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Advanced Differentiated Thyroid Cancer In the Era Of Multikinase Inhibitor Therapy
Marcia S. Brose MD PhD Associate Professor Department of Otorhinolaryngology: Head and Neck Cancer Department of Medicine, Division of Hematology/Oncology Abramson Cancer Center The University of Pennsylvania Philadelphia, PA
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Disclosures Companies: AstraZeneca, Bayer/Onyx, Eisai, Exelixis, Novartis, Roche/Genentech, Relationships: Advisory board consultant, honoraria, research grants, and primary investigator As there are currently three FDA approved agents for progressive DTC including doxorubicin, sorafenib and lenvatinib, all the remaining agents I will discuss will be in the context of a clinical trials 2
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Thyroid cancer: clinical pathology
Papillary (87%) Differentiated Follicular (6%) Follicular cells Hürthle cell (3%) Anaplastic (1%) Medullary (2%) Parafollicular cells Treatment of Differentiated Thyroid Cancer includes: Surgery – thyroidectomy Radioactive iodine Thyroid stimulating hormone (TSH) suppression Thyroid Grand has two cell types that give rise to cancer, the follicular cells - which give rise to DTC and ATC thyroid cancer, and the parafollicular C cells that give rise to medullary thyroid cancer. While there is also very exciting progress happening in Medullary thyroid cancer and Anaplastic thyroid cancers are desperately in need of clinical trials, I will focus today on the evolving treatment of differentiated thyroid cancer. Summarize treatment as listed in box. Carling T and Uldesman R. Cancer of the Endocrine System: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins Howlader N et al. SEER Cancer Statistics Review;
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Radioactive Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)
It is estimated1 that in the USA in 2013 there were: > new cases of thyroid cancer, and 1850 deaths due to thyroid cancer In approximately 5–15% of patients with thyroid cancer, the disease becomes refractory to RAI2,3 Median survival for patients with RAI-refractory DTC and distant metastases is estimated to be 2.5–3.5 years4,5 Patients often suffer multiple complications associated with disease progression There is no standard therapy for patients with RAI-refractory DTC 1. Howlader N et al. SEER Cancer Statistics Review; Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892– Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505.
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Managing RAI-Refractory DTC Patients in Accordance with NCCN Guidelines
Stop RAI treatment Suppress TSH secretion Local control of tumor foci when needed Assess progression When tumor burden is significant and progression has been documented: initiate systemic treatment TSH Thyroid stimulating hormone; RAI, Radioactive iodine NCCN Guidelines: Thyroid Carcinoma. v
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Genetics of Differentiated Thyroid Cancer: aberrant intracellular signaling
Poorly differentiated RAS (25–30%) TP53 (20–30%) CTNNB1 (10–20%) BRAF (10–15%) Anaplastic Medullary Oncocytic Conventional Papillary Mutations identified in ~70% BRAFa (40–50%) RASb (7–20%) RET/PTC (clonal; 10–20%) EGFR (5%) TRK (<5%) PIK3CA (2%) Follicular Mutations in 70–75% RAS (40–50%; lower in oncocytic) PAX8/PPARg (30–35%; lower in oncocytic) TP53 (21%) PTEN (8%) PIK3CA (7%) BRAF (2%) Papillary DTC aBRAF mutations are mostly V600E; 1–2% are K601E and others bRAS includes N-, H-, and K-RAS (predominantly NRAS and HRAS codon 61) Nikiforov YE et al. Arch Pathol Lab Med 2011;135:569–77; COSMIC database – Catalog of Somatic Mutations in Cancer (as of February 22, 2013)
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Kinase Inhibitors ATP KI ATP KI Y P Y RET, BRAF….. inhibition
Activated pathway Cancer Activated Pathway Cancer VEGFR inhibition RET, BRAF….. inhibition Tumor growth Tumor angiogenesis
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Targeting Cell Signaling in Thyroid Cancer
Tumor Cell Endothelial Cell RET/PTC EGFR VEGFR-2 Motesanib Sorafenib Sunitinib Vandetanib XL-184 Lenvatinib Vandetanib Axitinib Motesanib Sorafenib Sunitinib Vandetanib Lenvatinib Ras Ras B-Raf PI3K Raf PI3K AKT Sorafenib Sorafenib MEK AKT MEK mTOR mTOR ERK Everolimus Sirolimus ERK Everolimus Sirolimus S6K S6K Alterations Intracellular signaling pathway is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. • Growth • Survival • Proliferation • HIF1a • Inhibition of apoptosis • Migration • Growth • Survival • Proliferation • Migration •Angiogenesis EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:
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Background and rationale
Sorafenib is a multikinase inhibitor targeting VEGFRs1–3, PDGFRs, BRAF, RET, and c-Kit1 Sorafenib is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma Sorafenib has shown activity as monotherapy in Phase 2 trials in patients with advanced refractory thyroid cancer2–6 DECISION is a randomized, double-blinded, placebo- controlled Phase 3 trial designed to explore the efficacy and safety of sorafenib in patients with RAI-refractory DTC stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Wilhelm SM et al. Nature Rev Drug Discovery 2006;5:835–44; 2. Gupta-Abramson V et al. J Clin Oncol 2008; 26:4714–19; 3. Kloos RT et al. J Clin Oncol 2009;27:1675–84; 4. Lam ET et al. J Clin Oncol 2010;28:2323–30; 5. Ahmed M et al. Eur J Endocrinol 2011;165:315–22; 6. Schneider TC et al. Eur J Endocrinol 2012;167:643–50.
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DECISION study design 417 patients randomized from Oct 2009 to July 2011 Locally advanced or metastatic, RAI-refractory DTC Progression (RECIST) within the previous 14 months No prior chemotherapy, targeted therapy, or thalidomide Sorafenib 400 mg orally twice daily Primary endpoint Progression-free survival Randomization 1:1 Placebo orally twice daily Secondary endpoints Overall survival Response rate Safety Time to progression Disease control rate Duration of response Sorafenib exposure (AUC0–12) Stratified by: geographical region (North America or Europe or Asia) age (<60 or ≥60 years) Progression assessed by independent central review every 8 weeks At progression: patients on placebo allowed to cross over at the investigator’s discretion patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion
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Progression-free survival (by independent central review)
Median PFS, days (months) Sorafenib 207 329 (10.8) Placebo 210 175 (5.8) 10 20 40 60 80 100 30 50 70 90 HR: 0.587; 95% CI: 0.454–0.758; p<0.0001 Benefit Seen in all subgroups PFS probability (%) 100 200 300 400 500 600 700 800 Days from randomization Full analysis set. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival
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Other secondary efficacy endpoints
Sorafenib n (%) Placebo p value Total evaluable patients 196 201 Response rate 24 (12.2) 1 (0.5) <0.0001 Complete response – Partial response Stable disease for ≥6 months 82 (41.8) 67 (33.2) Disease control rate (CR + PR + SD ≥6 months) 106 (54.1) 68 (33.8) Median duration of response (PRs) months (range) 10.2 (7.4–16.6) NA CR, complete response; PR, partial response; SD, stable disease; NA, not assessed
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Maximum reduction in target lesion size (%)
Maximum reduction in target lesion size on the sorafenib arm (by independent central review) –70 –50 –40 –20 20 60 –30 –10 10 30 50 40 –60 73% of patients Maximum reduction in target lesion size (%) Maximum reduction is defined as the difference in the sum of the longest diameter of target lesions from baseline. Negative values refer to maximal reduction and positive values to the minimal increase.
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Treatment and dose modifications (double-blind period)
Sorafenib (n=207) Placebo (n=209) Mean dose 651 mg 793 mg Median (range) treatment duration 46.1 weeks (0.3−135.3) 28.3 weeks (1.7−132.1) Dose modification due to AEs, % Dose reduction Dose interruption 77.8 30.1 Permanent discontinuation due to AEs, % 18.8 3.8 AE, adverse event
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Sorafenib benefit by BRAF status (PFS) – Papillary histology only
BRAF wild-type BRAF mutation Median PFS, days (months) Sorafenib (n=42) 278 (9.1) Placebo (n=42) 170 (5.6) Median PFS, days (months) Sorafenib (n=32) 623 (20.5) Placebo (n=40) 286 (9.4) 20 40 60 80 100 200 400 600 800 20 40 60 80 100 200 400 600 800 HR: 0.58, 95% CI: 0.34–1.00, p=0.049 HR: 0.40, 95% CI: 0.20–0.80, p=0.008 PFS probability (%) Days from randomization Days from randomization BRAF mutation did not predict PFS benefit from sorafenib (biomarker- treatment interaction p=0.393)
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Sorafenib benefit by RAS status (PFS)
RAS wild-type RAS mutation Median PFS, days (months) Sorafenib (n=102) 329 (10.8) Placebo (n=104) 175 (5.7) Median PFS, days (months) Sorafenib (n=24) 167 (5.5) Placebo (n=26) 105 (3.4) 20 40 60 80 100 200 400 600 800 20 40 60 80 100 200 400 600 800 HR: 0.60, 95% CI: 0.42–0.85, p=0.004 HR: 0.49, 95% CI: 0.24–1.00, p=0.045 PFS probability (%) Days from randomization Days from randomization RAS mutation was not an independent prognostic factor for PFS Univariate (placebo arm only): mutant vs wild type RAS, HR=1.80; p=0.022 Multivariate (placebo arm only): mutant vs wild type RAS, HR=1.56; p=0.154 RAS mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.422)
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DECISION: Summary Sorafenib Prolonged PFS in patients with progressing RAI-Refractory DTC by 5 months PFS was 5.8 months in the placebo arm and 10.8 in the treatment arm Sorafenib was associated with similar toxicities to prior experience and were manageable Sorafenib was the first MKI inhibitor FDA approved November 2013 Sorafenib was active in BRAF and RAS mutant and wildtype tumors, so genetic testing should not be used to determine use in these patients
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A phase 3, multicenter, randomized, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT) Martin Schlumberger,1 Makoto Tahara,2 Lori J. Wirth,3 Bruce Robinson,4 Marcia S. Brose,5 Rossella Elisei,6 Corina E. Dutcus,7 Begoña de las Heras,8 Junming Zhu,7 Mouhammed Amir Habra,9 Kate Newbold,10 Manisha H. Shah,11 Ana O. Hoff,12 Andrew G. Gianoukakis,13 Naomi Kiyota,14 Matthew H. Taylor,15 Sung-Bae Kim,16 Monika K. Krzyzanowska,17 Steven I. Sherman9 1Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France; 2Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 3Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 4Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia; 5Department of Otorhinolaryngology: Head and Neck Surgery and the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 7Eisai Inc, Woodcliff Lake, NJ, USA; 8Eisai Limited, Hatfield, Hertfordshire, UK; 9Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 10Royal Marsden Hospital National Health Service Trust London, UK; 11Departments of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 12Department of Endocrinology, Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil; 13Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, Torrance, CA, USA; 14Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan; 15Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; 16Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 17Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
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Treatment until IRR-verified disease progression (RECIST v1.1)
SELECT: Study Schema Global, randomized, double-blind, phase 3 trial Patients with DTC (N = 392) IRR evidence of progression within previous 13 months 131I-refractory disease Measurable disease Up to 1 prior VEGF or VEGFR- targeted therapy Stratification Geographic region (Europe, N. America, Other) Prior VEGF/ VEGFR- targeted therapy (0,1) Age (≤ 65 years, > 65 years) Lenvatinib (n = 261) 24 mg daily PO Primary endpoint PFS Secondary endpoints ORR OS Safety Treatment until IRR-verified disease progression (RECIST v1.1) Randomization 2:1 Placebo (n = 131) Daily PO Lenvatinib (Optional, open-label) This slide deck provides an overview of Study 303, a randomized, double-blind, multicenter, phase 3 study of lenvatinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC).1 Study 303 enrolled a total of 362 patients from 5 August 2011 to 4 October 2012. To qualify for inclusion into Study 303, adult patients with RR-DTC had to have had independent, centrally reviewed radiologic evidence of progression within the previous 13 months. Patients also had to have adequately controlled blood pressure (≤150/90 mmHg), and were allowed to have received one prior VEGFR-targeted therapies Additional inclusion and exclusion criteria are detailed in the following slide Eligible patients were stratified by age (≤65, >65 years), geographic region (Europe, North America, Other), and prior VEGFR-targeted therapy (0,1), and randomized 2:1 to lenvatinib or placebo Treatment dose was 24 mg QD, in 28-day cycles, which continued until independently verified disease progression, or unacceptable toxicity Placebo-treated patients whose disease progressed could then elect to receive lenvatinib in the optional, open-label phase of the study The primary endpoint was progression-free survival (PFS) The secondary endpoints included overall response rate (ORR), overall survival (OS), and safety DTC, differentiated thyroid cancer; 131I, radioiodine; IRR, independent radiologic review, ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PO, by mouth; RECIST, response evaluation criteria in solid tumors; VEGF/VEGFR, vascular endothelial growth factor/receptor. Presented by: Martin Schlumberger, MD 21 21 21
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SELECT: Primary Endpoint: Kaplan-Meier Estimate of PFS
Median PFS, months (95% CI) Lenvatinib 18.3 (15.1–NE) Placebo 3.6 (2.2–3.7) HR (99% CI): 0.21 (0.14–0.31) Log-rank test: P < Progression events, 41% Progression events, 86% ‘Progression events’ was defined as the sum of ‘progressive disease’ and ‘death’. For lenvatinib, there were 93 progressive disease events and 14 deaths For placebo, there were 109 progressive disease events and 4 deaths CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.
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SELECT: PFS by Prior VEGF-Targeted Therapy
Progression-Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 Median (months) (95% CI) Lenvatinib 18.7 (16.4–NE) Placebo 3.6 (2.1–5.3) HR (95% CI): 0.20 (0.14–0.27) Log-rank Test: P < No Previous VEGF-Targeted Therapy (n = 299) Lenvatinib Placebo Number of subjects at risk: Time (months) Progression-Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 Median (months) (95% CI) Lenvatinib 15.1 (8.8–NE) Placebo 3.6 (1.9–3.7) HR (95% CI): 0.22 (0.12–0.41) Log-rank Test: P < Previous VEGF-Targeted Therapy: 1 line (n = 93) Lenvatinib Placebo Number of subjects at risk: Time (months) CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival; VEGF, vascular endothelial growth factor.
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SELECT: Response Rates
Lenvatinib (n = 261) Placebo (n = 131) Overall response rate 169 (65%) 2 (2%) Complete response 4 (2%) Partial response 165 (63%) Stable disease ≥ 23 weeks 40 (15%) 39 (30%) Progressive disease 18 (7%) 52 (40%) Duration of response, months, median (95% CI) NE (16.8–NE) – Median time to objective response for lenvatiniba: 2.0 months (range, 1.9–3.5 months) a Non-responders were not included in the median time to response assessment. CI, confidence interval; NE, not estimable. Presented by: Martin Schlumberger, MD
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SELECT: Overall Survival, ITT population
Median OS, months (95% CI) Lenvatinib NE (22.0–NE) Placebo NE (20.3–NE) HR (95% CI): 0.73 (0.50–1.07) Log-rank test: P = 1.0 0.9 0.8 0.7 0.6 Overall Survival 0.5 0.4 0.3 0.2 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (months) Number of subjects at risk: Lenvatinib Placebo CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; NE, not estimable; OS, overall survival. Presented by: Martin Schlumberger, MD
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SELECT: Study Medication Exposure
Nu Lenvatinib (n = 261) Placebo (n = 131) Duration of treatment, months, median (range) 13.8 (0–27) 3.9 (0–24) Dose intensity, mg/day, median (range) 16.8 (6–24) 24.0 (15–24) Time to first dose reduction, months, median (95% CI) 3.0 (2.7–3.7) NE CI, confidence interval; NE, not estimable. Presented by: Martin Schlumberger, MD 26
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Treatment-emergent Adverse Events
Lenvatinib (n = 261) Placebo (n = 131) TEAEs 260 (>99%) 118 (90%) TEAE reported as treatment-related 254 (97%) 78 (60%) Serious TEAEs 133 (51%) 31 (24%) TEAE resulting in Dose reduction 177 (68%) 6 (5%) Dose interruption 215 (82%) 24 (18%) Discontinuation of treatment 37 (14%) Fatal TEAE 20 (8%) Fatal TEAE reported by investigator as treatment-related 6/20 lenvatinib treatment-emergent deaths were considered by investigator as treatment-related: Pulmonary embolism (n = 1) Hemorrhagic stroke (n = 1) General health deterioration (n = 4) Presented by: Martin Schlumberger, MD 27
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Treatment Emergent AEs of Special Interest
Adverse Event, % Lenvatinib (n = 261) Placebo (n = 131) Any Grade Grade ≥ 3 Hypertension 69 43 15 4 Proteinuria 32 10 3 Arterial TEs 5 2 1 Venous TEs Renal failure Hepatic failure 0.4 PRES Please note that this slide reports all treatment-emergent adverse events; the previous slide reports treatment-related TEAEs and thus the numbers may be lower as this represents a smaller subset of patients (applies to the hypertension and proteinuria results) PRES, posterior reversible encephalopathy syndrome; TE, thromboembolic event; TEAEs, treatment-emergent adverse events. Presented by: Martin Schlumberger, MD 28
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Conclusions SELECTa In patients with RR-DTC, lenvatinib significantly prolonged median PFS by 14.7 months compared with placebo: Lenvatinib median PFS: 18.3 months (95% CI 15.1–NE) Placebo median PFS: 3.6 months (95% CI 2.2–3.7) HR 0.21 (99% CI, 0.14–0.31) Response rates for lenvatinib and placebo, respectively, were: ORR: 65% vs 2% (with CR: 2% vs 0%) The median time to objective response for lenvatinib was 2.0 months (range, 1.9–3.5 months) The median duration of response for lenvatinib has not been reached 75% of responders had an objective response >9.4 months Toxicities were manageable with dose modification and medication a Tumor assessments were performed using RECIST v1.1. CI, confidence interval; CR, complete response; HR, hazard ratio; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; RECIST, response evaluation criteria in solid tumors; RR-DTC, radioiodine-refractory differentiated thyroid cancer. Presented by: Martin Schlumberger, MD, ASCO 2014 29
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DECISION and SELECT: Next Steps
Patients on both DECISION and SELECT had a much shorter PFS on the placebo arm than treatment arms, confirming efficacy of both agents in RAI refractory DTC. Sorafenib was FDA approved in November 2014 We cannot compare across studies as the populations were different Use of RECIST 1.1 vs 1.0 for study entry Use of central review on SELECT resulted in almost 1/3rd of patients deemed eligible by investigators being deemed ineligible (selection for more aggressive disease) Central review of pathology to determine number of Poorly Differentiated subtype was done on DECISION but not on SELECT Lenvatinib had significantly higher number of deaths related to drug and incidence of thromboembolic events and hemorrhages. Requires further investigation of starting doses and safety. BOTH are now FDA approved, safety and efficacy of the two agents when used sequentially will need to be determined, ideally by a sequencing study (A then B vs B then A) for overall PFS and OS.
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UPCC 19309: Everolimus Plus Sorafenib for DTC Patients Who Progress on Sorafenib Alone
Eligibility criteria Metastatic, iodine- refractory thyroid cancer Life expectancy > 3 months PD on sorafenib ECOG PS 0-2 Good organ and bone marrow function Sorafenib + everolimus Intrapatient dose escalation Primary endpoints RECIST PFS Response rate n = 35 35 Patients accrued DTC, differentiated thyroid cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, progressive disease; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors. ClinicalTrials.gov identifier # NCT 31 31
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UPCC 18310: Vemurafenib in patients with Progressive PTC with BRAF V600E
Key Eligibility Criteria Recurrent, unresectable or metastatic PTC BRAFV600 mutation positive by cobas RAI refractory Evidence of progression within 14 months Prior chemotherapy allowed Cohort 1: VEGFR2i-naive (n = 26) Vemurafenib 960 mg bid until disease progression or unacceptable toxicity Cohort 2: VEGFR2i-pretreated (n = 25) Primary end point: response rate per investigator in VEGFR2i-naive patients. Secondary end points: safety, duration of response, PFS, OS, PK, response rate in VEGFR2 inhibitor–pretreated patients The key eligibility criteria are listed here – Patients were assigned to one of two cohorts All patients were given open label vemurafenib at a starting dose of 960mg po BID The primary endpoint was the response rate in the treatment naïve cohort, and secondary endpoints included the response rate in the retreated cohort, as well as PFS and OS for both arms Planned alaysis to be performed sixth months fo bid, 2 times a day; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; VEGFR, vascular endothelial growth factor receptor; VEGFR2i, vascular endothelial growth factor receptor 2 inhibitor.
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UPCC 28313: Cabozanitib for patients with progressive RAI refractory DTC
Eligibility criteria Metastatic, iodine- refractory thyroid cancer Life expectancy > 3 months ECOG PS 0-2 Good organ and bone marrow function cabozantinib 140mg daily Primary endpoints RECIST PFS Response rate n = 35 17 patients accrued 34 34
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Take Home Points: RAI-Refractory DTC
DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways, and iodine-refractory patients have an average survival of 3 years Results of phase 3 trials with sorafenib (DECISION) were positive, This was approved in November 2013 and was the first agent since doxorubicin in 1974. Phase 3 trial of lenvatinib (SELECT) was positive and was FDA approved in February of this year and Phase 3 of vandetanib (VERIFY) is ongoing. Sequencing is still a question. Additional MKIs are also now in development, many of which target VEGFR-2, but also mTOR, MEK, MET and BRAF and clinical trials will be needed to help us determine optimal sequencing of approved agents and second- and third-line treatments going forward. DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; mTOR, mammalian target of rapamycin; RAI, radioactive iodine; VEGFR, vascular endothelial growth factor. 35 35
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University of Pennsylvania Thyroid Cancer Therapeutics Program
Brose Translational Research Lab Mark Yarchoan MD Aaron Cohen MD Christian Squillante MD Waixing Tang, MD Zakkiyya Posey Thyroid Cancer Clinical Trials Unit Yvette Cruz, RN Carolyn Grande, RN, CRNP Kathleen Harlacker Thelma McCloskey Parna Prajapati Ramkrishna Makani Jessica Burrell Experimental Therapeutics Program Andrea Troxel, PhD Peter O’Dwyer, MD Pathology/Imaging Michael Feldman, MD, PhD Laurie Loevner, MD Thyroid Cancer Interest Group Susan Mandel, MD Ara Chalian, MD Douglas Fraker, MD Robert Lustig, MD Virginia LiVolsi, MD Zubair Baloch, MD Steve Keefe, MD Daniel Pryma MD Marcia Simpson Brose is a Damon Runyon-Siemens Clinical Investigator Many community endocrinologists who have referred their patients, and the patients who have agreed to participate in our trials
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