Transcript Document

Latest Treatment Options
in Carcinoid Cancer:
What we should know
Edward M. Wolin, M.D.
Outpatient Cancer Center at the
Samuel Oschin Comprehensive Cancer Institute
Cedars-Sinai Medical Center
Los Angeles, CA
Charles G. Moertel
An Odyssey in the Land of Small Tumors
KARNOFSKY MEMORIAL LECTURE
ASCO 1987
One would hope that the development of such methods
of tumor-specific therapy will proceed rapidly, since
certainly the necessary technology is now available. Our
current methods have been devised in a crude and
empiric fashion. Nevertheless we are now seeing
response rates that reach to 90%, with median durations
extending to 2 years. We are ever so close and it is
reasonable to predict that the gastrointestinal
neuroendocrine tumors will be the next medically curable
cancers.
Agent(s)
Patients
Biochemical
Response
rate,
percent
Tumor
Author, year
response
Rate,
percent
25
72
0
Kvols, L; 1986
22
63
0
Kvols, L; 1987
23
50
28
Oberg, K; 1991
34
NR
0
Saltz, L; 1993
55
37
2
Janson, E; 1993
103
NR
0
Arnold, R; 1996
58
77
0
DiBartolomeo,
M; 1996
19
58
5
Eriksson, B;
1997
39
42
0
Ruszniewski, P;
1996
18
R
0
Tomassetti, P;
1998
RESPONSE TO
SOMATOSTATIN
ANALOGS:
N
Somatostatin
Analogs
Octreotide
Lanreotide
Lanreotide-SR
Placebo-controlled, double-blind,
prospective, randomized study of the
effect of octreotide LAR in the control of
tumor growth in patients with metastatic
neuroendocrine midgut tumors: A report
from the PROMID study group.
R. Arnold, H. Müller, C. Schade-Brittinger, A. Rinke,
K. Klose, P. Barth, M. Wied, C. Mayer, B.
Aminossadati, PROMID Study Group
2009 Gastrointestinal Cancers
Symposium,Abstr.121
Octreotide LAR: The
PROMID Study
• 85 patients with midgut carcinoids randomized
to Octreotide LAR 30mg/month vs. placebo
• Progression-free survival was primary endpoint
• Median time to progression was 14.3 mo. with
octreotide vs. 6 mo. With placebo (P=0.000037)
• Stable disease at 6 mo. was 64% with
octreotide and 37.2% with placebo
Lanreotide Autogel
Formulation
•Lanreotide and Water are the only ingredients in this
formulation.
•Lanreotide molecules, at high concentrations in
water, spontaneously assemble into stable
aggregates.
•After injection, the aggregates disassemble, and
lanreotide is slowly released into the blood.
•This medication is effective as a subcutaneous
injection every 4 weeks, potentially improving quality of
life when compared to I.M. alternatives.
Phase III, Randomized, Double Blind,
Stratified Comparative, Placebo
Controlled, Parallel Group, Multicenter
Study To Assess The Effect Of Deep
Subcutaneous Injections Of Lanreotide
Autogel 120 Mg Administered Every 28
Days On Tumor Progression Free
Survival In Patients With Non-Functioning
Entero-pancreatic Endocrine Tumors
Study Design
• Randomized placebo-controlled multicenter study.
• 200 patients will be randomized to
receive either Lanreotide Autogel 120
mg or placebo every 28 days via deep
subcutaneous injection.
Inclusion Criteria
• Non-functional neuroendocrine tumor of pancreas,
mid-gut, or hind gut; or a controlled gastrinoma; or
unknown.
• Metastatic tumor and/or inoperable tumor.
• Positive OctreoScan within past 6 months.
• Ki-67 proliferation index below 10%, or a mitotic
index ≤2 mitosis/10HPF (not high grade).
• WHO performance score ≤ 2.
Phase III Study of
Lanreotide Autogel in the
symptomatic treatment of
carcinoid tumors to begin
now.
SOM230 (Pasereotide)
• Improved somatostatin receptor binding.
– High affinity binding to sst1, sst2, sst3, and
sst5 receptors.
– 30-40 fold higher affinity binding to sst1 and
sst5 than octreotide.
• Better and longer suppression of GH and
IGF-1.
Pasireotide LAR In Patients With
Metastatic Carcinoid Tumors: Interim
Safety Results From A Randomized,
Multicenter Phase I Study
Edward Wolin, Larry Kvols, Shereen Ezzat,
Walter Kocha, Eric Van Cutsem, Ulrike
Schönherr and Abderrahim Fandi
2009 Am Soc Clin Oncol Gastrointestinal Cancers Symposium, Abstr. 122
Pasireotide-LAR Study Design
• Phase I multicenter study.
• Initial dose of subcutaneous pasireotide 300 μg
to assess tolerability.
• Then intramuscular depot injection of
pasireotide-LAR 20, 40 or 60 mg every 28 days.
• Safety and tolerability assessments and
pharmacokinetic analyses were followed.
SOM 230-LAR (Pasereotide)
Eligibility
• Metastatic carcinoid tumors of the digestive
system, and elevated chromogranin A and/or 5hydroxyindole acetic acid (5-HIAA) levels.
• Symptoms of metastatic carcinoid that were
refractory or resistant to octreotide.
• Diarrhea or flushing.
Side Effects
• Well tolerated medication.
• 25 of the 42 patients (60%) had at least one
mild toxicity. Most common adverse events:
GI: diarrhea (5%), nausea (5%) and
steatorrhea (5%).
Injection-site reaction (5%)
Asthenia (5%).
Hyperglycemia (12%)
Blood Sugar Elevation
•
Hyperglycemia (12%)
•
Type 2 diabetes mellitus (7%).
•
HbA1c increased from a mean
5% at baseline to 7% at 3 months.
Conclusions
• A promising treatment for carcinoid syndrome.
• Generally well tolerated. Most common side effects
were mild GI problems, injection-site reaction,
fatigue, and hyperglycemia.
• Pasireotide LAR 20, 40 and 60 mg every 28 days
gave steady-state blood levels after 3 injections.
• Results from the Phase III are awaited.
Patients
N
Biochemical
Response Rate
Percent
Tumor
Response
Rate
Author, year
RESPONSE TO INTERFERON-ALPHA
Percent
IFN-alfa
27
39
20
Moertel, C;
1989
12
40
10
Hansen, C; 1989
20
55
0
Oberg, K; 1989
15
7
0
Creutzfeldt, W;
1991
111
42
15
Oberg, K; 1991
26
66
15
Schober, C;
1992
14
50
0
Joensuu, H;
1992
24
60
8
Biesma, B; 1992
12
8
16
Janson, E; 1992
34
24
12
Bajetta, E; 1993
22
58
18
DiBartolomeo,
M; 1993
7
71
0
Doberauer, C;
RESPONSE TO SOMATOSTATIN
Agent(s)
Patients
Biochemical
Tumor
Author, year
ANALOGS
PLUS
INTERFERON-ALPHA
N
Response
Response
Percent
Rate
Percent
19
72
0
Janson, E; 1993
21
69
5
Frank, M; 1999
Lanreotide
27
NR
4
Faiss, S; 2003
INF - alfa
28
NR
3.7
Lanreotide +
IFN-alfa
29
NR
7.1
Uncontrolled
series
Octreotide +
INF- alfa
Randomized
study
Regimen
Number Tumor
Median
Reference
Chemotherapy
for
Metastatic
Carcinoid
of
response overall
patients2 TRIALS
rate,
survival,
PHASE
*
percent months
Dacarbazine
56
16
20
Bukowski, R;
1994
Dacarbazine
(second line)
61
8
11.9
Sun, W;
2005
Etoposide
17
12
NR
Kelsen, D; 1987
Paclitaxel
24
8
18
Ansell, S;
2001
Docetaxel
21
0
24
Kulke, M;
2004
Gemcitabine
18
0
11.5
Kulke, M;
2004
Streptozocin +
fluorouracil +
doxorubicin +
cyclophosphamide
56
30
10.8
Bukowski, R;
1987
Streptozocin +
fluorouracil +
cyclophosphamide
9
22
Temozolomide +
thalidomide
15
7
NR
Kulke, M;
2006
Median overall
Reference
Chemotherapy for Tumor
Metastatic
Carcinoid
response
survival,
Number of rate,
months
RANDOMIZED
TRIALS
patients
percent
Regimen
Streptozocin +
Cyclophosphamide
VS.
Streptozocin +
fluorouracil
47
26
12.5
42
33
11.2
Doxorubicin
VS.
Streptozocin +
Fluorouracil
81
21
11.1
80
22
14.9
Doxorubicin +
Fluorouracil
VS.
Streptozocin +
Fluorouracil
88
16
15.7
88
16
24.3 (p=0.03)
Moertel, C; 1979
Engstrom, P;
1984
Sun, W; 2005
Agent
Molecular
Target(s)
Patients
Tumor
Type
Tumor
response
rate,
percent
Median
TTP or
PFS,
weeks
Reference
PDGFR-, - ;
KIT; Bcr - Abl
27
Carcinoid
4 (1/27)
24 (PFS)
Yao, J;
2007
Bevacizumab
VEGF
18
Carcinoid
17
NR
Yao, J;
2005
Sunitinib
VEGFR-1,-2,
-3; PDGFR –
,-; KIT;
RET; CSF –
1R; FLT3
41
66
Carcinoid
Pancreatic
NET
2
17
42 (TTP)
33 (TTP)
Kulke, M;
2005
Gefitinib
EGFR
40
Carcinoid
3 (1/40)
NR
Hobday, T;
2006
31
Pancreatic
NET
6 (2/31)
NR
VEGFR – 2,
PDGFR,
FGFR–1, FLT –
3, raf
51
42
Carcinoid
Pancreatic
NET
7
11
7.8
months
19.9
months
Hobday, T;
2007
mTOR
30
30
Carcinoid
Pancreatic
NET
13
26
64
50
Yao, J;
2007
mTOR
21
Carcinoid
5
15
Pancreatic
NET
7
Imatinib
Sorafenib
Everolimus +
Octreotide
Temsirolimus
Targeted therapies in
neuroendocrine tumors
Duran, I;
2006
Perspectives on Chemotherapy
for Carcinoid/NET
• Response rates are low.
• Despite low response rates, time to progression
is prolonged, potentially extending survival, and
quality of life.
• Progression-free survival may be at least as
important as response rate in evaluating
chemotherapy in these slow-growing tumors.
• Carcinoid/NET which are more metabolically
active (intermediate grade, moderatelydifferentiated, atypical carcinoid, high Ki-67) are
much more responsive to chemotherapy.
Phase 1 Atiprimod Trial
• 16 patients treated for advanced malignancies.
• 6 of these patients had NET’s.
• 5 of the 6 patients had a clinical benefit.
– 3 of 6 had tumor regression.
– 3 of 6 had improvement in carcinoid syndrome.
– 1 of 6 had no measurable response.
Phase II proof-of-concept study of
atiprimod in patients with advanced
low- to intermediate-grade
neuroendocrine carcinoma.
M. W. Sung, L. Kvols, E. Wolin, G. Jacob,
C. Talluto,J. C. Torres, A. Parta, E.
Rodriguez, R. Shepard
J Clin Oncol 26: 2008 (May 20 suppl; abstr 4611)
Phase-2 Trial Objective
Evaluate the safety and efficacy of
atiprimod in NET, who had either:
1) progressive disease or,
2) carcinoid symptoms not controlled
with octreotide treatment
RESPONSE TO ATIPRIMOD
BEST OVERALL RESPONSE
CR
PR
SD
PD
PROGRESSION-FREE at 6
cycles
(approx 6 mo)
PROGRESSION-FREE at 12
cycles
(approx 12 mo)
0
0
23/25 (92%)
Median duration 6
cycles
Range 2 to 12 and ongoing
2/25 (8%)
76.4% (Kaplan-Meier;
N=13 at risk)
50% (Kaplan-Meier;
N=2 at risk)
Some patients had dramatic symptomimprovement from Atiprimod
7
Average # Daily Flushing Episodes
Average Daily # Flushing
Episodes
2.5
Average Daily Flushing Episodes, Patient 008
2
1.5
1
0.5
0
Average Daily Flushing Episodes, Patient 033
6
5
4
3
2
1
0
1
2
3
4
5
6
7
Treatment Cycle # (#1=Screening)
8
9
1
2
3
4
5
Treatment Cycle # (#1=Screening)
6
7
Atiprimod Side Effects
6 patients had side effects.
- all involved AST/ ALT elevations with or
without nausea or vomiting.
- 3 also had mild bilirubin elevation.
-Liver function normalized, and 2 patients
safely resumed atiprimod.
-There were 2 deaths from infection
(unrelated to atiprimod.)
Efficacy of RAD001 (Everolimus)
and Octreotide LAR in Advanced
Low- to Intermediate-Grade
Neuroendocrine Tumors: Results of
a Phase II Study
Yao, J. et. al., Journal of Clinical Oncology,
Vol 26, No 26 (September 10), 2008: pp. 4311-4318
Methods
• Treatment consisted of RAD001 5 mg/d
(30 patients) or 10 mg/d (30 patients) and
octreotide LAR 30 mg every 28 days.
• Thirty carcinoid and 30 islet cell patients
were enrolled.
Results
• Partial responses 22%, stable disease 70%,
progressive disease 8%.
• Progression-free survival (PFS) was 60 weeks.
• Median PFS for patients with known SD at entry
was longer than for those who had progressive
disease (74 v 50 weeks; P < .01).
• Median overall survival has not been reached.
• One-, 2-, and 3-year survival rates were 83%,
81%, and 78%, respectively
Radiant-2 (RAD00g1C2325)
Study Design
Arm 1
• RAD 001 10 mg daily + octreotideLAR 30 mg I.M. every 4 weeks.
Arm 2
• Placebo daily + octreotide-LAR 30
mg I.M. every 4 weeks.
Combination of mTOR inhibitors (mTORi) with
other Cancer Treatments is synergistic
• mTORi + Chemotherapy
(platinum derivatives,
taxanes, anthracyclines, or gemcitabine)
Decreases tumor size in preclinical models.
• mTORi + Growth Factor Signaling inhibitors
Defects in mTOR signaling counteracts the effect of EGFR
inhibitors on cell growth and proliferation. Combined treatment
beneficial in preclinical studies.
• mTORi + Antiangiogenics
mTORi enhances anti-VEGF/VEGFR signaling
inhibitors to increase efficacy.
Radioembolization for Unresectable Neuroendocrine
Hepatic Metastases Using Resin 90Y-Microspheres:
Early Results in 148 Patients
Kennedy, AS et al. Am J Clin Oncol 2008;31: 271–279
• Radioembolization with 90Y microsphere
was used for neuroendocrine hepatic
metastases.
• 148 patients were treated with 185
separate procedures.
Radioembolization for NET Liver Metastases
Using Resin 90Y-Microspheres - Results
• 60.5% PR; 22.7% SD; 2.7% CR;4.9% PD
• 70 months median survival
• Results comparable to those achieved with
hepatic artery chemoembolization (HACE).
• These results were seen even with extensive
tumor replacement of normal liver and/or heavy
pretreatment.
• An outpatient procedure with little acute or
delayed toxicity in most patients.
Treatment With the Radiolabeled Somatostatin
Analog [177Lu-DOTA0,Tyr3]Octreotate: Toxicity,
Efficacy, and Survival
Kwekkeboom et al, J Clin Oncol. 2008 May 1;26(13):2124-30.
•Treatment was usually in four treatment cycles, with
intervals of 6 to 10 weeks between cycles.
•Toxicity analysis was done in 504 patients, and efficacy
analysis in 310 patients.
•Complete response seen in 2%, partial response in 28%,
and minimal response in 16%.
•Median time to progression was 40 months.
•If kidney protective agents are used, major side effects of
this therapy are few.