1. 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

2. 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

3. 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;

4. 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.

5. 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

6. 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)

7. 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

8. 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:

9. 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.

10. 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

11. 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

12. 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

13. 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.

14. 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

15. 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)

16. 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)

17. 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

18. 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.

19. 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

20. 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.

21. 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.

22. 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

23. 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

24. SELECT: Study Medication ExposureNu
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

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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.

31. 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

32. 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

33. 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