Transcript Randomized Phase III Trial of Regorafenib in Patients (pts)

Management Advances for Differentiated and
Medullary Thyroid Carcinoma
Marcia S. Brose MD PhD
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, PA
On behalf of: Christopher Nutting, Barbara Jarzab, Rossella Elisei,
Salvatore Siena, Lars Bastholt, Christelle de la Fouchardiere,
Furio Pacini, Ralf Paschke, Young Kee Shong, Steven I. Sherman,
Johannes WA Smit, John Woojune Chung, Harald Siedentop,
Istvan Molnar and Martin Schlumberger
Disclosures
• Companies: AstraZeneca, Bayer/Onyx, Eisai,
Exelixis, Novartis, Oxigene, Plexxikon, Roche
• Relationships: Advisory board consultant,
honoraria, research grants, and primary
investigator
• As there are currently no FDA approved agents
for progressive DTC, all agents I will discuss will
be off label use or in the context of a clinical trial
2
Thyroid cancer: clinical pathology
Papillary (87%)
Follicular cells
Differentiated
Follicular (6%)
Anaplastic (1%)
Parafollicular cells
Hürthle cell (3%)
Medullary (2%)
Treatment of Differentiated Thyroid Cancer includes:
• Surgery – thyroidectomy
• Radioactive iodine
• Thyroid stimulating hormone (TSH) suppression
• Recurrent progressive RAI refractory disease treated
with sorafenib
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.
Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.
Radioactive Iodine (RAI)-Refractory
Differentiated Thyroid Cancer (DTC)
• It is estimated1 that in the USA in 2013 there will be:
– >60 000 new cases of thyroid cancer, and
– 1850 deaths due to thyroid cancer
• In approximately 5–15% of patients with thyroid cancer, the
disease becomes refractory to RAI2,3
• Median survival for patients with RAI-refractory DTC and
distant metastases is estimated to be 2.5–3.5 years4,5
• Patients often suffer multiple complications associated with
disease progression
1. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html;
2. Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54;
4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892–99. 5. Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505.
FDG-PET Predicts Survival in Patients
With Metastatic Thyroid Cancer
Survival Distribution Function
1.00
FDG-negative
176/179 alive
0.75
FDG-positive
156/223 alive
0.50
0.25
Median survival = 53 months
0
0
10
20
30
Robbins et al. J Clin Endocrinol Metab. 2006;91:498-505.
40
50
Months
60
70
80
90
Genetics of Differentiated Thyroid Cancer:
aberrant intracellular signaling
Poorly differentiated

•
•

RAS (25–30%)
TP53 (20–30%)
CTNNB1 (10–20%)
BRAF (10–15%)
Anaplastic
Medullary
Oncocytic
Conventional
Follicular
Mutations in 70–75%
• RAS (40–50%;
lower in oncocytic)
• PAX8/PPARg (30–35%;
lower in oncocytic)
• TP53 (21%)
• PTEN (8%)
• PIK3CA (7%)
 BRAF (2%)
aBRAF
Papillary
Mutations identified in ~70%
 BRAFa (40–50%)
 RASb (7–20%)
• RET/PTC (clonal; 10–20%)
• EGFR (5%)
• TRK (<5%)
• PIK3CA (2%)
Papillary
DTC
mutations are mostly V600E; 1–2% are K601E and others
includes N-, H-, and K-RAS (predominantly NRAS and HRAS codon 61)
Nikiforov YE et al. Arch Pathol Lab Med 2011;135:569–77; COSMIC database – Catalog of Somatic Mutations in Cancer
bRAS
Targeting Cell Signaling in Thyroid Cancer
Tumor Cell
RET/PTC
Motesanib
Sorafenib
Sunitinib
Vandetanib
Cabozantinib
Lenvatinib
Endothelial
Cell
EGFR
VEGFR-2
Vandetanib
Ras
B-Raf
Sorafenib
MEK
ERK
Ras
PI3K
Raf
AKT
mTOR
S6K
Sorafenib
Everolimus
Sirolimus
• Growth
• HIF1a
• Survival
• Inhibition of
• Proliferation
apoptosis
• Migration
MEK
ERK
PI3K
Axitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
Lenvatinib
Cabozantinib
AKT
mTOR
S6K
• Growth
• Migration
• Survival
•Angiogenesis
• Proliferation
EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor.
Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-783.
Everolimus
Sirolimus
Targets of Kinase Inhibitors
Compound Name
VEGFR
BRAF
PDGFR
KIT
RET
Other
Sorafenib
+
+
+
+
+
FLT-3
Sunitinib
+
+
+
Axitinib
+
+
+
Motesanib
+
+
+
Pazopanib
+
+
+
Vandetanib
+
+
EGFR
Cabozantinib
+
+
C-MET
Lenvatinib
+
+
FGFR
Vemurafenib
+
+
FLT-3
+
BRAF
V600E
DTC, differentiated thyroid cancer; EGFR, endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR,
platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
1. Perez CA , et al. Biologics. 2012;6:257-265. 2. Pacini F. Expert Rev Endocrinol Metab. 2012;7:541-554.
Targeted Agents: Phase 2 Clinical Data
n
PFS
(months)
PR
SD
PD
Drug
Key Baseline Characteristics
Sorafenib
(Brose)
DTC + PDTC (90%)
47
20
38%
47%
2%
Sunitinib
(Cohen)
DTC (74%); MTC (26%)
51
—
17%
DTC
74%
DTC
9%
DTC
Axitinib
(Cohen)
Papillary (50%); medullary
(18%); follicular/Hürthle
(25%/18%); anaplastic (3%)
60
18.1
30%
48%
7%
Motesanib
(Sherman)
Papillary (61%);
follicular/Hürthle (34%)
93
10
14%
67%
8%
Pazopanib
(Bible)
PD and DTC (progression < 6
months)
37
12
49%
—
—
Lenvatinib
(Sherman)
DTC (100%)
58
13.3
45%
46%
5%
DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; PD, progressive disease; PDTC, poorlydifferentiated thyroid cancer; PFS, progression-free survival; PR, partial response; SD, stable disease.
DECISION study design1
417 patients
randomized from Oct 2009
to July 2011
• Locally advanced or
metastatic,
RAI-refractory DTC
• Progression (RECIST)
within the previous
14 months
• No prior chemotherapy,
targeted therapy, or
thalidomide
•
•
400 mg orally twice daily
Randomization 1:1
Placebo
orally twice daily
Stratified by:
–
–
•
Sorafenib
geographical region (North America or Europe or Asia)
age (<60 or ≥60 years)
Progression assessed by independent central review
every 8 weeks
At progression:
–
–
Primary endpoint
• Progression-free survival
Secondary endpoints
Overall survival
Response rate
Safety
Time to progression
Disease control rate
Duration of response
Sorafenib exposure (AUC0–12)
patients on placebo allowed to cross over at the investigator’s discretion
patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
Key inclusion and exclusion criteria (1)
Inclusion
• Locally advanced or metastatic DTC (papillary, follicular
including Hürthle cell or poorly differentiated)
• RAI-refractory DTC
– At least one target lesion without iodine uptake, or
– Progression following treatment dose of RAI, or
– Cumulative RAI treatment ≥600 mCi
• Progressive disease within the last 14 months (RECIST)
• Adequate TSH suppression (<0.5 mU/l)
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
Key inclusion and exclusion criteria (2)
Inclusion (cont.)
• Not a candidate for surgery or radiotherapy with curative
intent
• Adequate bone marrow, liver and renal function
• Eastern Cooperative Oncology Group (ECOG)
performance status (PS) 0–2
Exclusion
• Prior anti-cancer treatment with targeted therapy or
chemotherapy
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
Baseline disease characteristics
Sorafenib
(n=207)
Placebo
(n=210)
Histology, investigator assessed, %
Papillary
Follicular
Hürthle cell
Missing
66.2
21.3
11.6
1.0
67.1
26.2
6.7
0
Metastases
Locally advanced
Distant
3.4
96.6
3.8
96.2
Most common target/non-target lesion
sites, %
Lung
Lymph nodes (any)
Bone
Pleura
Head and neck
Liver
86.0
54.6
27.5
19.3
15.9
13.5
86.2
48.1
26.7
11.4
16.2
14.3
Prior thyroidectomy, %
100
99.0
Locoregional therapy or EBRT, %
40.1
43.3
400 mCi
376 mCi
Median cumulative RAI activity
EBRT, external beam radiation therapy
1. Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
Progression-free survival
(by independent central review)
n
Median PFS,
days (months)
Sorafenib
207
329 (10.8)
Placebo
210
175 (5.8)
100
PFS probability (%)
90
80
70
HR: 0.587; 95% CI: 0.454–0.758;
p<0.0001
60
50
40
30
20
10
0
0
100
200
300
400
500
600
700
800
Days from randomization
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival
Overall survival
100
Survival probability (%)
90
80
70
60
Median OS
50
Sorafenib
Not reached
Placebo
Not reached
40
30
HR: 0.802; 95% CI: 0.539–1.194
p=0.138, one-sided
20
10
0
0
100
200
300
400
500
600
700
800
900
1000
Days from randomization
At progression:
• 150 patients on placebo (71%) received open-label sorafenib
• 55 patients on sorafenib (27%) received open-label sorafenib
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival
Other secondary efficacy endpoints
Sorafenib
n (%)
Placebo
n (%)
196
201
24 (12.2)
1 (0.5)
<0.0001
0
0
–
24 (12.2)
1 (0.5)
–
Stable disease for ≥6 months
82 (41.8)
67 (33.2)
–
Disease control rate (CR + PR +
SD ≥6 months)
106 (54.1)
68 (33.8)
<0.0001
10.2 (7.4–16.6)
NA
–
Total evaluable patients
Response rate
Complete response
Partial response
Median duration of response (PRs)
months (range)
CR, complete response; PR, partial response;
SD, stable disease; NA, not assessed
p value
Maximum reduction in target lesion size
(by independent central review)
Maximum reduction in target lesion size (%)
60
50
40
30
20
73% of patients
27% of patients
10
0
–10
–20
–30
–40
–50
–60
–70
Sorafenib
Placebo
Maximum reduction is defined as the difference in the sum of the longest diameter of target lesions from baseline. Negative values refer to
maximal reduction and positive values to the minimal increase.
Treatment and dose modifications
(double-blind period)
Sorafenib
(n=207)
Placebo
(n=209)
651 mg
793 mg
46.1 weeks
(0.3−135.3)
28.3 weeks
(1.7−132.1)
Dose modification due to AEs, %
Dose reduction
Dose interruption
77.8
64.3
66.2
30.1
9.1
25.8
Permanent discontinuation due to
AEs, %
18.8
3.8
Mean dose
Median (range) treatment duration
AE, adverse event
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
Most common treatment-emergent AEs
(double-blind period)
AE*, %
Sorafenib (n=207)
Any grade
Grade 3/4
Placebo (n=209)
Any grade
Grade 3/4
Hand–foot skin reaction
76.3
20.3
9.6
0
Diarrhea
68.6
5.8
15.3
1.0
Alopecia
67.1
0
7.7
0
Rash/desquamation
50.2
4.8
11.5
0
Fatigue
49.8
5.8
25.4
1.4
Weight loss
46.9
5.8
13.9
1.0
Hypertension
40.6
9.7
12.4
2.4
Metabolic – lab (other)
35.7
0
16.7
0
Anorexia
31.9
2.4
4.8
0
Oral mucositis
Pruritus
Nausea
Hypocalcemia
23.2
21.3
20.8
18.8
1.0
1.0
0
9.2
3.3
10.5
11.5
4.8
0
0
0
1.4
*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0
Brose M et al. Oral presentation at the American Society of Clinical Oncology Annual Congress 2013; abstract 4
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival
Serious adverse events and deaths
(double-blind period)
Sorafenib
n=207
Placebo
n=209
77 (37.2)
55 (26.3)
Most frequent serious AEs*, n (%)
Secondary malignancy
• Squamous cell carcinoma of the skin
Dyspnea
Pleural effusion
9 (4.3)
7 (3.4)
7 (3.4)
6 (2.9)
4 (1.9)
0
6 (2.9)
4 (1.9)
Grade 5 events (deaths), n (%)
Drug-related**
14 (6.8)
1 (0.5)
6 (2.9)
1 (0.5)
Serious AEs, n (%)
* Occurring in ≥2.0% of sorafenib-treated patients
** Myocardial infarction (sorafenib); subdural hematoma (placebo)
Sorafenib benefit by BRAF status (PFS)
– Papillary histology only
BRAF wild-type
PFS probability (%)
100
80
Median PFS,
days (months)
Sorafenib (n=42)
278 (9.1)
Placebo (n=42)
170 (5.6)
HR: 0.58, 95% CI: 0.34–1.00, p=0.049
BRAF mutation
100
80
60
60
40
40
20
20
Median PFS,
days (months)
Sorafenib (n=32)
623 (20.5)
Placebo (n=40)
286 (9.4)
HR: 0.40, 95% CI: 0.20–0.80, p=0.008
0
0
0
200
400
600
800
Days from randomization
0
200
400
600
800
Days from randomization
BRAF mutation did not predict PFS benefit from sorafenib
(biomarker-treatment interaction p=0.393)
Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013
Sorafenib benefit by RAS status (PFS)
RAS wild-type
PFS probability (%)
100
80
Median PFS,
days (months)
Sorafenib (n=102)
329 (10.8)
Placebo (n=104)
175 (5.7)
HR: 0.60, 95% CI: 0.42–0.85, p=0.004
RAS mutation
100
80
60
60
40
40
20
20
0
0
0
200
400
600
800
Days from randomization
Median PFS,
days (months)
Sorafenib (n=24)
167 (5.5)
Placebo (n=26)
105 (3.4)
HR: 0.49, 95% CI: 0.24–1.00, p=0.045
0
200
400
600
800
Days from randomization
RAS mutation was not an independent prognostic factor for PFS
Univariate (placebo arm only): mutant vs wild type RAS, HR=1.80; p=0.022
Multivariate (placebo arm only): mutant vs wild type RAS, HR=1.56; p=0.154
RAS mutation did not predict PFS benefit from sorafenib (biomarker-treatment interaction p=0.422)
Brose M et al. Oral presentation at the European Society of Medical Oncology (ECCO-ESMO) Annual Congress 2013
UPCC 18310: Vemurafenib in patients with
Progressive PTC with BRAF V600E
Key Eligibility Criteria
• Recurrent, unresectable or
metastatic PTC
• BRAFV600 mutation positive by
cobas
• RAI refractory
• Evidence of progression
within 14 months
Cohort 1:
VEGFR2i-naive
(n = 26)
Cohort 2:
VEGFR2i-pretreated
(n = 25)
Vemurafenib
960 mg bid
until disease
progression
or
unacceptable
toxicity
• Prior chemotherapy allowed
Primary end point: response rate per investigator in VEGFR2i-naive patients.
Secondary end points: safety, duration of response, PFS, OS, PK, response rate
in VEGFR2 inhibitor–pretreated patients
bid, 2 times a day; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; VEGFR, vascular
endothelial growth factor receptor; VEGFR2i, vascular endothelial growth factor receptor 2 inhibitor.
Brose et al. ECCO-ESMO 2013
Cohort 1: VEGFR2i-Naive
Best Objective Response
Max change in sum of diameters
RECIST (%)
25.0
Cohort 1, N = 26
No confirmed objective response
Confirmed objective response
0.0
–25.0
–30.0
–50.0
–75.0
Objective response n (%) [95% CI]
CR, n (%)
PR, n (%)
SD ≥6 mo
Clinical benefit (CR, PR, or SD ≥6 mo), n (%) [95% CI]
0 (0)
9 (35%)
6 (23%)
15 (58%) [0.37-0.77]
–100.0
Each bar represents one cohort 1 patient
AE, adverse event; CR, complete response; PR, partial response; SD, stable disease.
24
aPatients with at least 2 postbaseline tumor scans or progressive disease/withdrawal because of death or AE within first 2 cycles.
Cohort 1: VEGFR2i-Naive
Survival Kaplan-Meier Curves
Censored
OS
PFS
1.0
Censore
d
Survival Probability
Survival Probability
1.
0
0.8
0.
6
0.
4
Median PFS 15.6 mo
(95% CI: 11.2–NR)a
0.
2
0.8
0.6
0.4
Median OS: Not reachedb
0.2
0.0
0.
0
0
5
10
15
20
0
patients continue therapy.
10
15
Months
Months
a13
5
bMedian
follow-up time: 11.4 mo.
Brose et al. ECCO-ESMO 2013
25
20
Summary: RAI-Refractory DTC
• DTC is a vascular tumor that has been associated with increased
activity of the MAPK pathways, and iodine-refractory patients
have an average survival of 3 years
• Results of phase 3 trials with sorafenib (DECISION) were positive,
This agent was the FDA approved November 2013, and is first
agent to be approved since doxorubicin in 1974.
• Two additional phase 3 trials of lenvatinib (SELECT) and
vandetanib (VERIFY) are ongoing
• Additional MKIs have also shown activity in the Phase II setting,
many of which target VEGFR-2, but also mTOR, MEK, MET and
BRAF and BRAF V600E and will be needed in the second- and
third-line setting
DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; mTOR, mammalian target of rapamycin; RAI, radioactive iodine;
VEGFR, vascular endothelial growth factor.
Thyroid cancer: clinical pathology
Papillary (87%)
Follicular cells
Differentiated
Follicular (6%)
Anaplastic (1%)
Parafollicular cells
Hürthle cell (3%)
Medullary (2%)
Treatment of Medullary Thyroid Cancer includes:
• Surgery – thyroidectomy
• Thyroid stimulating hormone (TSH) replacement
• Recurrent non surgical and metastatic disease treated
with Cabozantinib and Vandetanib
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.
Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html.
Medullary Thyroid Cancer
• From calcitonin-producing parafollicular
C cells
• Accounts for 2%-5% of thyroid cancers
– ~1400 cases per year in US
– Disproportionate number of thyroid cancer
deaths
– 350,000 Americans living with thyroid cancer
• Heritable in 25% of cases
• Mutations in the RET gene cause familial MTC–
multiple endocrine neoplasia 2 (MEN2)
• 30%-40% of sporadic MTC bear somatic RET
mutations
Plasma Markers in MTC
• Calcitonin
– Synthesized and excreted by C cells of the thyroid and
by some medullary thyroid tumors
– Diarrhea and flushing at high levels
– Calcitonin levels can be affected by RET inhibition
• Carcinoembryonic antigen (CEA)
– Synthesized and excreted by some medullary
thyroid tumors
– Synthesized by other types of tumors as well
Patients With Distant Metastasis at Diagnosis
Have a Poor Prognosis
• 10-year overall survival: 40%
• Median overall survival: 3.2 years
Roman et al. 2005.
MTC: Initial Treatment
• Complete surgical resection is the only curative treatment for MTC
• Metastasis (lymph node or systemic) is present at diagnosis in 40%-50%
of sporadic cases of MTC
• Surgery :
– Total thyroidectomy
– Extent of surgery depends on stage of disease
• Curable vs noncurable
• Central neck dissection +/- Ipsilateral neck dissection or
Contralateral neck dissection
– Goal
• Early disease: removal of all neoplastic disease
• Advanced disease: airway protection
MTC: Treatment
• Radiation therapy
– Adjunctive and palliative treatment for extensive neck or
mediastinal disease
– Palliative treatment for bony metastasis
– May be effective in controlling complications associated
with MTC activity in the neck and mediastinum
– No evidence that radiation therapy improves survival
– Radioactive Iodine is ineffective in the treatment of
MTC!!!
MTC: Treatment
• Follow-up postsurgery
– High level of calcitonin 2-3 months postsurgery indicates
persistent disease
– Most important prognostically is total calcitonin and the
doubling time (DT)
– Reoperation may allow removal of at least some
neoplastic tissue, but less likely to prevent recurrence
• Calcitonin levels normalize in 5%-35% of cases after
re-operation
– Radiation to the neck and mediastinum in cases of
persistent elevated calcitonin levels can decrease
the risk of recurrence (unlikely to affect survival)
Risk Stratification Using Serum Calcitonin DT
• Calcitonin DT highly predictive of mortality
• Independent predictor in multivariate analysis, controlled for
TNM stage
• Rapid DT could identify stage II and III patients at higher risk
for death
Barbet. JCEM. 2005.
MTC: Sites of Recurrent or Persistent Disease Optimal Imaging
Strategies
•
•
•
•
Cervical nodes and thyroid bed
Lungs and mediastinum
Liver and abdominal lymph nodes
Bone
CT, computed tomography; MRI, magnetic resonance imaging.
Giraudet. JCEM. 2007.
Neck ultrasound
Chest CT
Liver protocol MRI
MRI spine and pelvis
MTC: Treatment of Metastatic Disease
•
•
No standard of care
Rate or progression is variable
– Some patients survive for years with metastatic disease
•
Traditional chemotherapy
– Prior to 4/6/2011, doxorubicin was the only FDA-approved agent; relative risk
(RR) <40%; poorly tolerated, short duration response
– Dacarbazine-based regimens RR< 40% and generally short-lived
– NCCN practice guidelines (2008)
• Disseminated symptomatic disease
–
–
–
–
–
–
Clinical trial (preferred)
Radiation therapy for focal symptoms
Sorafenib
Dacarbazine-based chemotherapy
Consider bisphosphonate therapy for bone metastases
Best supportive care
Rationale for RET as a Therapeutic Target
• Activated by mutations in ~50% of cases (>60% of
progressive cases presenting for clinical trials)
• Somatic mutation of RET associated with poor prognosis
• Limited expression outside the thyroid, potentially high
therapeutic index
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.
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.
38
FDA Approves vandetanib in MTC
4/6/2011
• Approved for progressive or symptomatic
disease only
• MDs required to undergo Risk Evaluation and Mitigation
Strategy (REMS) training for QTc prolongation detection
– REMS program lays out a plan for EKG monitoring
throughout therapy for all patients treated with
vandetanib
– Training itself takes approximately 2 hours
• Starting dose 300 mg/d
Cabozantinib Phase III in MTC
Progression Free Survival by IRC
1.0
0.9
0.8
Probability
0.7
0.6
0.5
0.4
0.3
P<
0.0001
p<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
Placebo
121
78
55in tumor
31 response
12
•219 Significant
difference
rate 2
111
35
11
6
3
2
0
– 27% in cabozantinib vs 0% placebo; P<0.0001
• Median duration of response: 14.7 months
COMETRIQTM (cabozantinib) Capsules [package insert]. Exelixis, Inc: San Francisco, CA.
1
0
FDA Approves cabozantinib in MTC
11/29/2011
• Approved for progressive or symptomatic
disease only
• Warnings about gastrointestinal perforations and fistula
formations
• Starting dose 140 mg/d
Key Points: MTC for Oncologists
• MTC has a distinct clinical presentation, genetics, and
molecular targets compared with differentiated thyroid
cancer
• Importance of distinguishing progressive vs
indolent disease (imaging and CEA DT)
• Success of treatment will be strongly dependent on attention
to kinase-related symptom management
• REMS is required for vandetanib; oncologists are required
to follow EKGs closely
• Cabozantinib has black box warning about risk of fistula
formation in regions of prior invasive disease and radiation
• Either can be used in first or second line setting
University of Pennsylvania
Thyroid Cancer Therapeutics Program
•
Brose Translational Research Lab
–
–
–
–
•
Susan Mandel, MD
Ara Chalian, MD
Douglas Fraker, MD
Robert Lustig, MD
Virginia LiVolsi, MD
Zubair Baloch, MD
Steve Keefe, MD
Daniel Pryma MD
•
Marcia Simpson Brose is a Damon
Runyon-Siemens Clinical Investigator
•
Many community endocrinologists who
have referred their patients, and the
patients who have agreed to participate
in our trials
Experimental Therapeutics Program
–
–
•
Yvette Cruz, RN
Carolyn Grande, RN, CRNP
Thelma McCloskey
Parna Prajapati
Ramkrishna Makani
Jillian Stanley
Thyroid Cancer Interest Group
–
–
–
–
–
–
–
–
Raya Terry, MD
Tatyana Kuznetsova, PhD
Waixing Tang, MD
Zakkiyya Posey
Thyroid Cancer Clinical Trials Unit
–
–
–
–
–
–
•
•
Andrea Troxel, PhD
Peter O’Dwyer, MD
Pathology/Imaging
–
–
Michael Feldman, MD, PhD
Laurie Loevner, MD