NIH/NCI presentation provides an overview of and NIH clinical trials. Briefing covers: 1) Overview of GI and pancreatic Neuroendocrine Tumors (NETs) /Carcinoid Cancer; 2) Treatment options for patients with advanced GI and pancreatic NETs; 3) Clinical trials for/in patients with NETs

1. Treatments of AdvancedTreatments of Advanced
Neuroendocrine TumorsNeuroendocrine Tumors
and Current Clinical Trialsand Current Clinical Trials
Naris Nilubol, M.D.Naris Nilubol, M.D.
Endocrine Oncology Branch, NCI,Endocrine Oncology Branch, NCI,
NIHNIH

2. Topic of DiscussionTopic of Discussion
 Overview of GI and pancreaticOverview of GI and pancreatic
neuroendocrine tumors (NETs)neuroendocrine tumors (NETs)
 Treatment options for patients withTreatment options for patients with
advanced GI and pancreatic NETsadvanced GI and pancreatic NETs
 Clinical trials in patients with NETsClinical trials in patients with NETs

3. Neuroendocrine TumorsNeuroendocrine Tumors
 Heterogenous group of tumors inHeterogenous group of tumors in
various locations: GI track, lungs,various locations: GI track, lungs,
pancreas, other organspancreas, other organs
 Clinical behavior varies, not allClinical behavior varies, not all
behaves badly.behaves badly.
 Incidence increased over time forIncidence increased over time for
NETs of all GI sites exceptNETs of all GI sites except
appendix. Faster on small bowel andappendix. Faster on small bowel and
rectum.rectum.11
1. Tsikitis J Cancer 2012

4. Neuroendocrine TumorsNeuroendocrine Tumors
 NETs arise from neuroendocrine cells:NETs arise from neuroendocrine cells:
 Unique microscopic featuresUnique microscopic features
 Produce hormones and proteinsProduce hormones and proteins
 Zollinger-Ellison syndromeZollinger-Ellison syndrome
 Hypoglycemia (insulinoma)Hypoglycemia (insulinoma)
 Carcinoid syndromeCarcinoid syndrome

5. Pancreatic NeuroendocrinePancreatic Neuroendocrine
Tumors (PNETs)Tumors (PNETs)
 Arise from islet cells of LangerhansArise from islet cells of Langerhans
 Uncommon (2500 cases in US per year)Uncommon (2500 cases in US per year)
 Most are “Incidentalomas”Most are “Incidentalomas”
 Slow growing tumorsSlow growing tumors
 Prolonged survival is common even withProlonged survival is common even with
metastasis when compared to pancreatic adenoCAmetastasis when compared to pancreatic adenoCA

6. Pancreatic NeuroendocrinePancreatic Neuroendocrine
Tumors (PNETs)Tumors (PNETs)
Functioning (52%)Functioning (52%)
 InsulinomaInsulinoma 55%55%
 GastrinomaGastrinoma 36%36%
 VIPoma 5%VIPoma 5%
 Glucagonoma 3%Glucagonoma 3%
 ACTHoma 1%ACTHoma 1%
 Somatostatinoma 1%Somatostatinoma 1%
Nonfunctioning (48%)Nonfunctioning (48%)
Phan et al J Gastrointest Surg. 1998;2(5):472-82.

7. Gastrointestinal NETsGastrointestinal NETs
 Increase in incidence 2-5 times in 3 decadesIncrease in incidence 2-5 times in 3 decades
 Incidentally detected by EGDIncidentally detected by EGD
 Syndromes: carcinoid, Zollinger-EllisonSyndromes: carcinoid, Zollinger-Ellison
 Bleeding, obstruction, metastasisBleeding, obstruction, metastasis
 High rates of metastasis and multi-focal:High rates of metastasis and multi-focal:
jejunum and ileumjejunum and ileum 40-50% lymph node and40-50% lymph node and
liver metastasisliver metastasis

8. Concerns aboutConcerns about
Neuroendocrine Tumors:Neuroendocrine Tumors:
 Familial syndrome?Familial syndrome?
 Benign vs. MalignantBenign vs. Malignant
 Hormonally active?Hormonally active?
Primary Locations?
Metastases Locations?

9. Inherited neuroendocrineInherited neuroendocrine
syndromessyndromes
Syndrome Gene location Protein Incidence
Tumor
type/Location
MEN1 11q13 Menin 80-100%
Multiple
Pancreas/duodenum
(nonfunctional>gastr
inoma>insulinoma)
VHL disease 3p25.5 VHL 12-17%
Pancreas (all
nonfunctioning)
Von
Recklinghausen’
s disease (NF-1)
17q11.2 Neurofibromin 6%
Pancreatic
(somatostatinoma)
TSC
9q34 (TSC1)
16p13.3 (TSC2)
Namartin,
tuberin
<5% Pancreas
MEN1: multiple endocrine neoplasia type 1; NET: neuroendocrine tumor; NF-1: neurofibromatosis type 1; TSC: tuberous sclerosis; VHL: von Hippel-Lindau

10. When to do genetic testing?When to do genetic testing?
 A member of known familial syndromeA member of known familial syndrome
 Young patients with gastrinoma, insulinoma orYoung patients with gastrinoma, insulinoma or
multiple NETsmultiple NETs
 Patients with multiple features of clinicalPatients with multiple features of clinical
syndromes.syndromes.

11. Advanced NETsAdvanced NETs
 Common in SB and pancreatic NET ~50% atCommon in SB and pancreatic NET ~50% at
initial presentation and increases over follow up.initial presentation and increases over follow up.
 Lymph nodes and liver: most commonLymph nodes and liver: most common
 Bone metastases: <15% but underestimatedBone metastases: <15% but underestimated
 Carcinoid syndrome: concerning for distantCarcinoid syndrome: concerning for distant
metastasismetastasis
ENETS Consensus Guidelines 2016

12. Treatments of advanced NETsTreatments of advanced NETs
 Local-regional treatmentsLocal-regional treatments
 SurgerySurgery
 Organ-directed therapy (mostly liver)Organ-directed therapy (mostly liver)
 Systemic treatmentsSystemic treatments
 Somatostain analoguesSomatostain analogues
 Targeted therapyTargeted therapy
 Peptide receptor radionuclide therapyPeptide receptor radionuclide therapy
 Cytotoxic chemotherapyCytotoxic chemotherapy
 Investigational treatmentsInvestigational treatments

13. Local-regional treatments ofLocal-regional treatments of
advanced NETsadvanced NETs
 Accurate staging is MANDATORY.Accurate staging is MANDATORY.
 Goal of surgery: No evidence of disease (orGoal of surgery: No evidence of disease (or
>90%) even with lymph node or liver metastasis>90%) even with lymph node or liver metastasis
 Retrospective, uncontrolled studiesRetrospective, uncontrolled studies
 In severely symptomatic: <90% may be considered.In severely symptomatic: <90% may be considered.
 Liver-directed therapy: no evidence that oneLiver-directed therapy: no evidence that one
modality is significantly better than the others.modality is significantly better than the others.
NANETS 2013 and ENETS 2016 guidelines

14. Systemic therapy: SomatostatinSystemic therapy: Somatostatin
analogues (SSA)analogues (SSA)
 First line Rx in functioning NETs to controlFirst line Rx in functioning NETs to control
symptomssymptoms
 Dose escalation for refractory or shortening ofDose escalation for refractory or shortening of
administration interval.administration interval.
 27% of patients with carcinoid syndrome who failed27% of patients with carcinoid syndrome who failed
octreotide responded to pasireotide.octreotide responded to pasireotide.11
1. Kvols et al. Endocr Relat Cancer 2012

15. SSA and tumor growth controlSSA and tumor growth control
 Low to intermediate grade NETsLow to intermediate grade NETs
 Time to progressionTime to progression
 PROMIDPROMID11
: Octreotide in metastatic midgut: Octreotide in metastatic midgut
NETs (67% vs. 37% stable disease at 6 months)NETs (67% vs. 37% stable disease at 6 months)
 CLARINETCLARINET22
: lanreotide in advanced GI or: lanreotide in advanced GI or
PNETs (PFS not reached vs. 18 months)PNETs (PFS not reached vs. 18 months)
1. Rinke et al. J Clin Oncol 2009
2. Caplin et al. NEJM 2014

16. IFN-alphaIFN-alpha
 Approved therapy for syndrome control, andApproved therapy for syndrome control, and
primarily used as second-line (add-on) therapy inprimarily used as second-line (add-on) therapy in
refractory carcinoid syndrome or functionalrefractory carcinoid syndrome or functional
pancreatic NET.pancreatic NET.
 IFN is an option for inhibiting tumor growthIFN is an option for inhibiting tumor growth
and in midgut NET, it may be considered anand in midgut NET, it may be considered an
antiproliferative option (less so in pancreaticantiproliferative option (less so in pancreatic
NET).NET).

17. Targeted therapyTargeted therapy
 Low and intermediate gradeLow and intermediate grade
 SunitinibSunitinib11
: Approved for advanced PNETs: Approved for advanced PNETs
 PFS 11.4 vs. 5.5 months with overall survival benefitPFS 11.4 vs. 5.5 months with overall survival benefit
 Everolimus: RADIANT-3 and -4 for PNETsEverolimus: RADIANT-3 and -4 for PNETs22
,,
lung, and GI NETslung, and GI NETs33
 PFS 11 vs. 3.9-4.6 months, reduction in the risk ofPFS 11 vs. 3.9-4.6 months, reduction in the risk of
deathdeath
 >60% adverse events>60% adverse events
1. Raymond et al. NEJM 2011
2. Yao et al. NEJM 2011
3. Yao et al. Lancet 2016

18. Combination treatmentCombination treatment
 Combination sorafenib+ everolimusCombination sorafenib+ everolimus11
: Too toxic: Too toxic
 COOPERATE-2 trialCOOPERATE-2 trial22
: Everolimus +: Everolimus +
pasireotide showed NO benefit in PFSpasireotide showed NO benefit in PFS
 ENETS 2016 guidelines do not recommend theENETS 2016 guidelines do not recommend the
combination unless for symptom control.combination unless for symptom control.
1. Chan et al. Cancer Chemother Pharmacol 2013
2. Kulke et al. Annual ENETS Conference 2015

19. Cytotoxic chemotherapyCytotoxic chemotherapy
 Progressive, high tumor burden NETs, failure ofProgressive, high tumor burden NETs, failure of
other treatments and in high grade NETsother treatments and in high grade NETs
 STZ/5-FU: low, intermediate grade PNETsSTZ/5-FU: low, intermediate grade PNETs
 Gaining popularity: temozolamide andGaining popularity: temozolamide and
capecitabine with objective response rate 15-capecitabine with objective response rate 15-
70%70%
 High grade NETs: Platinum-baed/etoposideHigh grade NETs: Platinum-baed/etoposide

20. Peptide Receptor RadionuclidePeptide Receptor Radionuclide
Therapy (PRRT)Therapy (PRRT)
 Progressive, low and intermediate grade NETsProgressive, low and intermediate grade NETs
 Y-90 or Lu-177 (less kidney toxicity).Y-90 or Lu-177 (less kidney toxicity).
 NETTER-1 trial: Lu-177 vs. octreotideNETTER-1 trial: Lu-177 vs. octreotide
 Objective response:18% vs. 3%Objective response:18% vs. 3%
 PFS not reached in Lu-177 group vs. 8.4 months.PFS not reached in Lu-177 group vs. 8.4 months.
 Strongly suggests improved overall survivalStrongly suggests improved overall survival
 Rare grade 3-4 low WBC and plts.Rare grade 3-4 low WBC and plts.
 Soon to be approved in USSoon to be approved in US
1. Strosberg et al. J Nuc Med 2016

21. Current clinical trials at NIHCurrent clinical trials at NIH
 Mutation targeted therapy in advanced GI andMutation targeted therapy in advanced GI and
PNETsPNETs
 Ga-68 DOTATATE PET/CTGa-68 DOTATATE PET/CT
 Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1
 Natural history of familial small bowel carcinoidNatural history of familial small bowel carcinoid

22. Mutation targeted therapy inMutation targeted therapy in
advanced GI and PNETsadvanced GI and PNETs
 Progressive low or intermediate NETsProgressive low or intermediate NETs
 Everolimus or sunitinib chosen based onEverolimus or sunitinib chosen based on
patient’s tumor profilepatient’s tumor profile
 Cytoreductive surgery is allowed.Cytoreductive surgery is allowed.
 PFS is a primary endpoint.PFS is a primary endpoint.

23. Ga-68 DOTATATE PET/CTGa-68 DOTATATE PET/CT
 Over 300 enrolled.Over 300 enrolled.
 Resulted in FDA approvalResulted in FDA approval
 Currently accepting onlyCurrently accepting only
 Patients with NO known primary NETsPatients with NO known primary NETs
 Metastasis without primary tumor identifiedMetastasis without primary tumor identified
 Carcinoid symptoms WITH elevation of biomarkersCarcinoid symptoms WITH elevation of biomarkers
 Patients who are candidate for surgery: usePatients who are candidate for surgery: use
radioguided probe to find tumorsradioguided probe to find tumors

24. Natural history of MEN1Natural history of MEN1
syndromesyndrome
 NIDDK colleaguesNIDDK colleagues
 Patients with suspicious or confirmed MEN1Patients with suspicious or confirmed MEN1
 Family members of patients with MEN1Family members of patients with MEN1
syndromesyndrome
 Annual surveillance with imaging studies,Annual surveillance with imaging studies,
endoscopy (if needed), multi-team consensusendoscopy (if needed), multi-team consensus
 Treatment per standard of careTreatment per standard of care

25. Natural history of familial smallNatural history of familial small
bowel carcinoidbowel carcinoid
 2 or more members with small bowel NETs2 or more members with small bowel NETs
 Evaluation q 3 years with CT scan, capsuleEvaluation q 3 years with CT scan, capsule
endoscopy, 18F DOPA PET, Ga-68endoscopy, 18F DOPA PET, Ga-68
DOTATATE as needed.DOTATATE as needed.
 Biomarkers and gene testingBiomarkers and gene testing
 Treatment per standard of careTreatment per standard of care

26. Interested in the EOBInterested in the EOB
trials?trials?
ncieobinquiry@mail.nih.govncieobinquiry@mail.nih.gov
Fax: 301-451-5580Fax: 301-451-5580