Download Catecholamines - Asia & Oceania Thyroid Association

Recent progress of targeted kinase
inhibitors in thyroid cancer
A/Prof Rory Clifton-Bligh
Kolling Institute of Medical Research,
University of Sydney
Department of Endocrinology
Royal North Shore Hospital, St Leonards,
NSW
Royal North
Shore Hospital
10th Asia and Oceania Thyroid Association Congress, Bali 23rd October 2012
Overview
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Scope of problem for thyroid cancer
Molecular targets for thyroid cancer
Data
Success of kinase inhibitors in other
cancers
Pharmacogenomics
Conclusions
Thyroid cancer subtypes
15%
DTC
85%
cured with
treatment
25% 35% 100%
7%
“Unmet
need”
…10-year mortality
Tuttle et al J Natl Compr Canc Netw 2010;8:1228-1274
15% recurrent/metastatic
disease ~1/3 controlled by
I-131, T4 and/or local Rx
Metastatic Disease: existing therapies
Brain
Regional LNs
-surgery
-Surgery
-XRT
-RAI
Lung
-RAI
Bone
-RAI
-XRT
-Bisphosphonates
Challenge in designing clinical trials in DTC:
(sometimes) indolent natural history
!
Waterfall plot of best percentage change in target lesion size from baseline,
placebo group from Vandetanib trial in DTC, phase II
Leboulleux et al Lancet Oncol 2012;13:897–905
Growth signalling: targets for new drugs

RET
RET/PTC
RAS
Somatic mutations in papillary
thyroid cancer:


BRAF
PI3K


Cell proliferation
Differentiation
BRAF
RAS
RET/PTC
30-70%
0-20%
20-50%
PI3-kinase pathway also
involved (PIK3CA copy number
gain and mutation; PTEN):



FTC
PTC
ATC
Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13:1161-70.
55%
24%
58%
Growth signalling: targets for new drugs
VEGF
PDGF-β
RET
RET/PTC
VEGFR-2
RAS
PDGFR-β
BRAF
PI3K
DTC tumor cell
Adapted from Brose et al BMC Cancer 2011;11:349
Tumor endothelial cell
Rationale for targeting growth factor
signalling cascades in thyroid cancer
- Preclinical studies

conditional
expression of
BRAFV600E in adult
mice causes PTC

Treatment with MEK
inhibitor resulted in
partial tumor
regression
Charles et al Cancer Res 2011;71:3863-71
Rationale for targeting growth factor
signalling cascades in thyroid cancer
- Clinical data

Medullary thyroid
cancer in MEN2:


RET genotype/activity
determines biological
aggressiveness
Papillary thyroid
cancer:

BRAFV600E connotes
risk of death
Cote et al., 2003 N Engl J Med 2003;349: 1566-1569
BRAFV600E and immunohistochemistry
mouse monoclonal antibody, clone VE1 (Capper and von Deimling)
BRAFV600E positive by IHC
positive by sequencing
BRAFV600E positive by IHC
negative by sequencing
58%
10%
(32% negative for both IHC and sequencing)
Bullock et al Endocr Rel Cancer 2012
Kinase inhibitors

mimicking ATP within
catalytic sites

pseudosubstrate

alteration of kinase
stability
Wan et al Cell 2004;116:855-867
sorafenib
BRAF kinase
Phase
Medullary thyroid cancer
Cohen et al
2
Schlumberger et al
2
Wells et al
2
Robinson et al
2
Kuzrock et al
1
Ahmed et al
2
Lam et al
2
Hong et al
1
Carr et al
2
Differentiated thyroid cancer
Cohen et al
2
Sherman et al
2
Gupta-Abramson et al 2
Kloos et al
2
Ahmed et al
2
Carr et al
2
Hong et al
1
Bible et al
2
Drug
n
CR(%) PR(%) SD(%)
Axitinib
Motesanib
Vandetanib
Vandetanib
Cabozantinib
Sorafenib
Sorafenib
Sor’+tipifarnib
Sunitinib
11
91
30
19
37
15
16
13
7
0
0
0
0
0
0
0
0
0
18
2
20
16
29
25
6
38
50
27
48
53
53
41
na
50
31
na
Axitinib
Motesanib
Sorafenib
Sorafenib
Sorafenib
Sunitinib
Sor’+tipifarnib
Pazopanib
45
93
30
41
19
28
22
39
0
0
0
0
0
3
0
0
31
14
23
15
18
28
4.5
49
42
35
53
56
73
37
36
nr
Data from randomized, placebocontrolled studies
Typical inclusion criteria

Measurable disease

at least one measurable lesion as measured
by CT or MRI
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Disease progression (RECIST)

(RAI-refractory disease: for DTC trials)
Medullary Thyroid Cancer

Vandetanib

Cabozantinib
Vandetanib

RET, VEGF receptor, and EGFR tyrosine
kinases

MTC: approved for patients with
unresectable locally advanced or
metastatic disease (US, Canada,
Europe)
Vandetanib in MTC: phase III
Vandetanib
n = 231
Placebo
n = 100
HR/OR
p value
30.5 mo
19.3 mo
0.46
(0.31-0.69)
0.0001
Objective
response rate
45%
13%
5.48
(2.99-10.79)
<0.001
Disease
control rate
87%
71%
2.64
(1.48-4.69)
0.001
Calcitonin
response rate
69%
3%
72.9
(26.2-303.2)
<0.001
CEA
response rate
52%
2%
52.0
(16.0-320.3)
<0.001
1°endpoint
Progression
free survival
2°endpoints
Wells et al J Clin Oncol 2012;30:134-141
Vandetanib in MTC: phase III- PFS
Wells et al J Clin Oncol 2012;30:134-141
Vandetanib in MTC: phase III- OS
Overall survival data immature (HR 0.89; 0.48-1.65)
A final survival analysis planned when 50% pts dead
Wells et al J Clin Oncol 2012;30:134-141
Side-effects: vandetanib
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Diarrhoea (16%)
Palmar-plantar erythrodysethesia (13%)
Hypertension (8%)
Prolonged QT
Headache
Nausea
Leukopenia
Discontinued therapy because of AE:
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
Vandetanib 12%
Placebo 3%
Wells et al J Clin Oncol 2012;30:134-141
Cabozantinib (XL184) in MTC: phase III
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MET, VEGFR2, RET
EXAM trial, international multicentre
330 pts, median age 55 y



Cabozantinib n = 219
Placebo n = 111
PFS:
Cabo
11.2 mo
Placebo
4.0 mo
(HR 0.28, 0.19-0.4, p < 0.0001)

ORR:
28%
Schoffski et al J Clin Oncol 2012;30: suppl abstr 5508
0%
(p, ns)
Side-effects: cabozantinib
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

Diarrhoea (16%)
Palmar-plantar erythrodysethesia (13%)
Hypertension (8%)
Differentiated thyroid cancer
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Vandetanib
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(Lenvatinib)
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(Sorafenib)
Vandetanib in DTC: phase II
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16 medical centres in Belgium, Denmark, France, Norway,
Spain, Sweden, and Switzerland
Vandetanib
n = 72
Placebo
n = 73
HR/OR
p value
11.1 mo
5.9 mo
0.63
(0.54-0.74)
0.008
Objective
response rate
8%
5%
1.57
(0.42-5.81)
0.501
Disease
control rate
57%
42%
1.79
(0.93-3.46)
0.082
1°endpoint
Progression
free survival
2°endpoints
Leboulleux et al Lancet Oncol 2012;13:897–905
Progression-free survival
Vandetanib in DTC: phase II - PFS
Leboulleux et al Lancet Oncol 2012;13:897–905
Vandetanib in DTC: phase II - OS
(crossover from placebo to vandetanib allowed,
confouding assessment of the effects of treatment on overall
survival)
Leboulleux et al Lancet Oncol 2012;13:897–905
Vandetanib in DTC: phase II - OS
Two patients in the vandetanib group and one
in the placebo group died from “treatmentrelated” serious adverse events (haemorrhage
from skin metastases and pneumonia in the
vandetanib group and pneumonia in the
placebo group)
Leboulleux et al Lancet Oncol 2012;13:897–905
Lenvatinib (E7080)
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
VEGFR1-3, FGFR1-4, RET, KIT, PDGFRβ
Phase II

RAI-refractory DTC (papillary, follicular or Hurthle
Cell) and disease progression demonstrated by
RECIST during the prior 12 months

58 pts: PR 50% (CI, 37-63%)
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35% required dose reduction for management
of toxicity, and 23% were withdrawn
Sherman et al, J Clin Oncol 29: 2011 (suppl; abstr 5503)
Sorafenib
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Phase III trial ongoing (DECISION)
Phase II: four trials including 168 patients
with thyroid cancer treated with sorafenib
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Median progression-free survival (PFS)
ranged from 58-84 weeks
Partial responses in up to 25%
Disease control rates (SD+PR) 59-100%
Dose reductions due to AEs (mostly grade III) in 62%
Brose et al BMC Cancer 2011;11:349
Thyroid dysfunction in patients on
kinase inhibitors
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Elevated TSH/requirement for higher
Thyroxine dose in Thyroid cancer
patients:

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49-78% of patients receiving vandetanib
Hypothyroidism in patients with intact thyroid (eg
renal cell cancer)


In 36-85% pts treated with sunitinib
In 18-68% pts treated with sorafenib
Torino et al Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic
effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219–28.
Other kinase inhibitors

Dabrafenib





selective for mutant BRAF
Motesanib
Axitinib
Pazopanib
Sunitinib
I-131
Combinations

Receptor tyrosine
kinase + MEK
inhibitor

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RAI + MEK inhibitor


dabrafenib + MEKi
Selumetinib
(AZD6244)*
TKI + mTOR inhibitor

Temsirolimus +
sorafenib*
*Ho et al J Clin Oncol 2012;30:suppl abstr 5509
Sherman E et al J Clin Oncol 2012;30:suppl abstract 5514
BRAF
MEK
mTOR
Kinase inhibitors in other malignancies
Kinase inhibitors: haematologic
malignancies

CML: BCR-ABL




Imatinib
Nilotinib
Dasatinib
complete response
for up to 8 years in
85% of patients

Hairy cell
leukaemia:
BRAFV600E

Vemurafenib
Kinase inhibitors: melanoma
BRAF inhibitor
Chapman et al N Engl J Med 2011;364:2507-16
MEK inhibitor
Flaherty et al N Engl J Med 2012;367:107-114
Kinase inhibitor combinations to
overcome resistance: melanoma
dabrafenib+trametinib
dabrafenib
Flaherty et al N Engl J Med 2012;doi: 10.1056
Pharmacogenomics
BRAFV600E mutation:
pharmacogenomics

Clear evidence from hairy
cell leukemia and
melanoma that response
to BRAF-targeted therapy
is strongly associated with
tumor genotype
In vitro experience
suggests that thyroid cell
lines containing mutant
BRAF cell lines are more
sensitive to BRAF or MEK
inhibitors
 ?no clinical evidence for
pharmacogenomic effects
in thyroid cancer:
Motesanib (Phase 2, 93 pts)

DCR
BRAF+
BRAF-
Leboeuf et al JCEM 2008;93:2194
60% (6/10)
ns
33% (5/15)
Sherman et al N Engl J Med 2008;359:31
RET mutation:
pharmacogenomics

In subgroup analysis,
suggestion of higher
response rate to
vandetanib in
sporadic tumors with
M918T mutation

in vitro, Vandetanib
does not inhibit the
V804 mutations in
RET
Wells et al J Clin Oncol 2012;30:134-141
Conclusions
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Thyroid cancer mortality is related to:



These signalling pathways are targets for several drugs
in clinical use or development

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Well-defined activation of growth factor signalling pathways
Loss of iodine uptake (DTC)
Many pts require dose reduction or drug withdrawal to
manage toxicity
Some treatment-related deaths reported
Vandetanib has FDA approval for use in MTC
Balance of risks vs benefits needs to be carefully
addressed in phase III trials

Need greater definition of those pts who will have survival
benefit from treatment
Thyroid Group at RNSH, Sydney
Bruce Robinson Diana Learoyd
Rory
Leigh Delbridge Stan Sihdu
Clifton-Bligh
Endocrinologists
Scientists
Mark Sywak
Endocrine Surgeons
Pathologist PhD students
Jimmy
Lee
Dindy Benn
Anne-Louise
Richardson
Martyn
Bullock
Anthony Gill
Justin Julian
Gundara Ip
and Matti Gild