related to the drugs • Results in discontinuation of the drug in 15-20% of study subjects • Temporary interruption of drug and re-institution at lower doses in as many as 30-50% of study subjects

22. Translating All This Into the Clinic The essence of my clinical consults in October 2012 • Patient Selection • Clinically significant • Structurally progressive • RAI refractory thyroid cancer • Shortened life span if untreated • Likely Outcomes • Unlikely to “cure” • Occasionally cause the tumors to shrink • More commonly result in stable disease (50% of the time) • Toxicities are real, but tolerable, and usually reversible • May or may not prolong overall survival

23. Can we use targeted therapy to improve RAI avidity? LesionalDosimetry124I PET Sgouroset al, J Nucl Med. 2004 Aug;45(8):1366-72

24. Metastatic Papillary Thyroid Cancer Serum thyroglobulin is 13,470 ng/mL Post-Therapy Scan CT Scan

25. Metastatic Papillary Thyroid Cancer After 2 RAI therapies Before RAI

26. Lesional Dosimetry 9,000 rads 9,500 rads 8,500 rads 124 I PET Scan 120 mCi administered activity Therapeutic Goal: 8,500 – 10,000 rads

27. Whole Body RAI Scan Anterior Posterior 64 year old Stage IV, Follicular Thyroid Cancer

28. Lesional Dosimetry If 400 mCi131I administered 800 rads 3500 rads Therapeutic Goal: 8,500 – 10,000 rads

29. Heterogeneity in absorbed dose distribution in individual patient67 yo male, 9 cm, locally invasive, poorly differentiated thyroid cancerPresented with pulmonary mets on pre-op CXRStimulated Tg 245 ng/mL CT RAI Fused 250 mCi

30. Heterogeneity in absorbed dose distribution in individual patient 124I PET 42 Gy 3.7 Gy 124I PET 437 mCi I131 Desiree Deandreis, MSKCC

31. Heterogeneity in absorbed dose distribution in individual lesion 75% Yellow 50% Red 25% Blue 10% Green Sgouros et al. J Nuc Med. 45(8):1366-72, 2004.

32. Targeted Therapy to Improve RAI Avidity p21 ras p21 ras Tyr P B-Raf mSos PI3K Grb2 MEK AKT ERK mTOR c-jun c-fos ret/PTC GTP BRAF Activation Decreases NIS Decreases TSH receptor Decreases Tg

33. BRAF Off BRAF On BRAF Off BRAF On BRAF Inhibitor BRAF On MEK Inhibitor Chakravarty, Fagin. JCI 2011

34. MEK Inhibitor (AZD6244) Re-differentiation Trial Treat with oral MEK inhibitor for 4 weeks Post- MEK 124I PET scan Pre- MEK 124I PET scan Ho et al, In press, NEJM 2012

35. Baseline After MEK

36. Baseline After MEK After MEK Baseline

37. Trial Continues Lesionaldosimetry promising Treat with RAI Discontinue MEK inhibitor 2 days later Repeat CT scans 2 months later Ho et al, In press, NEJM 2012

38. LESION 3 19mm 10.8 mm LESION 4 12.9 mm 6 mm

39. LESION 5 11.4 mm 5.2 mm Serum Thyroglobulin Response Prior to MEK and RAI: 789 ng/mL (negative antibodies) 2 months after MEK and RAI: 35 ng/mL (negative antibodies)

40. Radioiodine Responses of Advanced Thyroid Cancers Treated with Selumetinib Genotype of Primary 45% BRAF 25% NRAS 15% RET/PTC 15% Wild Type 20 patients RAI refractory distant mets 25% PTC, 40% TCV, 35% PDTC 61 yrs old (44-77) 11M:9F Ho et al, In press, NEJM 2012

41. Radioiodine Responses of Advanced Thyroid Cancers Treated with Selumetinib 20 pts 12/20 had increased RAI uptake after 1 month selumetinib pre-treatment 8/20 had increase in RAI uptake sufficient to justify additional RAI therapy 5/8 had partial response by RECIST on follow up CT after RAI therapy 3/8 had stable disease after RAI therapy 8/8 had decrease in Tg (median 89% decrease) after RAI therapy Ho et al, In press, NEJM 2012

42. Molecular Profile of Differentiated Thyroid Cancer Receptor Tyrosine Kinase p21 ras p21 ras GTP Tyr P GDP B-Raf mSos PI3K Grb2 MEK AKT ERK mTOR c-jun c-fos MEK Inhibition Dramatic increase in RAI avidity Clinical significant response to therapy ret/PTC BRAF Mutation Response did not correlate with BRAF mutation status Not restricted to BRAF tumors Future Uses Enhance RAI effectiveness Distant metastases Loco-regional metastases Remnant ablation

43. Targeted TherapiesWhat are our options? Systemic Therapies Chemotherapy/Novel Therapies Radioactive Iodine Surgery External Beam Radiation Embolization Often, multiple “targeted therapies” are used over the life time of a patient with advanced thyroid cancer