New Approaches in the Treatment for the Advanced Thyroid Cancer
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Transcript of New Approaches in the Treatment for the Advanced Thyroid Cancer
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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
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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
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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
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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