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New Approaches in the Treatment for the Advanced Thyroid Cancer

Sun Wook Kim, MD PhD

Division of Endocrinology and Metabolism,

Sungkyunkwan University School of Medicine,

Samsung Medical Center,

Seoul, Korea

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Objectives

Conventional treatment in advanced thy-roid cancers

(differentiated thyroid cancers, DTCs)Genetic alterations in DTCsRECIST Newer molecular targeted therapies

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Background

DTCs comprise most of thyroid cancersRAI refractory DTCs have poorer progno-

sis

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Classification of Thyroid Cancers

Parafollicular cells

Follicular cells

Differenti-ated

Medullary

Follicular

Anaplastic (Undifferenti-ated)

Papillary

Hürthle

Sporadic (80%)

Hereditary (20%)

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Classification of Thyroid Cancers

Cancer type Clinical characteristics

Papillary ~80% of thyroid cancers 10-year survival: 74–93%

Follicular Constitute ~10% of thyroid cancers 10-year survival 43–94%

Hürthle cell Constitute ~4% of thyroid cancers 10-year survival: ~76%

Anaplastic Constitute ~2% of thyroid cancers Aggressive, rapidly invasive Median survival: 4–5 months from diagnosis

Diff

ere

nti

ate

d

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Background

DTCs comprise most of thyroid cancersRAI refractory DTCs have poorer progno-

sis

Initial disease stage predicts overall survival in patients with DTC

0 1084 62 12 14

100

80

60

40

20

0

Su

rviv

al (%

)

Years

75% of all tu-mours

25% of all tu-mours

Jonklaas J, et al. Thyroid 2006;16:1229–42

Stage II

Stage III

Stage IV

Stage I

p<0.001

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18FDG PET-CT

Approved for detection of occult thyroid cancer when serum thyroglobulin>10ng/ml and negative RAI scan

(Sensitivity 60-95%, specificity 50-90%

accuracy 75%)Flip-flop phenomenon between FDG and

RAI uptake

FDG Uptake Is a Marker of Resistance to 131I Treatment and of Poor Prognosis

• Estimated 60 months survival RAI +, FDG -: 95%

RAI -, FDG +: 45%

RAI +, FDG +: 45%• Presence of FDG uptake is related

to

– Age >40 years– Large metastases– Poorly differentiated or

papillary/follicular disease with necrosis and mitosis

Robbins RJ, et al. J Clin Endocrinol Metab. 2006

RAI +FDG -

RAI-FDG -

RAI +FDG +

RAI -FDG +

- - -

- - -

- - -

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Objectives

Conventional treatment in advanced DTCs

Genetic alterations in DTCsRECIST Newer molecular targeted therapies

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Therapeutic modalities for RAI refrac-tory recurrent DTCs

Indication Pros Cons

Surgery Surgically resectable lo-cal recurrences or metas-tatectomy

Potential for cure Potential significant morbidity

External beam radiation

Adjuvant: neck

Therapeutic and pallia-tive: metastatic sites

Decrease in recur-rences, progression and pain

May preclude future neck surgery; dysphagia and xerostomia; sec-ondary malignancy

PEIT and RFA Locally recurrent disease in patients at high risk for morbidity and mortality from surgery

Potential for avoid-ance of surgery

Local pain; injury to local structure; unknown effect on survival and recur-rence

Systemic chemotherapy

Unresectable, RAI-refrac-tory, metastatic disease

May slow progression of disease; may alle-viated disease symp-tom

Significant adverse events; unknown effect on survival

Busaidy and Cabanillas et al. J Thy Res 2012

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FDA approval of doxorubicin for treatment of metastatic thyroid cancer (1974)

Matuszczyk A, et al. Horm Metab Res 2008

Epithelial origin, 5% PR

FDA = Food and Drug Administration; PR = partial response

Thus, patients with progressive DTC have had

an unmet clinical need for over three decades

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Objectives

Conventional treatment in advanced DTCs

Genetic alterations in DTCsRECIST Newer molecular targeted therapies

Thyroid cancer is associated with aber-rant cell signaling

MA

P k

inase

PI3

K/A

KT

Genetic alteration Papillary thyroid cancer (%)

Follicular thyroid cancer (%)

B-Raf V600E 44─45% 0

B-Raf copy gain 3 35

RET/PTC (1 and 3) ~20 0

RAS ~10 40–50

PI3KCA mutations 3 <10

PI3KCA copy gain 12 28

PTEN 2 <10

Pax8/PPARγ 0 35

Total >70 >65

Nikiforov YE. Mod Path 2008;21 Suppl 2:S37–43Xing M. Endocr Relat Cancer 2005;12:245–62

Wang HM, et al. Ann Surg Oncol 2007;14:3011–8

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Cell signalling in differentiated thyroid cancer

Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.

RET/PTC

• HIF1a• Inhibition of apoptosis• Migration

EGFR

PI3K

VEGFR-2

Endothelial Cell

• Migration• Angiogenesis

Ras

B-Raf

MEK

ERK

PI3K

AKT

mTOR

S6K

Ras

Raf

MEK

ERK

AKT

mTOR

S6K

Tumor Cell

• Growth• Survival• Proliferation

• Growth• Survival• Proliferation

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Objectives

Conventional treatment in advanced DTCs

Genetic alterations in DTCsRECIST Newer molecular targeted therapies

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RECIST (1)

Response Evaluation Criteria In Solid Tu-mors

Defines when cancer patients improve ("re-spond"), stay the same ("stabilize"), or worsen ("progression") during treatments.

Published in February, 2000 by an interna-tional collaboration EORTC, NCI of US and NCI of Canada

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RECIST (2)

Eligibility

- Only patients with measurable disease at baseline (longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan)

Response Criteria

- CR: disappearance of target lesion

- PR: >30% decrease in longest diameter of target

- SD: neither PR nor PD

- PD: >20% increase in longest diameter of target

or appearance of one or more new lesionsFrequency of tumor re-evaluation

- usually every other cycle (6-8 weeks) is reasonable

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Objectives

Conventional treatment in advanced DTCs

Genetic alterations in DTCsRECIST Newer molecular targeted therapies

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Kinase inhibitor activities relevant to ad-vanced thyroid carcinomas

IC50(nm)

Drug VEGFR1 VEGFR2 VEGFR3 RET BRAF Other targets

Sorafenib 90 20 49 6

Sunitinib 2 9 17 41

Motesanib 2 3 6 59 PDGFR, C-KIT

Vandetanib 40 110 100 EGFR

Lenvatinib(E7080) 22 4 5 35 PDGFR, FGFR-1

Axitinib 1.2 0.25 0.29

Pazopanib 10 30 47 PDGFR, C-KIT

Schlumberger and Sherman, 2012 Eur J Endocrinology

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Motesanib (AMG 706)

First large, international trial for progres-sive DTC was a phase II study of mote-sanib (125mg/day) on 93 patients

- PR: 13 (14%)

- SD: 33 (35%) (>24 weeks)

- PFS (Progression Free Survival)

: 40 weeks

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Vandetanib

Randomized phase II in 145 patients with refractory DTC treated with vandetanib (300mg/day) vs placebo on PFS

Objective tumor response rate: <5% in vandetanib group

PFS: 11.1 mos (vandetabnib) vs 5.8 mos (placebo) (HR=0.63, 95% CI 0.43-0.92)

Leboulleux S et al, 2012 Lancet Oncol

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Vandetanib in locally advanced or metastatic differen-tiated thyroid cancer: a randomised, double-blind, phase 2 trial

Leboulleux S et al, 2012 Lancet Oncol

11.1 (vandetabnib) vs 5.8 (placebo) mos. (HR=0.63, 95% CI 0.43-0.92) (P=0.008)

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Sunitinib

First phase II (37.5mg qd) in 28 DTC patients with FDG-avid disease on FDG-PET scan

- One CR, 7 PR and 14 SD

- Decrease in FDG uptake at 7 days of med-ication predicts better response to therapy

Second phase II with 31 DTCs with progressive disease (50mg/day 4wks, 2wks off)

- PR 13%

- SD 68%

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Lenvatinib (E7080)

Phase II (24mg of lenvatinib) in 58 DTCs

- PR 45% (53% of naïve patients and 42% of pre-treated patients)

- SD 46%

- PFS (median) 13.3 mos

- Dose reduction 39%

- Withdrawal 29%Phase III comparing the effect of lenvatinib vs

placebo on PFS in progressive refractory DTC is on-going.

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Axitinib

Phase II (5mg twice daily) in 45 DTCs

- PR: 14

- SD: 19 2nd phase II is ongoing (NCT00389441)

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Pazopanib

Multi-targeted TKI (VEGFR, PDGFR and c-Kit)

Approved for renal cell cancer and soft tissue sarcoma in USFDA

Phase II (800mg daily) in 37 DTCs

- PR 49%

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Sorafenib

Reported in four phase II trials (400mg bid)Drugs Year n PR(%

)SD>6

mo.(%)PFS,

medianDose reduction for toxicity (%)

Sorafenib 2008 30 23 53 20 47

Sorafenib 2009 41 PTC 15 56 15 52

Sorafenib 2009 32 25 34 13.5 66

Sorafenib 2011 19 18 82 >24 79

•Better in PTCs, on lung than on bone metastses and among PTCs, with BRAF mutation•Also, active in children with PTC

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Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refract-ory Thyroid Cancer (DECISION) trial

Comparing the effect of sorafenib vs placebo on PFS in treatment of naïve patients with RAI refractory, progres-sive metastatic DTC

Crossover or Con-tinue Sorafenib

400 mg PO BID

Crossover or Con-tinue Sorafenib

400 mg PO BID

ProgressionProgression

OffStudyOffStudy

Doctor’s Decision

Disease Progression

Disease Progression

Eligibility Criteria:•Locally advanced or metastatic DTC

•Progression within 14 months

•RAI refractory •No prior targeted therapy, chemo-therapy or thalidomide

Eligibility Criteria:•Locally advanced or metastatic DTC

•Progression within 14 months

•RAI refractory •No prior targeted therapy, chemo-therapy or thalidomide

PlaceboPlacebo

Random

isati

on (

1:1

)(n

=3

80

)R

andom

isati

on (

1:1

)(n

=3

80

)

Sorafenib400 mg PO BIDSorafenib400 mg PO BID

www.clinicaltrials.gov. NCT00984282

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Agents to restore RAI uptake

13 cis-retinoic acidBexarotene (synthetic agonist of RXR)RosiglitazoneSelumetinib (AZD6244)

- MEK ½ inhibitor

- 11(65%) of 17 RAI refractory DTC restored

RAI uptake

- 6/7(86%) had PR to RAI (only in patients whose information on best response was available)

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Side effects of molecular targeted ther-apies

Fatigue, Hypertension, Anorexia, Diarrhea

Cytopenia, Skin toxicities

- Dose reduction in 11-73%

- Withdrawal in 7-25%Serum TSH should be monitored

- T4 dose increase is needed sometimesCutaneous squamous cell cancers and kera-

toacanthomas in up-to 21% of patients treated with BRAF inhibitors

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Take home messages

Patients with advanced DTC require novel ther-apies and should be considered in prospective trials of molecular targeted agents when the disease burden is large and when progression has been documented.

DECISION (sorafenib) and Phase III E7080 trial will provide evidence that kinase inhibitors are more effective in patients with DTC with metastatic disease refractory to RAI treatment.

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Thank youGreetings from South Korea