Presentation is loading. Please wait.

Presentation is loading. Please wait.

Targeted Therapy for Thyroid Cancer R Michael Tuttle, MD Professor of Medicine, Endocrine Service Memorial Sloan Kettering Cancer Center New York, NY R.

Similar presentations


Presentation on theme: "Targeted Therapy for Thyroid Cancer R Michael Tuttle, MD Professor of Medicine, Endocrine Service Memorial Sloan Kettering Cancer Center New York, NY R."— Presentation transcript:

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

2 Systemic Therapies Chemotherapy/Novel Therapies Targeted Therapies What are our options? SurgeryExternal Beam RadiationEmbolization Radioactive Iodine Often, multiple “targeted therapies” are used over the life time of a patient with advanced thyroid cancer

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 CXRRAI

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

5 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

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 female Locally aggressive, poorly differentiated Wide spread progressive distant mets

9 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 FDG PET CXR Post therapy

10 Traditional chemotherapyTraditional chemotherapy Overall response rates less than 0-20% Overall response rates less than 0-20% Doxorubicin (FDA approved for thyroid cancer), Cisplatin Doxorubicin (FDA approved for thyroid cancer), Cisplatin Responses Responses Generally partial and short lived Generally partial and short lived Response rates not determined by RECIST criteria Response rates not determined by RECIST criteria Seldom used in clinical practice 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 NCCN & ATA guidelines specifically note that failure of traditional chemotherapy is not a requirement prior to entry into experimental trials Overall response rates less than 0-20% Overall response rates less than 0-20% Doxorubicin (FDA approved for thyroid cancer), Cisplatin Doxorubicin (FDA approved for thyroid cancer), Cisplatin Responses Responses Generally partial and short lived Generally partial and short lived Response rates not determined by RECIST criteria Response rates not determined by RECIST criteria Seldom used in clinical practice 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 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 Tyr MAP Kinase Pathway 70% of all PTC have mutations in either the RET/PTC, RAS or BRAF RAS GTP BRAF MEK ERK c-jun c-fos P Grb2 mSos RAS GDP RET/PTC MTOR PI3K AKT

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

13 VEGFRETRET/ PTC BRAFC-KITEGFRC-METPDGFR Imatinib √√√ Axitinib √ Motesanib √√√√ Sorafenib √√√√√ Sunitinib √√√√√ Vandetanib √√√√ Cabozantinib √√√√ Linvatinib √√ Pazopanib √√√ Vemurafenib √ Specific Targets Differ Between Agents Adapted from Licitra, E Journal Cancer 2010

14 VEGFR 1, 2, 3 VEGFR 1, 2 VEGFR 2 VEGFR 3 Imatinib Axitinib √ Motesanib √ Sorafenib √ Sunitinib √ Vandetanib √ Cabozantinib √ Linvatinib √ Specific Targets Differ Between Agents Adapted from Licitra, E Journal Cancer 2010

15 Clinical Trials in Non-Medullary Thyroid CancerClinical Trials in Non-Medullary Thyroid Cancer AgentMechanismCohorts Ain2000PaclitaxelAnti-microtubule20 ATC Mrozek2006CelecoxibCox-2 inhibitor32 DTC Ain2007ThalidomideAnti-angiogenesis29 DTC, 7 MTC Woyach2008VorinostatHDAC-I16 DTC, 3 MTC Arigiris2008Adria & IF2Cytotoxic & Immun15 DTC, 2 ATC Pennell2008GefitinibEGFR18 DTC, 5 ATC, 4 MTC Sherman2008MotesanibVEGF, PDGFR, Kit93 DTC Cohen2008AxitinibVEGF46 DTC, 12 MTC, 2 ATC Gupta- Abramson 2008SorafenibVEGF, BRAF27 DTC, 1 MTC, 2 ATC Kloos2009SorafenibVEGF, BRAF43 DTC, 9HC, 4 ATC Bible2010PazopanibVEGF, PDGFR, Kit26 DTC, 11 HC Hayes2012SelumetanibMEK32 PTC Modified from Tuttle RM. Clinical Thyroidology 2009; 21(1):3-7.

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

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

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

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

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

21 Toxicity ProfileToxicity Profile Dose related and usually reversible Dose related and usually reversible Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension About 1% risk of death related to the drugs About 1% risk of death related to the drugs Results in discontinuation of the drug in 15-20% of study subjects 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 Temporary interruption of drug and re-institution at lower doses in as many as 30-50% of study subjects Dose related and usually reversible Dose related and usually reversible Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension Fatigue, diarrhea, skin toxicities, anorexia, weight loss, hypertension About 1% risk of death related to the drugs About 1% risk of death related to the drugs Results in discontinuation of the drug in 15-20% of study subjects 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 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 ClinicTranslating All This Into the Clinic Patient Selection Patient Selection Clinically significant Clinically significant Structurally progressive Structurally progressive RAI refractory thyroid cancer RAI refractory thyroid cancer Shortened life span if untreated Shortened life span if untreated Likely Outcomes Likely Outcomes Unlikely to “cure” Unlikely to “cure” Occasionally cause the tumors to shrink Occasionally cause the tumors to shrink More commonly result in stable disease (50% of the time) More commonly result in stable disease (50% of the time) Toxicities are real, but tolerable, and usually reversible Toxicities are real, but tolerable, and usually reversible May or may not prolong overall survival May or may not prolong overall survival Patient Selection Patient Selection Clinically significant Clinically significant Structurally progressive Structurally progressive RAI refractory thyroid cancer RAI refractory thyroid cancer Shortened life span if untreated Shortened life span if untreated Likely Outcomes Likely Outcomes Unlikely to “cure” Unlikely to “cure” Occasionally cause the tumors to shrink Occasionally cause the tumors to shrink More commonly result in stable disease (50% of the time) More commonly result in stable disease (50% of the time) Toxicities are real, but tolerable, and usually reversible Toxicities are real, but tolerable, and usually reversible May or may not prolong overall survival May or may not prolong overall survival The essence of my clinical consults in October 2012

23 Can we use targeted therapy to improve RAI avidity? Sgouros et al, J Nucl Med Aug;45(8): Lesional Dosimetry 124 I PET

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

25 Metastatic Papillary Thyroid Cancer Before RAI After 2 RAI therapies

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

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

28 3500 rads Lesional Dosimetry If 400 mCi 131 I administered 800 rads Therapeutic Goal: 8,500 – 10,000 rads

29 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 CTRAIFused 250 mCi

30 42 Gy3.7 Gy 437 mCi I 131 Heterogeneity in absorbed dose distribution in individual patient Desiree Deandreis, MSKCC 124 I PET

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

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

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

34 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

35 BaselineAfter MEK

36 Baseline After MEK

37 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

38 LESION 3 LESION 4 19mm10.8 mm 12.9 mm 6 mm

39 LESION mm5.2 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 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

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

43 Systemic Therapies Chemotherapy/Novel Therapies Targeted Therapies What are our options? SurgeryExternal Beam RadiationEmbolization Radioactive Iodine Often, multiple “targeted therapies” are used over the life time of a patient with advanced thyroid cancer


Download ppt "Targeted Therapy for Thyroid Cancer R Michael Tuttle, MD Professor of Medicine, Endocrine Service Memorial Sloan Kettering Cancer Center New York, NY R."

Similar presentations


Ads by Google