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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
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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
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23 year old female s/p total thyroidectomy 3
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 CXR RAI
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42 year old male Wide spread metastatic moderately differentiated papillary thyroid cancer
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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
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73 year old male with poorly differentiated papillary thyroid cancer
Positive on diagnostic RAI scan CT Scan T10 Lesion
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58 year old male with wide spread metastatic Hürthle Cell Carcinoma
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41 year old female Locally aggressive, poorly differentiated Wide spread progressive distant mets
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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
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Traditional chemotherapy
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York Traditional chemotherapy 4/7/2017 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
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Molecular Abnormalities in the Primary Tumor
MAP Kinase Pathway RAS GTP BRAF MEK ERK c-jun c-fos P Grb2 mSos GDP RET/PTC Tyr MTOR PI3K AKT 70% of all PTC have mutations in either the RET/PTC, RAS or BRAF Proliferation Growth
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Molecular Abnormalities in the Primary Tumor
MAP Kinase Pathway RAS GTP BRAF MEK ERK c-jun c-fos P Grb2 mSos GDP RET/PTC VEGF RET PDGF EGF Insulin IGF HGF FGF Tyr MTOR PI3K AKT Proliferation Growth
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R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York
4/7/2017 Specific Targets Differ Between Agents VEGF RET RET/PTC BRAF C-KIT EGFR C-MET PDGFR Imatinib √ Axitinib Motesanib Sorafenib Sunitinib Vandetanib Cabozantinib Linvatinib Pazopanib Vemurafenib Adapted from Licitra, E Journal Cancer 2010
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R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York
4/7/2017 Specific Targets Differ Between Agents VEGFR 1, 2, 3 1, 2 2 3 Imatinib Axitinib √ Motesanib Sorafenib Sunitinib Vandetanib Cabozantinib Linvatinib Adapted from Licitra, E Journal Cancer 2010
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Clinical Trials in Non-Medullary Thyroid Cancer
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York Clinical Trials in Non-Medullary Thyroid Cancer 4/7/2017 Agent Mechanism Cohorts Ain 2000 Paclitaxel Anti-microtubule 20 ATC Mrozek 2006 Celecoxib Cox-2 inhibitor 32 DTC 2007 Thalidomide Anti-angiogenesis 29 DTC, 7 MTC Woyach 2008 Vorinostat HDAC-I 16 DTC, 3 MTC Arigiris Adria & IF2 Cytotoxic & Immun 15 DTC, 2 ATC Pennell Gefitinib EGFR 18 DTC, 5 ATC, 4 MTC Sherman Motesanib VEGF, PDGFR, Kit 93 DTC Cohen Axitinib VEGF 46 DTC, 12 MTC, 2 ATC Gupta-Abramson Sorafenib VEGF, BRAF 27 DTC, 1 MTC, 2 ATC Kloos 2009 43 DTC, 9HC, 4 ATC Bible 2010 Pazopanib 26 DTC, 11 HC Hayes 2012 Selumetanib MEK 32 PTC Modified from Tuttle RM. Clinical Thyroidology 2009; 21(1):3-7.
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R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York
4/7/2017 Phase 2 Clinical Trials 1 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
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Clinical Implications of Trial Design
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York 4/7/2017 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
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Variations in Rate of Progression in Patients with Metastatic Disease
Impact on Eligibility Criteria For Clinical Trials RAI Refractory Anaplastic Goal Line Volume of Disease RAI Responsive Normal Life Span
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TKI therapy may alter rate of growth
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York TKI therapy may alter rate of growth 4/7/2017 MD Anderson Experience: Sorafenib/Sunitinib Cabanillas et al. JCEM June 2010
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TKI therapy may alter rate of growth
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York TKI therapy may alter rate of growth 4/7/2017 Pazopanib therapy Percentage change in tumor size (%) Time Bible et al. Lancet Oncology 2010
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R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York
Toxicity Profile 4/7/2017 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
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Translating All This Into the Clinic
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York Translating All This Into the Clinic 4/7/2017 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
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Can we use targeted therapy to improve RAI avidity?
Sgouros et al, J Nucl Med Aug;45(8): Lesional Dosimetry 124I PET
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Metastatic Papillary Thyroid Cancer
Serum thyroglobulin is 13,470 ng/mL Post-Therapy Scan CT Scan
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Metastatic Papillary Thyroid Cancer
After 2 RAI therapies Before RAI
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120 mCi administered activity Therapeutic Goal: 8,500 – 10,000 rads
Lesional Dosimetry 124 I PET Scan 120 mCi administered activity 9,000 rads 8,500 rads 9,500 rads Therapeutic Goal: 8,500 – 10,000 rads
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Stage IV, Follicular Thyroid Cancer
Whole Body RAI Scan Anterior Posterior 64 year old Stage IV, Follicular Thyroid Cancer
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Therapeutic Goal: 8,500 – 10,000 rads
Lesional Dosimetry If 400 mCi 131I administered 800 rads 3500 rads Therapeutic Goal: 8,500 – 10,000 rads
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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 Fused 250 mCi
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Heterogeneity in absorbed dose distribution in individual patient
124I PET 42 Gy 3.7 Gy 124I PET 437 mCi I131 Desiree Deandreis, MSKCC
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Heterogeneity in absorbed dose distribution in individual lesion
75% Yellow 50% Red 25% Blue 10% Green Sgouros et al. J Nuc Med. 45(8): , 2004.
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Targeted Therapy to Improve RAI Avidity
Tyr P Grb2 mSos p21 ras ret/PTC GTP B-Raf MEK ERK c-jun c-fos mTOR PI3K AKT BRAF Activation Decreases NIS Decreases TSH receptor Decreases Tg
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Chakravarty, Fagin. JCI 2011 BRAF Off BRAF On BRAF Off BRAF On BRAF
Inhibitor BRAF On MEK Inhibitor Chakravarty, Fagin. JCI 2011
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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
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Baseline After MEK
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Baseline After MEK After MEK Baseline
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Lesional dosimetry promising Treat with RAI
Trial Continues Lesional dosimetry promising Treat with RAI Discontinue MEK inhibitor 2 days later Repeat CT scans 2 months later Ho et al, In press, NEJM 2012
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LESION 3 19mm 10.8 mm LESION 4 12.9 mm 6 mm
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Serum Thyroglobulin Response
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)
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RAI refractory distant mets
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
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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
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Molecular Profile of Differentiated Thyroid Cancer
MEK Inhibition Dramatic increase in RAI avidity Clinical significant response to therapy Receptor Tyrosine Kinase Tyr GTP P Grb2 mSos p21 ras GDP ret/PTC B-Raf MEK ERK c-jun c-fos BRAF Mutation Response did not correlate with BRAF mutation status Not restricted to BRAF tumors mTOR PI3K AKT Future Uses Enhance RAI effectiveness Distant metastases Loco-regional metastases Remnant ablation
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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
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