Transcript New Approach in the Treatment for the Advanced Thyroid Cancer

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
thyroid cancers
(differentiated thyroid cancers, DTCs)
Genetic alterations in DTCs
RECIST
Newer molecular targeted therapies
2
Background
DTCs comprise most of thyroid cancers
RAI refractory DTCs have poorer prognosis
3
Classification of Thyroid Cancers
Follicular
Follicular cells
Differentiated
Hürthle
Papillary
Anaplastic (Undifferentiated)
Sporadic (80%)
Parafollicular cells
Medullary
Hereditary (20%)
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Differentiated
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
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Background
DTCs comprise most of thyroid cancers
RAI refractory DTCs have poorer prognosis
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Initial disease stage predicts
overall survival in patients with DTC
Stage I
100
Stage II
80
Survival (%)
75% of all
tumours
60
Stage III
25% of
all
tumours
40
20
0
Stage IV
p<0.001
0
2
4
6
8
10
12
14
Years
Jonklaas J, et al. Thyroid 2006;16:1229–42
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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
RAIFDG RAI +
FDG RAI FDG +
- - - RAI +, FDG -: 95%
- - - RAI -, FDG +: 45%
- - - RAI +, FDG +: 45%
RAI +
FDG +
• Presence of FDG uptake is related
to
– Age >40 years
– Large metastases
– Poorly differentiated or
papillary/follicular disease
with necrosis and mitosis
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Robbins RJ, et al. J Clin Endocrinol Metab. 2006
Objectives
Conventional treatment in advanced DTCs
Genetic alterations in DTCs
RECIST
Newer molecular targeted therapies
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Therapeutic modalities for RAI
refractory recurrent DTCs
Surgery
Indication
Pros
Cons
Surgically resectable
local recurrences or
metastatectomy
Potential for cure
Potential significant
morbidity
External beam Adjuvant: neck
Decrease in
radiation
recurrences,
Therapeutic and palliative: progression and pain
metastatic sites
May preclude future
neck surgery; dysphagia
and xerostomia;
secondary malignancy
PEIT and RFA
Local pain; injury to local
structure; unknown
effect on survival and
recurrence
Locally recurrent disease
in patients at high risk for
morbidity and mortality
from surgery
Systemic
Unresectable, RAIchemotherapy refractory, metastatic
disease
Potential for
avoidance of surgery
May slow progression Significant adverse
of disease; may
events; unknown effect
alleviated disease
on survival
symptom
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Busaidy and Cabanillas et al. J Thy Res 2012
FDA approval of doxorubicin for treatment
of metastatic thyroid cancer (1974)
Epithelial origin, 5% PR
Thus, patients with progressive DTC have had
an unmet clinical need for over three decades
FDA = Food and Drug Administration; PR = partial response
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Matuszczyk A, et al. Horm Metab Res 2008
Objectives
Conventional treatment in advanced DTCs
Genetic alterations in DTCs
RECIST
Newer molecular targeted therapies
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Thyroid cancer is associated with
aberrant cell signaling
Papillary thyroid
cancer (%)
Follicular thyroid
cancer (%)
44─45%
0
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
>70
>65
PI3K/AKT
MAP kinase
Genetic alteration
B-Raf V600E
B-Raf copy gain
Total
14
Nikiforov YE. Mod Path 2008;21 Suppl 2:S37–43
Xing M. Endocr Relat Cancer 2005;12:245–62
Wang HM, et al. Ann Surg Oncol 2007;14:3011–8
Cell signalling in differentiated thyroid cancer
Tumor Cell
RET/PTC
Endothelial Cell
EGFR
VEGFR-2
Ras
B-Raf
MEK
ERK
Ras
PI3K
Raf
PI3K
MEK
AKT
ERK
mTOR
AKT
mTOR
S6K
• Growth
• HIF1a
• Survival
• Inhibition of apoptosis
• Proliferation • Migration
S6K
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
15 from
Graphic adapted
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Objectives
Conventional treatment in advanced DTCs
Genetic alterations in DTCs
RECIST
Newer molecular targeted therapies
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RECIST (1)
Response Evaluation Criteria In Solid
Tumors
Defines when cancer patients improve
("respond"), stay the same ("stabilize"), or
worsen ("progression") during treatments.
Published in February, 2000 by an
international 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 lesions
 Frequency 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 DTCs
RECIST
Newer molecular targeted therapies
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Kinase inhibitor activities relevant
to advanced thyroid carcinomas
IC50(nm)
Drug
VEGFR1
Sorafenib
VEGFR2
VEGFR3
RET
BRAF
90
20
49
6
Other targets
Sunitinib
2
9
17
41
Motesanib
2
3
6
59
PDGFR, C-KIT
40
110
100
EGFR
35
PDGFR, FGFR-1
Vandetanib
Lenvatinib(E7080)
22
4
5
Axitinib
1.2
0.25
0.29
Pazopanib
10
30
47
PDGFR, C-KIT
21
Schlumberger and Sherman, 2012 Eur J Endocrinology
Motesanib (AMG 706)
First large, international trial for progressive
DTC was a phase II study of motesanib
(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)
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Leboulleux S et al, 2012 Lancet Oncol
Vandetanib in locally advanced or metastatic differentiated
thyroid cancer: a randomised, double-blind, phase 2 trial
11.1 (vandetabnib) vs 5.8 (placebo) mos.
(HR=0.63, 95% CI 0.43-0.92) (P=0.008)
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Leboulleux S et al, 2012 Lancet Oncol
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
medication 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
pretreated 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,
Dose reduction
median 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
Refractory Thyroid Cancer (DECISION) trial
 Comparing the effect of sorafenib vs placebo on PFS in
treatment of naïve patients with RAI refractory,
progressive metastatic DTC
Progression
Eligibility Criteria:
•RAI refractory
•No prior targeted th
erapy, chemotherap
y or thalidomide
Doctor’s Decision
Randomisation (1:1)
(n=380)
•Locally advanced or
metastatic DTC
•Progression within
14 months
Sorafenib
400 mg PO BID
Crossover or Continue
Sorafenib
400 mg PO BID
Placebo
Off
Study
Disease
Progression
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www.clinicaltrials.gov. NCT00984282
Agents to restore RAI uptake
 13 cis-retinoic acid
 Bexarotene (synthetic agonist of RXR)
 Rosiglitazone
 Selumetinib (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
therapies
 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 sometimes
 Cutaneous squamous cell cancers and
keratoacanthomas in up-to 21% of patients
treated with BRAF inhibitors
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Take home messages
 Patients with advanced DTC require novel
therapies 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 you
Greetings from South Korea
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