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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 Targeted Therapies What 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 23 year old female s/p total thyroidectomy 3.5 cm PTC, 18/26 lymph nodes positive Her first diagnostic WBS in preparation for RRA RAI CXR 42 year old male Wide spread metastatic moderately differentiated papillary thyroid cancer 38 year old female, metastatic papillary thyroid cancer diagnosed age 15, multiple RAI therapies for RAI avid pulmonary mets, at age 36 developed bone mets 73 year old male with poorly differentiated papillary thyroid cancer Positive on diagnostic RAI scan CT Scan T10 Lesion 58 year old male with wide spread metastatic Hürthle Cell Carcinoma 41 year old female Locally aggressive, poorly differentiated Wide spread progressive distant mets 67 year old female 5 cm tall cell variant PTC with extrathyroidal extension 150 mCi RRA one year ago, neck uptake only Now with suppressed Tg 378 ng/mL CXR Post therapy FDG PET 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 Molecular Abnormalities in the Primary Tumor MAP Kinase Pathway RET/PTC RAS RAS Tyr PI3K AKT P GTP GDP mSos Grb2 70% of all PTC have mutations in either the RET/PTC, RAS or BRAF BRAF MEK ERK MTOR c-jun c-fos Proliferation Growth Molecular Abnormalities in the Primary Tumor MAP Kinase Pathway VEGF RET PDGF EGF Insulin IGF HGF FGF RET/PTC RAS RAS Tyr PI3K P GTP GDP mSos Grb2 BRAF MEK AKT ERK MTOR c-jun c-fos Proliferation Growth Specific Targets Differ Between Agents VEGF RET Imatinib RET/ PTC C-KIT EGFR C-MET PDGFR √ √ √ √ √ Axitinib √ Motesanib √ √ Sorafenib √ √ √ Sunitinib √ √ √ Vandetanib √ √ √ Cabozantinib √ √ Linvatinib √ Pazopanib √ Vemurafenib BRAF √ √ √ √ √ √ √ √ √ √ Adapted from Licitra, E Journal Cancer 2010 √ Specific Targets Differ Between Agents VEGFR 1, 2, 3 VEGFR 1, 2 VEGFR 2 VEGFR 3 Imatinib Axitinib √ Motesanib √ Sorafenib √ Sunitinib √ Vandetanib √ Cabozantinib √ √ Linvatinib Adapted from Licitra, E Journal Cancer 2010 Clinical Trials in Non-Medullary Thyroid Cancer Agent Mechanism Cohorts Ain 2000 Paclitaxel Anti-microtubule 20 ATC Mrozek 2006 Celecoxib Cox-2 inhibitor 32 DTC Ain 2007 Thalidomide Anti-angiogenesis 29 DTC, 7 MTC Woyach 2008 Vorinostat HDAC-I 16 DTC, 3 MTC Arigiris 2008 Adria & IF2 Cytotoxic & Immun 15 DTC, 2 ATC Pennell 2008 Gefitinib EGFR 18 DTC, 5 ATC, 4 MTC Sherman 2008 Motesanib VEGF, PDGFR, Kit 93 DTC Cohen 2008 Axitinib VEGF 46 DTC, 12 MTC, 2 ATC GuptaAbramson 2008 Sorafenib VEGF, BRAF 27 DTC, 1 MTC, 2 ATC Kloos 2009 Sorafenib VEGF, BRAF 43 DTC, 9HC, 4 ATC Bible 2010 Pazopanib VEGF, PDGFR, Kit 26 DTC, 11 HC Hayes 2012 Selumetanib MEK 32 PTC Modified from Tuttle RM. Clinical Thyroidology 2009; 21(1):3-7. Phase 2 Clinical Trials Progression Stable Paclitaxel (ATC) 1 Celecoxib (DTC) 2 Thalidomide (DTC/ATC) 3 Vorinostat (DTC/MTC) 4 Adria/IF alpha (DTC/ATC) 5 Gefitinib (DTC/ATC/MTC) 6 Motesanib (DTC) 7 81% Axitinib (DTC/MTC/ATC) 8 67% Sorafenib (DTC/ATC/MTC) 9 Sorafenib (DTC/ATC) Pazopanib (DTC) Partial 5 0% 47 5% 47% 38% 3% 32% 56% 63% 6 14 40% 40% 28% 51% 64% 10 11 Complete 46% 20% 49% 40% 60% 80% 100% 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 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 Variations in Rate of Progression in Patients with Metastatic Disease Impact on Eligibility Criteria For Clinical Trials Volume of Disease G o a Anaplastic RAI Refractory l L i RAI Responsive n e Normal Life Span TKI therapy may alter rate of growth MD Anderson Experience: Sorafenib/Sunitinib Cabanillas et al. JCEM June 2010 TKI therapy may alter rate of growth Percentage change in tumor size (%) Pazopanib therapy Time Bible et al. Lancet Oncology 2010 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 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 • • • • • 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 • Likely Outcomes Can we use targeted therapy to improve RAI avidity? Lesional Dosimetry 124I PET Sgouros et al, J Nucl Med. 2004 Aug;45(8):1366-72 Metastatic Papillary Thyroid Cancer Serum thyroglobulin is 13,470 ng/mL CT Scan Post-Therapy Scan Metastatic Papillary Thyroid Cancer Before RAI After 2 RAI therapies Lesional Dosimetry 124 I PET Scan 120 mCi administered activity 9,500 rads 9,000 rads 8,500 rads Therapeutic Goal: 8,500 – 10,000 rads Whole Body RAI Scan Anterior Posterior 64 year old Stage IV, Follicular Thyroid Cancer Lesional Dosimetry If 400 mCi 800 rads 131I administered 3500 rads Therapeutic Goal: 8,500 – 10,000 rads Heterogeneity in absorbed dose distribution in individual patient 67 yo male, 9 cm, locally invasive, poorly differentiated thyroid cancer Presented with pulmonary mets on pre-op CXR Stimulated Tg 245 ng/mL CT RAI 250 mCi Fused Heterogeneity in absorbed dose distribution in individual patient 124I PET 42 Gy 124I 3.7 Gy PET 437 mCi I131 Desiree Deandreis, MSKCC Heterogeneity in absorbed dose distribution in individual lesion 75% 50% 25% 10% Yellow Red Blue Green Sgouros et al. J Nuc Med. 45(8):1366-72, 2004. Targeted Therapy to Improve RAI Avidity ret/PTC p21 ras GTP p21 ras Tyr P PI3K B-Raf mSos Grb2 MEK AKT ERK mTOR c-jun c-fos BRAF Activation Decreases NIS Decreases TSH receptor Decreases Tg BRAF Off BRAF On BRAF Off BRAF On BRAF Inhibitor BRAF On MEK Inhibitor Chakravarty, Fagin. JCI 2011 MEK Inhibitor (AZD6244) Re-differentiation Trial Treat with oral MEK inhibitor for 4 weeks Pre- MEK 124I PET scan Post- MEK 124I PET scan Ho et al, In press, NEJM 2012 Baseline After MEK Baseline After MEK Baseline After MEK 124-I SUV Max 60 MEK Trial Continues Lesional dosimetry promising Treat with RAI Discontinue MEK inhibitor 2 days later Repeat CT scans 2 months later 40 n= 46 lesions Post-therapy SUVmax 50 30 100 (+50%) (+25%) (+0%) 20 (-25%) (-50%) 10 MEk 0 0 0 10 20 30 40 50 60 Pre-therapy SUVmax n= 31 lesions Ho et al, In press, NEJM 2012 LESION 3 19mm 10.8 mm LESION 4 12.9 mm 6 mm 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) Radioiodine Responses of Advanced Thyroid Cancers Treated with Selumetinib 20 patients RAI refractory distant mets 25% PTC, 40% TCV, 35% PDTC 61 yrs old (44-77) 11M:9F Genotype of Primary 45% BRAF 25% NRAS 15% RET/PTC 15% Wild Type Ho et al, In press, NEJM 2012 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 Molecular Profile of Differentiated Thyroid Cancer MEK Inhibition Dramatic increase in RAI avidity Clinical significant response to therapy Receptor Tyrosine Kinase ret/PTC p21 ras p21 ras TyrP BRAF Mutation Response did not correlate with BRAF mutation status PI3K Not restricted to BRAF tumors AKT Future Uses Enhance RAI effectiveness Distant metastases Loco-regional metastases Remnant ablation mTOR GTP GDP B-Raf mSos Grb2 MEK ERK c-jun c-fos Targeted Therapies What 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