2014 Debates and Didactics in Hematology and Oncology New treatments in the management of thyroid cancer Taofeek K. Owonikoko, MD/PhD Associate Professor Department of Hematology/Medical Oncology Emory University August 9, 2014 Disclosures • Novartis – thyroid cancer research funding 1
Outline • Pathology and epidemiology of thyroid cancer • Newly established treatment approaches for advanced thyroid cancer • Emerging approaches within the thyroid oncology program at the Winship Cancer Institute Histologic Variants • Well-Differentiated – 90% • Papillary – 80% • Follicular – 5-10% • Hurthle Cell - <5% • Medullary – 5% • Familial • As part of MEN2 Syndrome • Sporadic • Poorly Differentiated/Anaplastic – 5% • Others - <1% • Lymphoma, sarcoma, etc. http://www.ouhsc.edu/histology/ 2
Cancer Statistics 2013 Siegel R. et al. CA CANCER J CLIN 2013;63:11–30 US Incidence of Thyroid Cancer by Size and Histology Davies, L. et al. JAMA 2006;295:2164 ‐ 2167. 3
Survival in differentiated thyroid carcinoma 2936 patients (1987-2001) 1 I 0.9 II 0.8 0.7 III Surviving 0.6 0.5 0.4 0.3 0.2 IV 0.1 0 0 2 4 6 8 10 12 14 16 18 Time to Death, Yrs FuTimeFINAL Jonklass J, et al, Thyroid 2006 Management of Progressive or Metastatic Disease • Multidisciplinary approach – Endocrinology – continuing management of thyroid hormone replacement and TSH suppression – Surgeons – resection of amenable solitary lesions – Radiation oncologist – Irradiation for local control or symptom palliation – Nuclear medicine physician – dosimetry-based I131 therapy – Medical Oncologist – targeted biologic agents; cytotoxics?? 4
Systemic therapy • Cytotoxic chemotherapy currently plays no significant role in the management of advanced DTC and MTC • Considerations for initiation of biologic therapy – Symptom – Disease burden – Objective progression (biomarker doubling time and anatomic imaging) – Tumor histology – tall cell, insular and poorly differentiated histology – I131 avidity and response Chemotherapy Regimen # of RR PFS Remarks Patients Adriamycin# 18 15% NR Medullary only Cisplatin# 14 21% NR Medullary only Adriamycin ± 92 17% vs. NR Increased toxicity 26% with combination Cisplatin* Adriamycin + Interferon 17 6% 5.9 Increased toxicity Gemcitabine/Oxaliplatin 14 57% 10.1 Retrospective single site study # Droz et al. 1984; *Shimaoka et al. 1986; ^ Argiris et al. 2008; Spano et al. 2012 5
Gemcitabine/Oxaliplatin in refractory thyroid cancer Spano et al. Med Oncol 2012 29:1421 ‐ 1428 Molecular understanding of thyroid tumor development Hyperfunctioning Adenoma TSH-R G-protein p53 Pax8-PPAR γ Ras Signaling PI3K 3p (TR β ) Epigenetic Changes β catenin Follicular Anaplastic Adenoma Thyroid Carcinoma Follicular Follicular Carcinoma Cell RET/PTC Ras p53 Papillary BRAF PI3K Trk Thyroid β catenin Met Carcinoma Abbosh and Nephew, Thyroid:15, 551 ‐ 561, 2005 6
Aberrant signaling pathway in thyroid cancer 15-20% PTC FTC RET/PTC 20-30% Ras PDTC, ATC Ras 15-20% PI3K Pax8-PPAR γ 40-60% AKT BRAF 20-30% NIS PDTC β catenin MEK-ERK p53 Tumor growth, dedifferentiation PDTC, ATC Abbosh and Nephew, Thyroid:15, 551 ‐ 561, 2005 Multikinase inhibitors Thyroid carcinoma Drug IC 50 (nm) VEGFR1 VEGFR2 VEGFR3 RET RET/PTC3 RAF Other Axitinib 1.2 0.25 0.29 - - - PDGFR 1.7 Lenvatinib 22 4 5.2 35 - - FGFR 46 Motesanib 2 3 6 59 - - PDGFR 84 Pazopanib 10 30 47 2800 - - PDGFR 74 Sorafenib - 90 20 49 50 6 PDGFR 58 Sunitinib 2 9 17 41 224 - - Vandetanib 1600 40 110 100 50-100 - EGFR 500 Carbozantinib - 0.035 - 4.5 - - C-MET 1.8 Sherman SI , JCEM, 2009 7
Phase II evaluation of biologic agents in thyroid cancer Drug # of patients RR/SD/CBR PFS (months) Molecular and Biologic Target Axitinib 60 30%/38%/68% 18.1 VEGFR 1, 2, & 3; Angiogenesis Pazopanib 32 19%/69%/88% NR VEGFR 1, 2, 3 Motesanib 93 14%/67%/81% 10 VEGFR 1, 2, 3; (WDC) PDGFR; c-kit; Angiogenesis; Motesanib 91 2%/81%/83% 11 (medullary) Carr et al. J Clin Oncol 27:15s, 2009; Cohen et al. J Clin Oncol 26: 2008; Cohen et al. J Clin Oncol. 26(29):4708 ‐ 13, 2008; Bible KC et al. J Clin Oncol 27:15s, #3521 2009 Phase II evaluation of biologic agents in thyroid cancer Drug Patients RR / SD / CBR PFS Molecular and (months) Biologic Target Sunitinib 43 13%/68%/81% NR Angiogenesis; RET tyrosine 33 34%/48%/82% 6.5 kinase Sunitinib Sorafenib 41 15%/56%/71% 15 B-Raf VEGFR 1, 2, 3 30 23%/53%/76% 19 Sorafenib Kloos et al. J Clin Oncol 1675 ‐ 84. 2009; Gupta ‐ Abramson et al. J Clin Oncol 2008 8
Phase III clinical trial of vandetanib versus placebo in MTC Wells et al. J Clin Oncol. 2012 Jan 10;30(2):134 ‐ 41 Phase III clinical trial of vandetanib versus placebo in MTC Wells et al. J Clin Oncol. 2012 Jan 10;30(2):134 ‐ 41 9
Meaningful benefit but potential cardiac toxicity Most common grade 3+ adverse events (>2% incidence in either arm) Vandetanib 300 mg Placebo (n=231) (n=99) Diarrhea 25 (11%) 2 (2%) Hypertension 20 (9%) 1 (1%) ECG QT prolonged 18 (8%) 1 (1%) Fatigue 13 (6%) 1 (1%) Decreased appetite 10 (4%) 0 Rash 8 (3%) 1 (1%) Asthenia 6 (3%) 1 (1%) Dyspnea 4 (2%) 3 (3%) Back pain 1 (0.4%) 3 (3%) Syncope 0 2 (2%) Wells et al. Proc. ASCO Annual Meeting June 2010 Efficacy of Cabozantinib (Cabo) in Medullary Thyroid Cancer (MTC) Patients with RAS or RET Mutations: Results from a Phase 3 Study Steven I. Sherman 1 , Ezra E. W. Cohen 2 , Patrick Schöffski 3 , Rossella Elisei 4 , Martin Schlumberger 5 , Lori Wirth 6 , Milan Mangeshkar 7 , Dana T. Aftab 7 , Douglas O. Clary 7 , and Marcia S. Brose 8 1 University of Texas MD Anderson Cancer Center; 2 University of Chicago; 3 University Hospitals Leuven, KU Leuven; 4 University of Pisa; 5 Institut Gustave Roussy, University Paris-Sud; 6 Massachusetts General Hospital; 7 Exelixis Inc; 8 University of Pennsylvania Health System 10
MTC and Cabozantinib • MTC is a rare form of thyroid cancer 1 – Patients with distant metastases have a median survival of ~2 years 2 75% of cases occur sporadically, 25% are hereditary 3,4 • – Up to 65% of sporadic cases have somatic RET mutations 3 – >95% of hereditary cases have germline RET mutations 4 • RET M918T mutation associated with poor prognosis 5 • Cabozantinib is a potent inhibitor of receptor tyrosine kinases MET, VEGFR2, and RET 6 • Cabozantinib treatment resulted in significant prolongation in PFS in pts with progressive, metastatic MTC in Phase 3 evaluation 7 1 Schlumberger et al. (2008) Nat Clin Prac, v4(1); 2 Modigliani et al. (1998) Clin Endocrinol, v48; 3 Moura et al. (2009) Br J Cancer, v100; ; 4 Kouvaraki et al. (2005) Thyroid, v15(6); 5 Schilling et al. (2001) Int J Canc v95; 6 Yakes et al. (2011) Mol Canc Ther v10(12); 7 Schöffski et al. J Clin Onc 2012 30 Suppl:5508 Phase 3 Trial Design Treatment until progression or unacceptable toxicity Locally advanced Cabozantinib 140 mg PROGRESSION or metastatic MTC with No Cross-Over Survival documented 2:1 Randomization No Unblinding follow-up RECIST progression (N=330) Placebo • Key eligibility criterion – L ocally advanced or metastatic MTC with radiographic progressive disease within 14 months per mRECIST* • Key study endpoints – Primary: PFS per mRECIST* determined by IRC. – Secondary: response rate per mRECIST and overall survival * mRECIST: modified Response Evaluation Criteria in Solid Tumors 11
PFS and ORR per IRC Cabozantinib Placebo 1.0 0.9 Median PFS 11.2 mo 4.0 mo 0.8 1 year PFS 47.3% 7.2% 0.7 HR (95% CI) 0.28 (0.19, 0.40) Probability 0.6 0.5 0.4 0.3 p <0.0001 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Time, mo • Tumor response rate of 28% in cabozantinib arm vs 0% in placebo arm 1 • Median tumor response duration of 14.7 months 1 Determined in patients with measurable disease RET Mutation Study Results RET Mutational Analysis Results Unknown RET Status RET Mutation Positive Insufficient Sample 57 M918T 1 126 Assay Failure 33 C611-C634 mutations 33 Novel RET Mutation 2 21 A883F 7 Small Deletions 16 Y791F 1 Point Mutations 5 V804M 1 Sample Discrepancies 4 S891A 1 Total 115 RET Mutation Negative 46 RET Mutation Unknown 115 Total 330 • M918T is the predominant RET mutation in this patient population 1 Includes 4 compound M918T mutations 2 Mutations not listed in ATA Guidelines (Kloos et al, 2009) 12
RET Mutational Subgroups Assessed for Relationship to PFS and Response Rate • Sporadic versus Hereditary MTC – Hereditary MTC: patients with RET mutation detected in blood – Sporadic MTC: blood sample lacks RET mutation • Tumor mutational status: RET positive vs RET negative • RET mutation type: M918T vs other RET mutations – RET M918T is most common and associated with poor prognosis Similar Effect of Cabozantinib on PFS in Hereditary and Sporadic MTC Fraction event free Median PFS Median PFS Cabozantinib 36 weeks Cabozantinib 48 weeks Placebo 24 weeks Placebo 17 weeks 13
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