Advanced Thyroid Cancer - MECC...
Transcript of Advanced Thyroid Cancer - MECC...
Advanced Thyroid Cancer:
A New Disease for Medical Oncology
Thomas Semrad MD, MAS, FACP
Assistant Professor of Medicine
Division of Hematology/Oncology
Recent Developments in Cancer Therapy
Disclosures
• Speakers Bureau: Novartis
• Consulting: Amgen, Genentech, Genomic
Health, Onyx
• Research Funding: Astex, Eisai,
Genentech, Millenium, Morphotek,
Novartis
Outline
• Thyroid Cancer Landscape
• Differentiated Thyroid Cancer – What is Iodine Refractory?
– Multi-kinase inhibitors targeting VEGFR
• Medullary Thyroid Cancer – Multi-kinase inhibitors targeting RET
Who To Treat and Who Not To Treat
Differentiated Thyroid Cancer
Medullary Thyroid Cancer
Anaplastic Thyroid Cancer
Follicular Thyroid Cancer
Papillary Thyroid Cancer
Hereditary
Sporadic
Lymphoma and Other
5%
12%
80%
2%
1%
~25%
~75%
Thyroid Cancer 101
Hughes et al. Thyroid 2011;(21)3:231-236
New
cases o
f papill
ary
thyro
id c
ancer
in the U
nited s
tate
s b
y a
ge
>45
Years old
<45 years
old
Principles of Treatment High Risk Patients
• Total Thyroidectomy
• Radioiodine – Gross Extrathyroidal Extension
– > 4cm primary
– Distant metastases
• Neck Dissection – Clinical or US-detected disease
– Locoregional recurrence
• TSH Suppression – <0.1 for those at high risk or with known residual
disease ATA Guidelines. Cooper et al. Thyroid 2009. 19(11).
NCCN Guidelines. Thyroid Carcinoma v2.2013.
Radioiodine Refractory Criteria
A. One or more (measurable) lesions that do
not demonstrate 131I uptake on diagnostic
radioiodine scan
B. One or more lesions that has progressed
within 12 months of 131I therapy.
C. Cumulative activity of 131I of > 600 mCi
Radioiodine Refractory Prognosis
Outcome1
– Median Survival 3-6
years
– 10-year survival less
than 15%
Prognostic Factors2,3
– Age
– BRAF Mutation
– PET positivity
Durante et al. J Clin Endocrinol Metab 2006;91(8):2892–2899.
Elisei et. al, J Clin Endocrinol Metab 2008;93(10):3943-9
Robbins and Weil. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047-59
Cytotoxic Agents for DTC
• Adriamycin is the most studied agent
– Others include bleomycin, platinums,
etoposide, and pemetrexed
• 1974, 37% PR in 30 patients1
– Based on > 50% decrease on x-rays
• 5-17% in subsequent trials2
• Common AEs include myelosuppression,
nausea, vomiting, and cardiotoxicity
1 Gottleib et al. NEJM 1974 2 Matuszczyk et al Horm Metab Res 2008
Cytotoxics have no established role
for the management of DTC
Molecular Pharmacology of DTC
Kapiteijn et al. Annals Oncology 2011
20 - 40% PTC
~50% PTC
10% PTC
50% FTC
Molecular Pharmacology of DTC
Kapiteijn et al. Annals Oncology 2011
gefitinib
vemurafenib
? sorafenib
sorafenib
sunitinib
axitinib
pazopanib
lenvatinib
cabozantinib
selumetinib
tremetinib
everolimus
temsirolimus
vandetanib
sunitinib
cabozantinib
Phase II Trials of Kinase Inhibitors
Agent Phase N ORR (%) DCR (%) PFS
(mos) Ref
Gefitinib II 27 0 81 3.7 Thyroid 2008;18:317-323
Motesanib II 93 14 81 9.2 NEJM 2008;359:31-42
Axitinib II 60 30 68 18.1 JCO 2008;26:4708-4713
Sunitinib II 29 28 78 12.8 Clin Cancer Res 2010;
16:5260-5268
Pazopanib II 39 49 NR 11.7 Lancet 2010; 11:962-972
Sorafenib UPENN
II 30 23 76 18.2 JCO 2008;26:4714-4719
Sorafenib OHSU
II 56 12 77 15 JCO 2009;27:1675-1684
Lenvatinib E7080
II 58 50 95 13.3 ASCO 2011, abstract
5503
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DECISION Design
DTC (including
poorly differentiated)
Measurable
Disease
PS 0-2
RECIST
progression in prior
14 months
Adequate TSH
suppression
I131 refractory
Sorafenib 400 mg BID
Primary Objective: • Progression-free
Survival (PFS)
Secondary
Objectives: • Overall Survival
• Response Rate
• Safety and
tolerability
• DCR
• Duration of disease
control
• Sorafenib Exposure
Placebo
R 1:1
Stratified by: Geographic region, age
International n = 417
Crossover
allowed at
progression
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RAI-refractory DTC 2013
DECISION establishes sorafenib as a standard therapy
Multiple Questions Raised
Who to treat?
With what agent?
Can we identify alternative targets? • Will selective BRAF V600E inhibitors be effective?
Sorafenib resistance?
Is this the right strategy?
With what agent? E7080 (lenvatinib) phase II results
Overall (n=58)
CR 0
PR 26 (45%)
SD 27 (46%)
PD 3 (5%)
DCR 53 (91%)
Sherman et al. ASCO 2011, abstr 5503
Overcoming sorafenib resistance Targeting alternative pathways
J Clin Oncol 31, 2013 (suppl; abstr 6024)
Are there better strategies? Restoration of Radioiodine Sensitivity
Ho et al. N Engl J Med 2013;368:623-32.
Take Home Message
Who To Treat?
• Radioiodine Refractory
– Negative RAI Scan
– Progression Despite
Recent RAI
– >600 mCi prior RAI
• Non-surgical candidates
• Established Progression
– Threatened Symptoms
Who Not To Treat?
• No radiographic disease
(TG only)
• RAI Sensitive
• No progression
• Very slow progression
without threatened
symptoms
Refer to Clinical Trials Whenever Possible!
Medullary Thyroid Cancer
Sites of Metastases
• Liver
• Bone
Tumor Markers
• Calcitonin
• CEA
Not of Follicular Origin
• No role for RAI
• No role for TSH suppression
Houvras. JCO 2012;30:200-202.
A Disease of RET Mutations
ZETA Phase III Study design
Vandetanib 300 mg/day
n=231
Follow for progression Follow for progression
Optional open-label vandetanib 300 mg/day
Follow for survival
Patients with unresectable locally advanced or metastatic MTC (N=331)
Placebo
n=100
2:1 randomization
Discontinue blinded treatment at progression
Wells et al. JCO 2012;30:134-141.
PFS (primary endpoint)
0
Hazard ratio = 0.46 (0.31–0.69); P<0.0001
Median: not reached (vandetanib); 19.3 months (placebo)
Vandetanib 300 mg
Placebo
Time (months)
231 198 171 141 42 1 0
100 72 57 45 13 0 0
At risk (n)
Vandetanib
Placebo
0.6
0.8
Pro
gre
ssio
n-f
ree s
urv
ival
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
6 12 18 24 30 36
Wells et al. JCO 2012;30:134-141
Vandetanib (%) Placebo (%)
ORR 45 13
DCR 87 71
Calcitonin
Response
69 3
CEA Response 52 2
Vandetanib 300 mg
(n=231)
Placebo
(n=99)
Diarrhea 25 (11%) 2 (2%)
Hypertension 20 (9%) 1 (1%)
ECG QT prolonged 18 (8%) 1 (1%)
Fatigue 13 (6%) 1 (1%)
Decreased appetite 10 (4%) 0
Rash 8 (3%) 1 (1%)
Asthenia 6 (3%) 1 (1%)
Dyspnea 4 (2%) 3 (3%)
Back pain 1 (0.4%) 3 (3%)
Syncope 0 2 (2%)
Most common grade 3+ adverse events (>2% incidence in either arm)
FDA REMS Program: Frequent EKG monitoring required
Wells et al. JCO 2012;30:134-141
EXAM Phase III Design
MTC
Measurable
Disease
PS 0-2
RECIST
progression in prior
14 months
Cabozantinib 140 mg
daily Primary Objective: • Progression-free
Survival (PFS)
Secondary
Objectives: • Overall Survival
• Response Rate
• Safety and
tolerability Placebo
R 2:1
International n = 330
Elisei et al. JCO 2013;31:3639-3646.
PFS by Independent Review
ORR 28% in cabozantinib arm, 0% in placebo arm, p<0.001
Median Duration of Response 14.6 months
Elisei et al. JCO 2013;31:3639-3646.
Unfair Comparison
Parameter Vandetanib (ZETA) Cabozantinib (EXAM)
ORR 45% 28%
PFS Not reached, 30.5
months estimated
11.2 months
PFS HR 0.46 0.28
Placebo PFS 19.0 months 4.0 months
These trials are not comparable!
Unanswered Question:
Which drug for which patient?
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Concluding Thoughts
Kinase inhibitors have changed the landscape of RAI-refractory DTC and MTC.
• Patient selection is paramount.
• More questions than answers: – Who
– What
– When
– Why
• No one has been cured…
SEE YOU NEXT YEAR!!!!