Post on 03-Apr-2018
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Winship Cancer Institute of Emory University
New Treatments for Neuroendocrine Cancers
George Fisher, MD, PhD
Professor of Medicine
Stanford University School of Medicine
Disclosures
• Contracted research support from:
• Genentech, Bristol‐Myers Squibb, Ipsen, Eli Lilly, Polaris, X‐Biotech, and New Link
• Fees for non‐CME services:
Pharmaceutical Research Associates
• Stock ownership: Seattle Genetics (spouse)
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Topics
NET 101: the basics
Biological “targets”–Somatostatin receptors
–mTOR
–Angiogenesis
Chemotherapy
Liver directed options
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Topics
NET 101: the basics
Biological “targets”–Somatostatin receptors
–mTOR
–Angiogenesis
Chemotherapy
Liver directed options
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“Rare-omas”
Incidence is low # diagnosed per year per 100,000 people
Site Incidence(per 100,000)
Lung 1.35
Thymus 0.02
Stomach 0.30
Small intestine 0.86
Colon 0.36
Appendix 0.15
Rectum 0.86
Pancreas 0.32
Liver 0.04
Other / unknown 0.74
Total 5.00
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Increasing Incidence
Yao et al JCO ‘08
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Increasing Incidence
Yao et al JCO ‘08
OctreotideApproved
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Not really that rare…
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Imaging Issues with NETs
Non-contrast scan
Arterial phase scan
Venous phase scan
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NET Path: Grading System
NET (ENETS, WHO) Grade Designation
<2 mitoses/10hpf AND <3% Ki67 index
Low grade
Well-differentiated2-20 mitoses/10hpf OR 3-20% Ki67 index
Intermediate grade
>20 mitoses/10hpf OR >20% Ki67 index
High grade Poorly-differentiated
Adapted from: Klimstra DS, et al: Pancreas 39:707–712, 2010.
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NET Biology
5 somatostatin receptors (SSTR 1-5)
80% NETs over-express SSTR2, followed by SSTR1 and SSTR5
Octreotide has high affinity for SSTR2
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Radiolabelled somatostatin: imaging
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Radiolabelled somatostatin: imaging
Octreoscan image
Krenning EP et al. Somatostatin receptor scintigraphy with [IIIIn-DTPA-D-Phe1]- an [123]-Ty3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716-731.
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Radiolabelled somatostatin: imaging
68Ga-DOTATATE PET111In-octreotideOctreoscan
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Targeting the Somatostatin Receptors
Function SST1 SST2 SST3 SST4 SST5
Antisecretory Anti-angiogenic Antiproliferative/Inhibition of cell cycle
Induction of apoptosis
Adapted from Susini C, Buscail L and Weckbecker G, Lewis I, Albert R, et al.1References: 1. Weckbecker G, Lewis I, Albert R, et al. Nature Rev Drug Discov. 2003, 2:999-1017. 2. Öberg K, Kvols L,
Caplin M, et al. Ann Oncol. 2004; 15:966-973. 3. Susini C, Buscail L. Ann Oncol. 2006; 17:1733-1742.
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Somatotatin Analogs: OctreotidePROMID STUDY IN MIDGUT CARCINOID
Primary EndpointTime to Progression
Secondary EndpointsOverall Survival
Response Rates
Arnold, GI ASCO 2009, abstract #121.
85 patients with well-differentiatedmetastatic midgut
NETs
RANDOMIZE
Octreotide LAR 30 mg IM q4wks
N=42
Placebo IM q4wksN=43
p=0.000072, HR 0.34 (95% CI 0.20-0.59)
Time to Progression Overall Survival
Octreotide
Placebo
Median OS not yet reached
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Somatostatin Analogs: LanreotideCLARINET STUDY IN GEP-NETS (MIDGUT + PANCREATIC NETS)
P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model. HR, hazard ratio; ITT, intention-to-treat.
Lanreotide Autogel 120 mg32 events / 101 patients
median, not reached
Placebo60 events / 103 patients
median, 18.0 months [95% CI: 12.1, 24.0]
Lanreotide Autogel vs. placebop=0.0002 HR=0.47 [95% CI: 0.30, 0.73]
0 3 6 9 12 18 24 270
10
20
30
40
50
60
70
80
90
100
Pat
ient
s al
ive
and
with
no
prog
ress
ion
(%)
Time (months)
62%
22%
Primary endpoint: Progression Free Survival (n=204)
Caplin et al, ESMO Annual Meeting Amsterdam 2013
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Peptide Receptor Radionuclide Therapy
Retrospective Analysis Key Inclusion: Octreoscan positive, Karnofsky performance status >50% 504 patients (1772 total treatments) 310 patients available for analysis
Results Median Overall Survival = 46 months; Median Progression-free Survival = 33 months Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss);
rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome)
Kwekkeboom, JCO, 2008: 2124.
Tumor type Response Minor Response Stable Progressiven (%) n (%) n (%) n (%)
Carcinoid 42(23) 31 (17) 78 (42%) 37 (20%)Pancreas NET 30 (42%) 13 (18%) 19 (26%) 10 (14%)Other 19 (38%) 7 (14%) 10 (20%) 14 (28%)Total 86 (28) 51 (16) 107 (35) 61 (20)
Responses 3 Months After Last Administration of 177Lu-Octreotate (n=310)
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Current Trial: PRRT with 177Lu-DOTAPhase III: NETTER-1 Trial
Advanced, progressive, somatostatin
receptor positive, midgut carcinoid
tumours
R
Octreotide LAR 60 mg
177Lu-DOTA0-Tyr3-Octreotate
+ Octreotide LAR
1°endpoint PFS
Sponsor: Advanced Accelerator Applications, France
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Future Attempts at Targeting SSTR:
177Lu-DOTA-JR11: SSTR2 antagonist–Wolfgang Weber @ Memorial Sloan Kettering
Nanoparticle delivery targeting SSTR2–Herb Chen @ University of Wisconsin
Adeno-associated viral construct targeting SSTR2–Renata Pasquilini @ MD Anderson
Immunologic targeting of SSTR2 with CAR-T cells–David Metz et al @ University of Pennsylvania
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Targeting the mTOR pathway
Cancer Cell Endothelial Cell
Reduced Cell Growth and
Proliferation
Protein Production
Reduced Gene
Transcription
Reduced VEGFProduction
Reduced
Cell Growth
Reduced
Proliferation
NutrientsAmino Acids
Integrins
ILK
VEGF
VEGFR
Growth Factors
RAD001
elF-4E
4E-BP1
PTEN
FKBP-12
TSC1/TSC2
mTOR
PI3-K
Akt/PKB
S6K1
RAD001
FKBP-12
RAD001mTOR
PI3-K
Akt/PKB
Energy
LKB1
AMPK
S6P
Bjornsti M-A, Houghton PJ. Nat Rev 2004;4:335
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Targeting mTOR in PNETs: Ph III Everolimus (RADIANT 3)
Yao. NEJM.2011.
Advanced pancreatic NETsn=410
R
Everolimus10 mg qd
N=207
PlaceboN=203
Median PFSEverolimus11.0 moPlacebo 4.6 mo
P<0.001
FDA approved forPancreatic NET
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Targeting mTOR in non-pancreatic NETs: Ph III Everolimus (RADIANT 2)
Pavel. Lancet, 2011
Advanced carcinoidn=429
R
Everolimus 10 mg+ Octreotide
LARN=216
Placebo + Octreotide
LARN=213
PFS by Central Review
Best Percentage Change from Baseline
Everolimus 16.4 mo Placebo 11.3 mo
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Recently Completed Trial Targeting mTOR:Phase III RADIANT 4
Advanced, progressive,
somatostatin receptor positive, GI and lung
carcinoid tumours
RBest Supportive Care
Everolimus + BSC
1°endpoint Progression Free Survival [closed to accrual]
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Angiogenesis as a Target
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Taking Advantage of Hypervascular Features of NETs
Ligand Receptor Interaction
AngiogenicFactors
Tumor Cells
Invasion and Migration
Proliferation
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New blood vessels grow due to Receptor Mediated Signaling Pathway
Endothelial Cell
Flk-1/KDR(VEGFR-2)
Growth, Migration, Permeability, Anti-apoptosis
VEGF
Kinase Activation Cascade
PPPLC
VEGF-C VEGF-D
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New blood vessels grow due to Receptor Mediated Signaling Pathway
Endothelial Cell
Flk-1/KDR(VEGFR-2)
Growth, Migration, Permeability, Anti-apoptosis
VEGF
Kinase Activation Cascade
PPPLC
VEGF-C VEGF-D
Bevacizumab
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New blood vessels grow due to Receptor Mediated Signaling Pathway
Endothelial Cell
Flk-1/KDR(VEGFR-2)
Growth, Migration, Permeability, Anti-apoptosis
VEGF
Kinase Activation Cascade
PPPLC
VEGF-C VEGF-D
Aflibercept
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New blood vessels grow due to Receptor Mediated Signaling Pathway
Endothelial Cell
Flk-1/KDR(VEGFR-2)
Growth, Migration, Permeability, Anti-apoptosis
VEGF
Kinase Activation Cascade
PPPLC
VEGF-C VEGF-D
Ramicurumab
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New blood vessels grow due to Receptor Mediated Signaling Pathway
Endothelial Cell
Flk-1/KDR(VEGFR-2)
Growth, Migration, Permeability, Anti-apoptosis
VEGF
Kinase Activation Cascade
PPPLC
VEGF-C VEGF-D
SunitinibSorafenibPazopanibAxitinib, etc
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Yao, J. C. et al. J Clin Oncol; 26:1316-1323 2008
Bevacizumab effect on tumor blood flow
CT Perfusion ScansYao J, JCO, 2008: 1316.
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Yao, J. C. et al. J Clin Oncol; 26:1316-1323 2008
Bevacizumab effect on tumor blood flow
Yao J, JCO, 2008: 1316.
CT Perfusion Scans
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Sunitinib vs Placebo in Pancreatic NET
RANDOMIZE
*159 patients:
• Well-differentiated
• Progression in past 12 months
Sunitinib 37.5 mg/day orally, continuous daily dosing*
Placebo*
1:1
*With best supportive care; somatostatin analogs were permitted
Primary endpoint: Progression Free Survival
*Accrual goal of 340 patients Trial closed early by DSMC
Niccoli P, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 4000)
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Sunitinib: Progression Free Survival
Placebo, n 79 25 6 1 0Sunitinib, n 74 32 14 2 0
Sur
viva
l pro
babi
lity
Efficacy endpoint variable value (months)
Estimate of median PFS:• sunitinib: 11.1 months (95% CI: 7.4–NR)• placebo: 5.5 months (95% CI: 3.5–7.4)
Hazard ratio 0.397 (95% CI: 0.243–0.649)P<0.001
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20
Raymond E, et al. N Engl J Med. 2011
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Carcinoid Trials targeting angiogenesis
Advanced, progressive carcinoids
RInterferon +
Octreotide LAR
Bevacizumab + Octreotide LAR
SWOG Trial (Yao PI)
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Carcinoid Trials targeting angiogenesis
Advanced, progressive carcinoids
RInterferon +
Octreotide LAR
Bevacizumab + Octreotide LAR
Alliance Trial (Bergsland PI)
Advanced, progressive carcinoids
R
Placebo
Pazopanib
Closed to accrual
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Completed Trial Combining Targeted Agents: Everolimus +/- Bevacizumab
Advanced, progressive
pancreatic NETsR
Everolimus + Bevacizumab + Octreotide LAR
Everolimus + Octreotide LAR
CALGB 80701 (Kulke PI): Phase II; 1°endpoint PFS
Sponsor: CALGB
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Chemotherapy for NETs
Streptozocin
Naturally occurring nitrosourea
Initially identified in 1950’s as an antibiotic
Found to be “selectively toxic” to beta cells of islets
Approved by FDA for islet cell tumors in 1976
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Streptozocin-based regimens
Regimen *N Tumor Type
Response**Rate
Reference
STZ/5-FUvs. STZ/Dox
105 PNET 45%69%
Moertal et alNEJM ‘92
***STZ/5-FU/Dox 84 PNET 39% Kouvaraki et alJCO ‘04
STZ/Doxvs. Dox/5-FU
176 carcinoid 16%16%
Sun et alJCO ‘05
STZ/5-FUvs. Interferon
64 carcinoid 3%9%
Dahan et alEndocr Rel Ca ‘09
*Studies with > 20 patients**Response criteria inconsistent***Retrospective report
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DTIC and Temozolomide
Both are alkylators and share an active metabolite
DNA adduct repaired by MGMT–Data from glioblastoma suggests MGMT deficient tumors predict for better response
DTIC has single agent activity in NETs–PNET 33% response rate (Bukowski et al. Cancer ‘94)
–Carcinoid 8-16% response rate (Sun et al. JCO ’05)
Temozolomide with better blood brain barrier penetration and greater convenience
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Role of MGMT in Temozolomide Resistance
Kulke et al, Proc ASCO 2007.
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MGMT expression and response to *Temozolomide in NETs
N Tumor type Radiologic Response (RECIST)
Biochemical Response
(CGA)
Median
PFS
(months)
Median
Survival
(months)
MGMT +
16 3 pancreas
13 carcinoid
0/16 0/10 9.25 14
MGMT - 5 All pancreas 4/5** 4/5 19 Not reached
MGMT intact tumor
*Temozolomide was given in combination with either thalidomide or bevacizumab in separate phase II trial** p<0.05
MGMT deficient tumor
Kulke, et al. Clinical Cancer Res. 2009
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*Temozolomide-based Regimens
NTumor Type
Response
RateReference
TMZ 36PNET
Carcinoid
8%
**30%
Ekeblad et al
Clin Cancer Res ’07
TMZ + Thalidomide
29 PNET
Carcinoid
45%
7%
Kulke et al
JCO ‘06
TMZ+Bev 34PNET
Carcinoid
24%
0%
Kulke, et al
Clin Cancer Res ‘09TMZ +
Capecitabine33 PNET 67% Strosberg, et al
Cancer ‘10
*Variety of dosing regimens used**4 of 13 bronchial carcinoids responded (one was atypical); 3 of the 4 responding patients were deficient in MGMT
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Temozolomide-Based Therapy in Pancreatic NET
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Regimen N RR TTP/PFS (mo.)
Reference
Retrospective Series
Tem 12 8% NR Ekeblad, Clin Cancer Res, 2007
Tem/Capecitabine 30 70% 18 Strosberg,Cancer, 2011
Tem (various regimens) 53 34% 13.6 Kulke, Clin Cancer Res, 2009
Prospective Trials
Tem/Thalidomide 11 45% NR Kulke, JCO, 2006
Tem/Bevacizumab 15 33% 14.3 Chan, JCO, 2012
Tem/Everolimus 40 40% 15.4 Chan, Cancer, 2013
Tem/Capecitabine 11 36% >20 Fine, ASCO GI, 2014*Data shown above limited to panc NET only, although studies may have included both pNET and carcinoid.
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Trials in progress: Chemo Combination
Low and intermediate grade
advanced pancreatic NETs
RTemozolomide /
Capecitabine
Temozolomide
ECOG 2211 (Kunz PI): Phase II, 1°endpoint PFS
MGMT will be assessed
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Cancer Cell Biology (CCB) Research Program
Erwin Van Meir, PhD, Program Leader
Lawrence Boise, PhD, Program Co-Leader
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Conclusions
Management of NETs has changed over last 10 years
Somatostatin analogues effective
PRRT in randomized trial
mTOR and angiogenesis validated targets
Chemo can still be effective (predominantly in PNETs)
First ever adjuvant trial open for resected liver mets