NIH Presentation Nov 2016 Neuroendocrine Tumor Clinical Trials
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Transcript of NIH Presentation Nov 2016 Neuroendocrine Tumor Clinical Trials
Treatments of Treatments of Advanced Advanced
Neuroendocrine Neuroendocrine Tumors and Current Tumors and Current
Clinical TrialsClinical TrialsNaris Nilubol, M.D.Naris Nilubol, M.D.
Endocrine Oncology Branch, Endocrine Oncology Branch, NCI, NIHNCI, NIH
Topic of DiscussionTopic of Discussion Overview of GI and pancreatic Overview of GI and pancreatic
neuroendocrine tumors (NETs)neuroendocrine tumors (NETs) Treatment options for patients Treatment options for patients
with advanced GI and pancreatic with advanced GI and pancreatic NETsNETs
Clinical trials in patients with Clinical trials in patients with NETsNETs
Neuroendocrine TumorsNeuroendocrine Tumors Heterogenous group of tumors Heterogenous group of tumors
in various locations: GI track, in various locations: GI track, lungs, pancreas, other organslungs, pancreas, other organs
Clinical behavior varies, not all Clinical behavior varies, not all behaves badly.behaves badly.
Incidence increased over time Incidence increased over time for NETs of all GI sites except for NETs of all GI sites except appendix. Faster on small appendix. Faster on small bowel and rectum.bowel and rectum.11
1. Tsikitis J Cancer 2012
Neuroendocrine TumorsNeuroendocrine Tumors NETs arise from neuroendocrine NETs arise from neuroendocrine
cells: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
Pancreatic Pancreatic Neuroendocrine Tumors Neuroendocrine Tumors
(PNETs)(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 Prolonged survival is common even
with metastasis when compared to with metastasis when compared to pancreatic adenoCApancreatic adenoCA
Pancreatic Pancreatic Neuroendocrine Tumors Neuroendocrine Tumors
(PNETs)(PNETs)Functioning (52%)Functioning (52%) Insulinoma Insulinoma 55%55% Gastrinoma Gastrinoma 36%36% VIPoma 5%VIPoma 5% Glucagonoma 3%Glucagonoma 3% ACTHoma 1%ACTHoma 1% Somatostatinoma Somatostatinoma
1%1%
Nonfunctioning Nonfunctioning (48%)(48%)
Phan et al J Gastrointest Surg. 1998;2(5):472-82.
Gastrointestinal NETs Gastrointestinal NETs Increase in incidence 2-5 times in 3 Increase in incidence 2-5 times in 3
decadesdecades Incidentally detected by EGDIncidentally detected by EGD Syndromes: carcinoid, Zollinger-Ellison Syndromes: carcinoid, Zollinger-Ellison Bleeding, obstruction, metastasisBleeding, obstruction, metastasis High rates of metastasis and multi-High rates of metastasis and multi-
focal: jejunum and ileumfocal: jejunum and ileum 40-50% 40-50% lymph node and liver metastasislymph node and liver metastasis
Concerns aboutConcerns about Neuroendocrine Tumors: Neuroendocrine Tumors: Familial syndrome?Familial syndrome?
Benign vs. Malignant Benign vs. Malignant
Hormonally active?Hormonally active?
Primary Locations?
Metastases Locations?
Inherited Inherited neuroendocrine neuroendocrine
syndromessyndromesSyndrome Gene
location Protein IncidenceTumor type/Location
MEN1 11q13 Menin 80-100%
Multiple Pancreas/duodenum (nonfunctional>gastrinoma>insulinoma)
VHL disease 3p25.5 VHL 12-17% Pancreas (all nonfunctioning)
Von Recklinghausen’s disease (NF-1)
17q11.2 Neurofibromin 6%
Pancreatic (somatostatinoma)
TSC9q34 (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
When to do genetic When to do genetic testing?testing?
A member of known familial A member of known familial syndromesyndrome
Young patients with gastrinoma, Young patients with gastrinoma, insulinoma or multiple NETsinsulinoma or multiple NETs
Patients with multiple features of Patients with multiple features of clinical syndromes.clinical syndromes.
Advanced NETsAdvanced NETs Common in SB and pancreatic NET Common in SB and pancreatic NET
~50% at initial presentation and ~50% at initial presentation and increases over follow up.increases over follow up.
Lymph nodes and liver: most commonLymph nodes and liver: most common Bone metastases: <15% but Bone metastases: <15% but
underestimatedunderestimated Carcinoid syndrome: concerning for Carcinoid syndrome: concerning for
distant metastasisdistant metastasis
ENETS Consensus Guidelines 2016
Treatments of advanced Treatments of advanced NETsNETs
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
Local-regional Local-regional treatments of advanced treatments of advanced
NETsNETs Accurate staging is MANDATORY.Accurate staging is MANDATORY. Goal of surgery: No evidence of disease Goal of surgery: No evidence of disease
(or >90%) even with lymph node or liver (or >90%) even with lymph node or liver metastasismetastasis Retrospective, uncontrolled studiesRetrospective, uncontrolled studies In severely symptomatic: <90% may be In severely symptomatic: <90% may be
considered.considered. Liver-directed therapy: no evidence that Liver-directed therapy: no evidence that
one modality is significantly better than one modality is significantly better than the others.the others.
NANETS 2013 and ENETS 2016 guidelines
Systemic therapy: Systemic therapy: Somatostatin analogues Somatostatin analogues
(SSA)(SSA) First line Rx in functioning NETs to First line Rx in functioning NETs to
control symptomscontrol symptoms Dose escalation for refractory or Dose escalation for refractory or
shortening of administration interval.shortening of administration interval. 27% of patients with carcinoid syndrome 27% of patients with carcinoid syndrome
who failed octreotide responded to who failed octreotide responded to pasireotide.pasireotide.11
1. Kvols et al. Endocr Relat Cancer 2012
SSA and tumor growth SSA and tumor growth controlcontrol
Low to intermediate grade NETsLow to intermediate grade NETs Time to progressionTime to progression PROMIDPROMID11: Octreotide in metastatic : Octreotide in metastatic
midgut NETs (67% vs. 37% stable midgut NETs (67% vs. 37% stable disease at 6 months)disease at 6 months)
CLARINETCLARINET22: lanreotide in advanced : lanreotide in advanced GI or PNETs (PFS not reached vs. 18 GI or PNETs (PFS not reached vs. 18 months)months)
1. Rinke et al. J Clin Oncol 20092. Caplin et al. NEJM 2014
IFN-alphaIFN-alpha Approved therapy for syndrome Approved therapy for syndrome
control, and primarily used as control, and primarily used as second-line (add-on) therapy in second-line (add-on) therapy in refractory carcinoid syndrome or refractory carcinoid syndrome or functional pancreatic NET. functional pancreatic NET.
IFN is an option for inhibiting tumor IFN is an option for inhibiting tumor growth and in midgut NET, it may be growth and in midgut NET, it may be considered an antiproliferative option considered an antiproliferative option (less so in pancreatic NET).(less so in pancreatic NET).
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 PFS 11.4 vs. 5.5 months with overall survival benefitbenefit
Everolimus: RADIANT-3 and -4 for Everolimus: RADIANT-3 and -4 for PNETsPNETs22, lung, and GI NETs, lung, and GI NETs33
PFS 11 vs. 3.9-4.6 months, reduction in the PFS 11 vs. 3.9-4.6 months, reduction in the risk of deathrisk of death
>60% adverse events >60% adverse events 1. Raymond et al. NEJM 20112. Yao et al. NEJM 20113. Yao et al. Lancet 2016
Combination treatmentCombination treatment Combination sorafenib+ Combination sorafenib+
everolimuseverolimus11: Too toxic: Too toxic COOPERATE-2 trialCOOPERATE-2 trial22: Everolimus + : Everolimus +
pasireotide showed NO benefit in pasireotide showed NO benefit in PFSPFS
ENETS 2016 guidelines do not ENETS 2016 guidelines do not recommend the combination unless recommend the combination unless for symptom control.for symptom control.
1. Chan et al. Cancer Chemother Pharmacol 20132. Kulke et al. Annual ENETS Conference 2015
Cytotoxic chemotherapyCytotoxic chemotherapy Progressive, high tumor burden NETs, Progressive, high tumor burden NETs,
failure of other treatments and in high failure of other treatments and in high grade NETsgrade NETs
STZ/5-FU: low, intermediate grade PNETsSTZ/5-FU: low, intermediate grade PNETs Gaining popularity: temozolamide and Gaining popularity: temozolamide and
capecitabine with objective response rate capecitabine with objective response rate 15-70%15-70%
High grade NETs: High grade NETs: Platinum-baed/etoposidePlatinum-baed/etoposide
Peptide Receptor Peptide Receptor Radionuclide Therapy Radionuclide Therapy
(PRRT) (PRRT) Progressive, low and intermediate grade Progressive, low and intermediate grade
NETsNETs 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 PFS not reached in Lu-177 group vs. 8.4
months.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
Current clinical trials at Current clinical trials at NIHNIH
Mutation targeted therapy in Mutation targeted therapy in advanced GI and PNETsadvanced GI and PNETs
Ga-68 DOTATATE PET/CT Ga-68 DOTATATE PET/CT Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 Natural history of familial small Natural history of familial small
bowel carcinoidbowel carcinoid
Mutation targeted Mutation targeted therapy in advanced GI therapy in advanced GI
and PNETsand PNETs Progressive low or intermediate Progressive low or intermediate
NETsNETs Everolimus or sunitinib chosen Everolimus or sunitinib chosen
based on patient’s tumor profilebased on patient’s tumor profile Cytoreductive surgery is allowed.Cytoreductive surgery is allowed. PFS is a primary endpoint.PFS is a primary endpoint.
Ga-68 DOTATATE Ga-68 DOTATATE PET/CT PET/CT
Over 300 enrolled.Over 300 enrolled. Resulted in FDA approvalResulted in FDA approval Currently accepting only Currently 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 Carcinoid symptoms WITH elevation of
biomarkersbiomarkers Patients who are candidate for surgery: Patients who are candidate for surgery:
use radioguided probe to find tumorsuse radioguided probe to find tumors
Natural history of MEN1 Natural history of MEN1 syndromesyndrome
NIDDK colleagues NIDDK colleagues Patients with suspicious or confirmed Patients with suspicious or confirmed
MEN1MEN1 Family members of patients with MEN1 Family members of patients with MEN1
syndromesyndrome Annual surveillance with imaging Annual surveillance with imaging
studies, endoscopy (if needed), multi-studies, endoscopy (if needed), multi-team consensus team consensus
Treatment per standard of careTreatment per standard of care
Natural history of familial Natural history of familial small bowel carcinoidsmall bowel carcinoid
2 or more members with small bowel 2 or more members with small bowel NETsNETs
Evaluation q 3 years with CT scan, Evaluation q 3 years with CT scan, capsule endoscopy, 18F DOPA PET, capsule endoscopy, 18F DOPA PET, Ga-68 DOTATATE as needed. Ga-68 DOTATATE as needed.
Biomarkers and gene testingBiomarkers and gene testing Treatment per standard of careTreatment per standard of care
Interested in the Interested in the EOB trials?EOB trials?
[email protected]: 301-451-5580Fax: 301-451-5580