1. What Do We Still Need to Know?
New Frontiers and Treatment Advances for Metastatic Enteropancreatic Neuroendocrine Tumors
What Do We Know?
What Do We Still Need to Know?
The Rapidly Evolving Landscape of Therapeutic Options and Patient Selection Strategies for GEP-NETs—
A Year 2015 Status Report for the GI Cancer Specialist

2. GEP-NET Overview
Annual incidence of NET is 5.25 cases per 100,000 Americans (SEER Database)1
Incidence has increased by 500% in the past 30 years – more than other cancers.
Today, NET is the most prevalent GI malignancy after colon cancer, affecting over 100,000 Americans.
3X more prevalent than pancreatic adenocarcinoma
2X more prevalent than stomach adenocarcinoma
1. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. J Clin Gastroenterol. 2006;40(7): Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26: Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:

3. GEP-NET Overview
NET is usually metastatic at diagnosis, and 65% will die in the first 5 years after diagnosis (SEER data).
Conventional chemotherapy has limited efficacy.
Lanreotide is approved therapy for GEP-NETs including carcinoids.
For NET of pancreatic origin, streptozocin, sunitinib, everolimus, and lanreotide have all been approved.
Octreotide LAR is approved as a symptom control medication (flushing and diarrhea in carcinoid, diarrhea in VIPoma syndrome.1
There remains a significant unmet need for effective and safe therapies in patients with metastatic NET.
1. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. J Clin Gastroenterol. 2006;40(7): Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26: Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:

4. Carcinoid – Neuroendocrine Tumor Program
Multidisciplinary Management Team
Medical
Oncology
Endocrinology
Radiation
Cardiology
Gastro-
enterology
Pathology
Interventional
Radiology
Diagnostic
Nuclear
Medicine
Surgery
PATIENT

5. Perspectives on Chemotherapy for GEP-NET
Chemotherapy for NET usually has a lower objective response rate than for most solid tumors. Pancreatic NET (pNET) is the exception.
Despite the low response rate, progression-free survival can be prolonged with appropriate chemotherapy, and quality of life can be improved.
More metabolically active NETs (high Ki-67, high SUV on FDG-PET) are more likely to respond to chemotherapy by tumor shrinkage.

6. Perspectives on Chemotherapy for GEP-NET 2
GEP-NETs are very vascular and cells express VEGF and other pro-angiogenic targets.
Growth factor receptors and their downstream effectors are prominently expressed, inviting new targets such as c-KIT, EGFR, IGF-1R, phosphoinositide-3-kinase, AKT, mTOR, and PDGF.
Optimal integration of new systemic therapies with local and regional cytoreductive techniques, and PRRT remains a challenge.
Optimal sequencing of the multiple active agents in pancreatic NET remains a challenge.

7. Approved Systemic Therapy for Pancreatic NET
Streptozocin
Everolimus
Sunitinib
Lanreotide

8. Streptozocin Chemotherapy for Pancreatic NET: Overview and Status
Streptozotocin + doxorubicin + 5-FU in pancreatic NET: 39% PR by RECIST.
Median response duration was 9.3 months.
Nephrotoxicity can compromise future PRRT.
Kouvaraki, MA et al, J Clin Oncol 2004 Dec 1;22(23):

9. Everolimus in Pancreatic NET: RADIANT-3 Trial Progression-free Survival*
Kaplan-Meier medians PFS
Everolimus: 11.4 months
Placebo: 5.4 months
Hazard ratio = 0.34; 95% CI [ ] P-value: <0.0001
100 80 60
Percentage event-free 40 20
Censoring Times
Everolimus (n/N = 95/207)
Placebo (n/N = 142/203) 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (months)
No. of patients still at risk
Everolimus
Placebo
207
203
187
180
152 99
126 60
117 52 81 22 49 12 36 5 27 3 22 1 10 1 6 1 2
* Independent adjudicated central review committee
P-value obtained from stratified one-sided log rank test
Hazard ratio is obtained from stratified unadjusted Cox model

10. Sunitinib – Phase 3 Trial in Pancreatic NET
Pancreatic NETs which had progressed in the last 12 months were randomized to either sunitinib or placebo plus(n=79).
Average time to progression was 11.1 months with sunitinib vs. 5.5 months with placebo (hazard ratio 0.397, p<0.001).
Significant side effects included low white blood count hypertension, abdominal pain, diarrhea, low blood sugar and hand-foot syndrome (less than 10% of patients).
Common mild side effects included mild fatigue, nausea, altered taste, tongue tenderness
N Engl J Med Volume s364(6): February 10, 2011

11. Lanreotide Autogel Newly Approved for Treatment of GEP-NETs
A novel somatostatin analog with high affinity binding to SSTR2.
After subcutaneous injection, self-assembly reverses, releasing lanreotide, with 80-85% of drug released by 80 days.
Suitable for giving higher and potentially more effective doses in a small volume.
Better tolerated by thin or cachectic individuals than I.M. injections
Clinical trials of lanreotide autogel have led to recent FDA approval and will be discussed in detail in this meeting.

12. CLARINET: Primary Endpoint Prespecified PFS Subanalyses – Tumor Location
Midgut NETs (n=73)
Lanreotide 120 mg vs. PBO
HR=0.35
[95% CI: 0.16, 0.80]
Pancreatic NETs (n=91)
Lanreotide 120 mg vs. PBO
HR=0.58
[95% CI: 0.32, 1.04] 3 6 9 12 18 24 27 10 20 30 40 50 60 70 80 90
100
Patients alive and with no progression (%)
Time (months) 10 20 30 40 50 60 70 80 90
100
Time (months)
Lanreotide
8 events / 33 patients
Median PFS not reached
Lanreotide
18 events / 42 patients
Median PFS not reached
Placebo
21 events / 40 patients
Median PFS = 21.1 months [95% CI: 17.0, NC]
Placebo
31 events / 49 patients
Median PFS = 12.1 months [95% CI: 9.4, 18.3] 3 6 9 12 18 24 27 33 32 30 28 24 40 39 36 20 16
Numbers of patients at risk of death or PD 13 42 39 32 29 24 20 49 48 38 33 23 17 13
Numbers of patients at risk of death or PD 8
HR derived from Cox proportional hazards model.
CI, confidence interval; HR, hazard ratio; NETs, neuroendocrine tumors; PBO, placebo; PD, progressive disease; PFS, progression-free survival; PNETs, pancreatic neuroendocrine tumors.
Caplin ME, et al. N Engl J Med. 2014;371(3):

13. Approved Systemic Therapy for Carcinoid Tumors
Octreotide and octreotide LAR are approved for the treatment of flushing and diarrhea from carcinoid syndrome.
Lanreotide Autogel approved as an antineoplastic for treatment of GEP-NETS, including carcinoid tumors.

14. New Directions and Clinical Challenges for Treatment and Sequencing Therapy for NET
How should the sequence of systemic therapies in NET management be optimized? Based on what evidence?
How should local/regional therapy be integrated with systemic therapy? Patient selection? Clinical profiles?
Now that lanreotide is approved, when should it be started, and how should it be incorporated into the therapeutic plan of patients with GEP-NETs? What is the roadmap?
How should peptide receptor radiotherapy (PRRT) be incorporated into NET management?
How should advances in molecular biology/genomics inform treatment decisions?
What ongoing large clinical trials are likely to influence therapy in the near future?