msb 05/30/09 advances in the management of iodine-refractory thyroid cancers marcia brose md phd...
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MSB 05/30/09
Advances in the management of iodine-refractory thyroid cancers
Marcia Brose MD PhD
Department of Otorhinolaryngology: Head and Neck SurgeryDepartment of Medicine, Division of Hematology/Oncology
Abramson Cancer CenterThe University of Pennsylvania
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870
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
MSB 05/30/09
Thyroid Cancer: Clinical Pathology
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.
Parafollicular cells
Follicular cells Differentiated
Anaplastic
Medullary
Papillary
Follicular
Hurtle Cell
Sporadic
Familial
>5.0cm
2.1-5.0cm
Thyroid cancer in the United States
0-1.0cm
1.1-2.0cm
Davies, JAMA 2006295:2164
Differentiated Thyroid Cancer
MSB 09/21/09
MSB 05/30/09
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+/I- Symporter (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.
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
Genetic Alteration PTC FTC
BRAF V600E 44% 0%
BRAF copy gain 3% 35%
RET/PTC (1 and 3) 20% 0%
RAS 8-10% 17-45%
PI3KCA mutations 3% 6%
PI3KCA copy gain 12% 28%
PTEN 2% 7%
Pax8/PPARγ 0% 35%
Total >70% >65%
MA
P K
inas
eP
I3K
/AK
T
Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
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
Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.
MotesanibSorafenibSunitinibVandetanibXL-184
Axitinib MotesanibSorafenibSunitinibVandetanib
Vandetanib
Sorafenib Sorafenib
Targeting cell signaling in thyroid cancer
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
EverolimusSirolimus
EverolimusSirolimus
UPCC 03305: Sorafenib in Advanced Thyroid Cancer
February 2006-February 2011
Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9
n=55
Eligibility criteria
• Metastatic, iodine refractory thyroid cancer
• Life expectancy >3 months
• Evidence of PD within 6 months of study entry
• ECOG 0–2
• Good organ and bone marrow function
Sorafenib400mg b.i.d.
Primary endpoints
• RECIST
• PFS
• Response rate
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
Eligibility criteria• Locally advanced
or metastatic DTC• Progression
within 14 months • RAI refractory • No prior targeted
therapy, chemotherapy or thalidomide
Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial
• An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC
www.clinicaltrials.gov. NCT00984282
Offstudy
Disease progression
Crossover or continue
sorafenib 400mg orally b.i.d.
Ran
do
mis
atio
n (
1:1)
(n=
380)
ProgressionSorafenib
400mg orallyb.i.d.
Placebo
Investigator’s decisionn=190
n=190
Primary Endpoint:PFS (RECIST)Independent reviewMet primary endpointJanuary 2013
Secondary Endpoints:OS, TTP, RR, DCR, PRO, PKSafetyExploratory Biomarkers
Targets of Kinase InhibitorsCompound Name VEGFR BRAF
PDGFR KIT RET Other
Sorafenib + + + + + FLT-3
Sunitinib + + + FLT-3
Axitinib (AG-013736) + + +
Motesanib (AMG-706) + + + +Pazopanib(GW786034) + + +
Vandetanib + + EGFR
Cabozantinib (XL184) + + C-MET
Lenvatinib(E7080) + + + + FGFR
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 RAI-refractory 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
Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.
MotesanibSorafenibSunitinibVandetanibXL-184
Axitinib MotesanibSorafenibSunitinibVandetanib
Vandetanib
Sorafenib Sorafenib
Targeting cell signalling in thyroid cancer
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
EverolimusSirolimus
EverolimusSirolimus
UPCC 19309: Everolimus + Sorafenib for DTC patients who
progress on Sorafenib alone
n=35
Eligibility criteria
• Metastatic, iodine refractory thyroid cancer
• Life expectancy >3 months
• PD on sorafenib
• ECOG 0–2
• Good organ and bone marrow function
Sorafenib + Everolimus
Intra-patientDose escalation
Primary endpoints
• RECIST
• PFS
• Response rate
b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
22 patients accrued so far
Eligibility criteria:• Locally advanced
or metastatic DTC• Progression
within 14 months • RAI refractory
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 forthe BRAF V600 Mutation and Resistant to
Radioactive Iodine
RO5185426 BID
Primary Endpoint:Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve ptsIndependent review
Secondary Endpoints:• PFS, TTP, OS, TTP, in
sorafenib naïve pts• BORR, CB, TTP, PFS and
OS, in soraefnib exposed patients
Info
rmed
Co
nse
nt
BR
AF
V60
0E t
esti
ng + First Line
Sorafenib Naïve (n=25)
Second Line Prior Sorafenib
(n=15+)
+
Status:Accrual Complete
Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced DTC
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
BRAF
MEK
ERK
RAS
AKT
VEGF
VEGFR
Tumorcell
En
do
thelial
cellY1062
-P
X
RET
PI3K
EGFR
VEGFRPLC-g
PKC
Multikinase inhibitor activities relevant to MTC
Drug In vitro IC50 (nm)
VEGFR1
VEGFR2
VEGFR3 RET RET/PTC3 RAF Other
Sorafenib - 90 20 49 50 6PDGFR
58
Vandetanib 1600 40 110 100 50-100 - EGFR 500
Cabozantinib (XL 184) - 0.035 - 4.5 - -
C-MET 1.8
Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494
27
ZETA Study: VandetanibSignificantly Prolonged PFSa vs Placebo
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.
0 6 12 18 24 30 36
Months
Pro
gre
ssio
n-f
ree
Su
rviv
al Median PFS not reached(95% CI: 22.6 months, nonestimable)
16.4 months median PFS(95% CI: 8.3-19.7)
HR=0.35 (95% CI: 0.24-0.53)P<0.0001
▬▬ CAPRELSA 300 mg ▬▬ PlaceboEvents/Patients 59/231 41/1001.0
0.75
0.50
0.25
0.0
PFS: 65% Relative Reduction in Risk of Progression1
Number at RiskCAPRELSA 300 mg 231 173 145 118 33 1 0Placebo 100 47 30 24 6 0 0
Cabozantinib Ph III in MTCProgression Free Survival by IRC
Cabozantinib Placebo
Median PFS(months) 11.2 4.0
1 year PFS 47.3% 7.2%
HR (95% CI) 0.28 (0.19, 0.40)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Months
Pro
ba
bilit
y
219 121 78 55 31 12 2 1
111 35 11 6 3 2 0 0
Cabozantinib
Placebo
p<0.0001p < 0.0001
• 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
Thyroid Cancer Therapeutics Program: Treatment Algorithm for Advanced MTC
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
• 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.
University of PennsylvaniaThyroid 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
MSB 10/16/10
Questions?
Marcia S. Brose MD PhD
Email: [email protected]
Telephone: 215-615-6519
Thank you for your courage and attention!