Download Thyroid Cancer

Advances in the management of
iodine-refractory thyroid cancers
Marcia Brose MD PhD
Department of Otorhinolaryngology: Head and Neck Surgery
Department of Medicine, Division of Hematology/Oncology
Abramson Cancer Center
The University of Pennsylvania
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
MSB
05/30/09
Disclosure Elements
– My goal is to present information on several agents
currently under investigation for the treatment of
advanced thyroid. As none of the agents other than
doxorubicin and vandetanib and cabozantinib are FDA
approved for the use in thyroid cancer, the rest of the
new agents that will be discussed here are in clinical
trials (not FDA approved) at this time.
– Marcia S. Brose MD PhD
DISCLOSURE:
In the last three years I have financial interest/arrangement
or affiliation with:
Name of Organization
Relationship
Bayer Healthcare
research funding,
honorarium
Onyx
research funding,
honorarium
Novartis
research funding,
Exelixis
research funding
honorarium
Astrazeneca
consulting
Bristol-Myers Squibb
consulting
Genentech/Roche
research funding
Thyroid Cancer: Clinical
Pathology
Papillary
Follicular cells
Differentiated
Follicular
Hurtle Cell
Anaplastic
Parafollicular cells
Medullary
Sporadic
Familial
American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and
Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott
Williams and Wilkins. 2005.
MSB
05/30/09
Thyroid cancer in the United States
0-1.0cm
1.1-2.0cm
2.1-5.0cm
Davies, JAMA 2006
295:2164
>5.0cm
Differentiated Thyroid Cancer
MSB
09/21/09
Thyroid Cancer: Treatment Strategy
• High Risk: (Age >45, male, metastasis,
extrathyroidal extension, >4cm)
– Total Thyroidectomy
– RAI (131I) Ablation
– TSH Suppression Therapy with Thyroid
Hormone
– Follow Serial Thyroglobulin Levels (Tg)
– XRT for recurrent local disease/positive margins
– Surveillance: NeckUS, Tg, Neck MRI, Chest CT,
RAI Whole body scan, FDG-PET
MSB
05/30/09
RAI-Refractory Disease
• 25-50% of Metastatic Thyroid Cancers loose
ability to take up Iodine
• This is attributed to down regulation of the Na+/ISymporter (NIS) and other genes of NaI
metabolism
–In other words, the cancer cells
“forget” how to take up iodine and
so they are immune to the
treatment.
MSB
05/30/09
RAI-refractory disease
• Standard Chemotherapy has minimal
efficacy. 1974 Doxorubicin became the
only FDA approved drug for the treatment
of advanced thyroid cancer.
–No longer used because recent data
shows response is 5%
–High toxicity in patient with otherwise
good QOL
Cooper DS, et al. Thyroid. 2009;9:1176-214.
Hodak SP, Carty SE. Oncology. 2009;23:775-6.
Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.
Thyroid Cancer is associated with
aberrant cell signaling
MAP Kinase
Genetic Alteration
PTC
FTC
BRAF V600E
44%
0%
BRAF copy gain
3%
35%
RET/PTC (1 and 3)
20%
0%
8-10%
17-45%
PI3KCA mutations
3%
6%
PI3KCA copy gain
12%
28%
PTEN
2%
7%
Pax8/PPARγ
0%
35%
>70%
>65%
PI3K/AKT
RAS
Total
Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
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
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Targeting cell signaling in thyroid
cancer
Tumor Cell
RET/PTC
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Endothelial Cell
EGFR
VEGFR-2
Vandetanib
Ras
B-Raf
Sorafenib
MEK
ERK
Ras
PI3K
AKT
mTOR
S6K
Sorafenib
Everolimus
Sirolimus
• Growth
• HIF1a
• Survival
• Inhibition of apoptosis
• Proliferation • Migration
Raf
PI3K
MEK
AKT
ERK
mTOR
Axitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
Everolimus
Sirolimus
S6K
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
UPCC 03305: Sorafenib in
Advanced Thyroid Cancer
February 2006-February 2011
Eligibility criteria
• Metastatic, iodine
refractory thyroid cancer
• Life expectancy >3
months
Primary endpoints
n=55
• Evidence of PD within 6
months of study entry
Sorafenib
400mg b.i.d.
• RECIST
• PFS
• Response rate
• ECOG 0–2
• Good organ and bone
marrow function
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In
Solid Tumors; ULN = upper limit of normal
Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9
Phase III Study of Sorafenib in Locally Advanced
or Metastatic Patients with Radioactive Iodine
Refractory Thyroid Cancer (DECISION) trial
Eligibility criteria
• Locally advanced
or metastatic DTC
• Progression
within 14 months
• RAI refractory
• No prior targeted
therapy,
chemotherapy or
thalidomide
Primary Endpoint:
PFS (RECIST)
Independent review
Met primary endpoint
January 2013
Randomisation (1:1)
(n=380)
• An International, multicentre, randomised, double-blind, phase III study of
sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC
Sorafenib
400mg orally
b.i.d.
n=190
Placebo
n=190
Secondary Endpoints:
OS, TTP, RR, DCR, PRO, PK
Safety
Exploratory Biomarkers
Progression
Investigator’s decision
Crossover or
continue
sorafenib 400mg
orally b.i.d.
Off
study
Disease
progression
www.clinicaltrials.gov. NCT00984282
Targets of Kinase Inhibitors
Compound
Name
VEGFR
BRAF
PDGFR
KIT
RET
Other
Sorafenib
+
+
+
+
+
FLT-3
Sunitinib
+
+
+
Axitinib
(AG-013736)
+
+
+
Motesanib
(AMG-706)
+
+
+
Pazopanib
(GW786034)
+
+
+
Vandetanib
+
+
EGFR
Cabozantinib
(XL184)
+
+
C-MET
Lenvatinib
(E7080)
+
+
FGFR
+
+
FLT-3
+
Summary
• DTC is a vascular tumor that has been associated with
increased activity of the MAPK pathways
• Iodine-refractory patients have an average survival of 3
years
• Phase III study of sorafenib in this patient population is
positive. Results are expected at ASCO 2013.
• Results of phase II trials with lenvatinib have led to the
initiation of a phase III trials for patients with RAIrefractory DTC
• Additional MKIs are also now in development many of
which target VEGFR2, but also mTOR, MEK, and BRAF
Advanced Thyroid Cancer’s New Unmet Need:
Progression on Sorafenib/VEGFR2 inhibitor
• Patients progress but maintain good
performance status
• Most patients respond then progress in a
new lesion or a subset of lesions
What to do?
• We need additional treatment options
Targeting cell signalling in
thyroid cancer
Tumor Cell
RET/PTC
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Endothelial Cell
EGFR
VEGFR-2
Vandetanib
Ras
B-Raf
Sorafenib
MEK
ERK
Ras
PI3K
AKT
mTOR
S6K
Sorafenib
Everolimus
Sirolimus
• Growth
• HIF1a
• Survival
• Inhibition of apoptosis
• Proliferation • Migration
Raf
PI3K
MEK
AKT
ERK
mTOR
Axitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
Everolimus
Sirolimus
S6K
• Growth
• Survival
• Proliferation
• Migration
• Angiogenesis
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
UPCC 19309: Everolimus +
Sorafenib for DTC patients who
progress on Sorafenib alone
Eligibility criteria
• Metastatic, iodine
refractory thyroid cancer
• Life expectancy >3
months
n=35
• PD on sorafenib
Sorafenib
+ Everolimus
Intra-patient
Dose escalation
Primary endpoints
• RECIST
• PFS
• Response rate
• ECOG 0–2
• Good organ and bone
marrow function
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In
Solid Tumors; ULN = upper limit of normal
22 patients accrued so far
Primary Endpoint:
Best Overall response Rate (BORR)
(RECIST 1.1) (Partial and complete
RR) in sorafenib naïve pts
Independent review
BRAF V600E testing
Eligibility criteria:
• Locally advanced
or metastatic DTC
• Progression
within 14 months
• RAI refractory
Informed Consent
NO25530: An Open-Label, Multi-Center Phase II Study of
the BRAF Inhibitor RO5185426 in Patients with Metastatic
or Unresectable Papillary Thyroid Cancer (PTC) positive for
the BRAF V600 Mutation and Resistant to
Radioactive Iodine
+
First Line
Sorafenib Naïve
(n=25)
RO5185426
+
BID
Second Line
Prior Sorafenib
(n=15+)
Secondary Endpoints:
•PFS, TTP, OS, TTP, in
sorafenib naïve pts
•BORR, CB, TTP, PFS and
OS, in soraefnib exposed
patients
Status:
Accrual Complete
Thyroid Cancer Therapeutics Program:
Treatment Algorithm for Advanced DTC
First Line:
Sorafenib
For PTC only:
Second Line:
VEGR2+BRAF+mTOR
Third Line:
Phase II – Add
Everolimus or
off label - Sirolimus
VEGFR/MET/RET
Inhibitors
Personalized
Pazopanib
Cabozantinib
BRAF V600E
Inhibitor
Phase II – vemurafenib
ASCO 2012: Selumetinib: MEK
inhibition to increase RAI uptake
(Ho et al)
Going forward as an earlier treatment:
1. Use for patients with high risk disease to increase uptake,
2. Unclear where in the treatment paradigm this will end up.
Summary Second Line Agents
• Due to tumor heterogeneity, a patient with
progression on a multikinase inhibitor may
continue to derive benefit from that inhibitor
• Combination or Sequential treatments with MKIs
(sorafenib + everolimus, or sorafenib +
vemurafenib) are likely to aid patients with
progression
• New agents in development that specifically target
mutations (BRAF V600E) may also play a role in
the treatment of thyroid cancer in the first or
second line settings and carry the most promise
Medullary Thyroid Cancer
MSB
09/21/09
Signaling pathways in MTC
C-MET
EGFR
RET
PKC
RAS
BRAF
VEGF
Tumor
cell
PI3K
MEK
AKT
ERK
VEGFR
Endothelial
cell
PLC-g
Multikinase inhibitor activities
relevant to MTC
Drug
In vitro IC50 (nm)
VEGFR
1
Sorafenib
Vandetanib
Cabozantinib
(XL 184)
VEGFR
VEGFR3 RET RET/PTC3 RAF
2
Other
-
90
20
49
50
6
PDGFR
58
1600
40
110
100
50-100
-
EGFR 500
-
0.035
-
4.5
-
-
C-MET
1.8
Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494
ZETA Study: Vandetanib
Significantly Prolonged PFSa vs Placebo
PFS: 65% Relative Reduction in Risk of Progression1
▬▬ CAPRELSA 300 mg
Events/Patients
59/231
Progression-free Survival
1.0
▬▬ Placebo
41/100
Median PFS not reached
0.75
(95% CI: 22.6 months,
nonestimable)
0.50
16.4 months median PFS
0.25
(95% CI: 8.3-19.7)
HR=0.35 (95% CI: 0.24-0.53)
P<0.0001
0.0
0
6
12
18
24
30
36
33
6
1
0
0
0
Months
Number at Risk
CAPRELSA 300 mg
Placebo
231
100
173
47
145
30
118
24
CI=confidence interval; HR=hazard ratio.
aPFS is defined as time from the date of randomization until the date of objective disease progression based on Response
Evaluation Criteria In Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided
death was within 3 months from the last evaluable RECIST assessment. 2 Centralized, independent blinded review of the
imaging data was used in the assessment of PFS.1
1. CAPRELSA® (vandetanib) Tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2. Wells SA Jr et al. J Clin Oncol.
2012;30(2):134-141.
27
Cabozantinib Ph III in MTC
Progression Free Survival by IRC
1.0
Probability
0.9
Cabozantinib
Placebo
0.8
Median PFS
(months)
11.2
4.0
0.7
1 year PFS
47.3%
7.2%
0.6
HR (95% CI)
0.28 (0.19, 0.40)
0.5
0.4
0.3
pp<0.0001
< 0.0001
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Months
Cabozantinib
219
121
78
55
31
12
2
Placebo
35
11
6
3
2
0
•111 Significant
difference
in tumor
response
rate
– 28% in cabozantinib vs. 0% placebo; p<0.0001
• Median duration of response: 14.6 months
ASCO 2012 oral presentation
1
0
Thyroid Cancer Therapeutics Program:
Treatment Algorithm for Advanced MTC
First Line:
Vandetanib
Cabozantinib
Second Line:
Cabozantinib
Vandetanib
Third Line/(First):
Sorafenib
Pazopanib
Third Line:
Sunitinib/Other?
Summary: Agents for MTC
• Phase II data shows that several multikinase
inhibitors are clinically active in patients with
advanced Differentiated and Medullary thyroid
cancer.
• Vandetanib was approved last year and
Cabozantinib just received FDA approval for
MTC
• Response in these patients result in prolonged
disease control
• Additional agents are needed as these agents
last only 10-12 months, there is a great unmet
need to identify additional agents for this
disease.
Summary: Targeted therapy for
Advanced Thyroid Cancer
• Where do we go from here?
– Completion of large randomized trials:
• Phase III of sorafenib is positive. Phase III of lenvatinib is
underway.
– More data on the activity of the targeted agents used
sequentially:
• So patients are to benefit from the number of agents
available
– Novel strategies for treatment bear investigating:
• including novel targets and the use of combination therapies
to improve outcome.(Sor+Ev, Sor + Vem)
– Further subgroup analysis to identify subpopulations:
• use of clinical and molecular markers to identify patients that
may benefit better with some therapies over others. Pts with
Ras mutations, Poorly differentiated TC
– Registration trial for sorafenib in MTC!!!
Agents currently available in our Thyroid
Cancer Therapeutics Program
Agent
Sub-types
Vandetanib
MTC, (DTC)
Sorafenib
DTC, MTC, ATC
Everolimus
DTC
Pazopanib
DTC
Lenvatinib (E7080)
DTC
Cabozantinib (XL184)
MTC, DTC
Vemurafenib (PLX4322 – BRAF V600Ei)
PTC
Combretastatin
ATC
PLX3397
ATC
MSB
10/16/10
University of Pennsylvania
Thyroid Cancer Therapeutics Program
•
Brose Group
– Carolyn Grande RN, CRNP
– Steve Keefe MD
– Thelma McClosky
– Tatyana Kuznetsova, PhD
– Waixing Tang MD
– Stephen Stopenski
•
Thyroid Cancer Clinical Trials Unit
– Larisa Zifchak RN
– Parna Prajapati
– Ramkrishna Makani
– Jillilan Stanley
•
•
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
– Kelly Malloy MD
– Douglas Fraker MD
– Robert Lustig MD
– Virginia LiVolsi MD
– Zubair Baloch MD
•
MSB is a Damon Runyon-Siemens
Clinical Investigator
•
Many Community Endocrinologists that
have referred their patients, and the
patients that have agreed to participate
in our trials.
Questions?
Marcia S. Brose MD PhD
Email: [email protected]
Telephone: 215-615-6519
Thank you for your courage and attention!
MSB
10/16/10