Pancreatic NET Pancreatic NET What’s new?What’s new?

George Fisher, MD PhDGeorge Fisher, MD PhDPamela Kunz, MDPamela Kunz, MD

Division of OncologyDivision of OncologyStanford University Medical SchoolStanford University Medical School

March 29, 2009March 29, 2009

Establish extent of disease

Surgically resectable

Unresectable or metastatic

SurgeryHepatic metastases

predominateMultiple metastatic

sites

Locoregional Treatments:Chemoembolization

Radiofrequency ablationSIR-Spheres

Systemic Treatments:Somatostatin analogues

ChemotherapyPRRT

Newer agents

Treatment options for pancreatic NETsTreatment options for pancreatic NETs

Systemic Treatments:Somatostatin analogues

ChemotherapyPRRT

Newer agents

Chemotherapy in NETChemotherapy in NET

“ “Old” drugsOld” drugs 5-FU5-FU AdriamycinAdriamycin StreptozocinStreptozocin CisplatinCisplatin DTIC (dacarbazine)DTIC (dacarbazine)

“ “Newer” versionsNewer” versions Capecitabine*Capecitabine* Epirubicin / DoxilEpirubicin / Doxil

OxaliplatinOxaliplatin Temazolamide**Temazolamide**

*Xeloda; **Temador

““Cytotoxic” ChemotherapyCytotoxic” Chemotherapy

Temazolamide (oral version of DTIC)Temazolamide (oral version of DTIC) Capecitabine (oral version of 5-FU)Capecitabine (oral version of 5-FU) Oxaliplatin (newer version of cisplatin)Oxaliplatin (newer version of cisplatin)

Temozolamide-Based Therapy in Temozolamide-Based Therapy in NET: EfficacyNET: Efficacy

Tumor type nResponse (RECIST)

Pancreatic NET 35 11 (31%)

Carcinoid 38 0

Pheo/Paraganglioma 3 1 (33%)

Combined analysis (76 patients)Combined analysis (76 patients)

Kulke et al, Proc ASCO 2007.

Role of MGMT in Modulating Role of MGMT in Modulating Temozolamide SensitivityTemozolamide Sensitivity

Kulke et al, Proc ASCO 2007.

MGMT expression predicts response MGMT expression predicts response to Temozolamide in NETto Temozolamide in NET

n Tumor type Radiologic Response (RECIST)

Biochemical Response (Chromogranin A)

Median Progression Free Survival

(months)

Median Overall 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

* p<0.05

MGMT deficient tumor

Kulke et al, Proc ASCO 2007.

PRRT in pancreatic NETsPRRT in pancreatic NETsTreatment with the Radiolabeled Somatostatin Analogue Treatment with the Radiolabeled Somatostatin Analogue

[[177177Lu-DOTA Lu-DOTA 00,Tyr ,Tyr 33]Octreotate: Toxicity, Efficacy and Survival]Octreotate: Toxicity, Efficacy and Survival

Study DesignStudy Design Key Inclusion: Octreoscan positive, Karnofsky performance status >50%Key Inclusion: Octreoscan positive, Karnofsky performance status >50% 504 patients (1772 total treatments) 504 patients (1772 total treatments) 310 patients available for analysis 310 patients available for analysis

ResultsResults Median Overall Survival = 46 months; Median Progression-free Survival = 33 monthsMedian Overall Survival = 46 months; Median Progression-free Survival = 33 months Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss); Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss);

rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome)rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome)

Kwekkeboom, JCO, 2008: 2124.

Tumor type CR PR MR SD PDn (%) n (%) n (%) n (%) n (%)

Carcinoid 1 (1%) 41(22) 31 (17) 78 (42%) 37 (20%)Pancreas (non-functioning) 4 (6%) 26 (36%) 13 (18%) 19 (26%) 10 (14%)Other 0 19 (38%) 7 (14%) 10 (20%) 14 (28%)Total 5 (2) 86 (28) 51 (16) 107 (35) 61 (20)

Tumor Responses 3 Months After the Last Administration of 177Lu-Octreotate (n=310)

Somatostatin analoguesSomatostatin analogues

Symptom control from secretory syndromesSymptom control from secretory syndromes VIPoma, glucagonoma, etcVIPoma, glucagonoma, etc

Anti-proliferative effect?Anti-proliferative effect? Validity of PROMID trial?Validity of PROMID trial?

Somatostatin AnaloguesSomatostatin AnaloguesPROMID: PROMID: PPlacebo Controlled, Double Blind, Prospective lacebo Controlled, Double Blind, Prospective RRandomized andomized Study of the Effect of Study of the Effect of OOctreotide LAR in the control of tumor growth in ctreotide LAR in the control of tumor growth in

patients with Metastatic Neuroendocrine patients with Metastatic Neuroendocrine MidMidgut Tumorsgut Tumors

Primary EndpointPrimary Endpoint Time to ProgressionTime to Progression

Secondary EndpointsSecondary Endpoints Overall SurvivalOverall Survival Response RatesResponse 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

TYPICAL COLORECTALCANCER METASTASES

TYPICAL NETMETASTASES

Angiogenesis as a TargetAngiogenesis as a Target

Ligand Receptor Interaction

AngiogenicFactors

Tumor Cells

Venule or Capillary

Invasion and Migration

Proliferation

Strategies for Blocking VEGFR-2Strategies for Blocking VEGFR-2

Antibody to VEGF-A• Blocks ligand binding• Blocks receptor activation

and signaling

Antibody to VEGFR-2• Blocks binding• Blocks receptor activation

and signaling

TKI to VEGFR-2• Blocks receptor activation

and signaling

VEGF

VEGF-C VEGF-D VEGF VEGF-D VEGF VEGF-C VEGF-DVEGF-C

BevacizumabSunitinib Sorafenib

Efficacy of VEGF pathway Efficacy of VEGF pathway inhibitors in NETsinhibitors in NETs

Agent Targets Patients RR (%)

Med PFS (mo)

Reference

Sunitinib VEGFR, PDGFR, c-Kit

41 Carcinoid

61 Pancreas

2

13

10.5

8.3

Kulke, Proc ASCO 2005; A# 4008.

Bevacizumab / Temozolamide

VEGF 12 Carcinoid

17 Pancreas

0

24

NR Kulke, Proc ASCO 2006; A# 4044

Sorafenib VEGFR, PDGFR, b-Raf

42 Carcinoid

35 Pancreas

7

11

7.8

11.9

Hobday, Proc ASCO 2007, A# 4504.

UCSF: Phase II trial of FOLFOX plus bevacizumab UCSF: Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumorsin advanced, progressive neuroendocrine tumors

EligibilityEligibility Clinical or radiographic Clinical or radiographic

evidence of progressionevidence of progression No prior anti-VEGF therapyNo prior anti-VEGF therapy

EndpointsEndpoints Toxicity, Response RatesToxicity, Response Rates

Study DesignStudy Design mFOLFOX-6 + Bev (5 mFOLFOX-6 + Bev (5

mg/kg) Q 2 wksmg/kg) Q 2 wks Bolus 5FU used initially, Bolus 5FU used initially,

then switched to infusionalthen switched to infusional

Venook, ASCO 2008, abstract #15545.

CharacteristicPancreatic NET

(n=6)Small Bowel

(n=6)Poorly differentiated NET

(n=1)% total(n=13)

Partial Response 3 1 0 31%

Stable Disease 2 4 1 54%

Not Evaluable 1 1 0 15%

Best Radiographic Response

Stanford: A phase II study of capecitabine, Stanford: A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or oxaliplatin, and bevacizumab for metastatic or

unresectable neuroendocrine tumorsunresectable neuroendocrine tumors

Eligibility:Eligibility: No prior oxaliplatin or No prior oxaliplatin or

angiogenesis inhibitorsangiogenesis inhibitors EndpointsEndpoints

PFS, toxicity, OS, RRPFS, toxicity, OS, RR

Study DesignStudy Design Bevacizumab 7.5 mg/kg IV D1Bevacizumab 7.5 mg/kg IV D1 Oxaliplatin 130 mg/m2 IV D1Oxaliplatin 130 mg/m2 IV D1 Capecitabine 850 mg /m2 po Capecitabine 850 mg /m2 po

BID x 14DBID x 14D Q 21 day cyclesQ 21 day cycles

CharacteristicPancreatic NET

(n=15)

Small bow el NET

(n=4)

Unknow n primary

(n=5)

Other

(n=2)

% total

(n=26)

Duration of

response

Partial Response 6 0 0 0 23% 4-20

Stable Disease 8 3 4 1 62% 3-28

Progressive Disease 0 0 0 1 4% n/a

Not Evaluable 1 1 1 0 12% n/a

Best Radiographic Response

14 of 15 pNETs (93%) had some clinical benefit defined as PR or SD

Waterfall Plot of Best Response by RECIST

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

Percent Change Compared to Baseline

Green bars = PRBlue bars = SDRed bar = PD

Stanford: Phase II study Cape-Ox-BevStanford: Phase II study Cape-Ox-Bev

Stanford: Phase II study Cape-Ox-BevStanford: Phase II study Cape-Ox-Bev

SunitinibSunitinib

Started 3/07, Started 3/07, Stopped earlyStopped early by safety monitoring committee in 3/09 by safety monitoring committee in 3/09 Key inclusions: Key inclusions:

Progressive advanced or metastatic well-differentiated pancreatic islet cell tumorsProgressive advanced or metastatic well-differentiated pancreatic islet cell tumors No prior Tyrosine Kinase Inhibitor (TKI) / anti-VEGFNo prior Tyrosine Kinase Inhibitor (TKI) / anti-VEGF

Study Design: Study Design: Phase 3, randomized, double-blindPhase 3, randomized, double-blind 340 pts 340 pts Sunitinib (37.5 mg) vs. Placebo Sunitinib (37.5 mg) vs. Placebo Endpoints: PFS, RR, OS, toxicityEndpoints: PFS, RR, OS, toxicity

A Phase II Study of Pertuzumab and Erlotinib for A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Metastatic or Unresectable Neuroendocrine

TumorsTumors

PertuzumabPertuzumab Inhibits HER 2 dimerization with other HER receptors Inhibits HER 2 dimerization with other HER receptors

RationaleRationale In a Ph I study, 1 patient with a well-differentiated pancreatic In a Ph I study, 1 patient with a well-differentiated pancreatic

NET experienced symptomatic relief and a durable PRNET experienced symptomatic relief and a durable PR Neuroendocrine tumors express EGFRNeuroendocrine tumors express EGFR Combined inhibition of the EGFR family has shown enhanced Combined inhibition of the EGFR family has shown enhanced

antitumor activity in preclinical models and early clinical studiesantitumor activity in preclinical models and early clinical studies

A Phase II Study of Pertuzumab and Erlotinib for A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine TumorsMetastatic or Unresectable Neuroendocrine Tumors

PertuzumabFor cycle 1: 840 mg IV D1 (loading dose)

For subsequent cycles: 420 mg IV D1

PR at Cycle 4 SD or PD at Cycle 4

Continue single agent Pertuzumab

PD at or after Cycle 8

Pertuzumab 420 mg IV D1Erlotinib 150 mg PO daily

Continue until PD then OFF STUDY

Pertuzumab 420 mg IV D1Erlotinib 150 mg PO daily

Continue until PD then OFF STUDY

Adapted from Faivre, et al. Nature Reviews; 2006: 5.

EverolimusTemsirolimus

EGFR PDGFR VEGFR

Growth Factors

Targeted TherapiesTargeted Therapies1900 2000

Surgery

Chemotherapy

1950

Chemoembolization

Interferon / Octreotide

Targeted Rx

GefitinibSorafenibSunitinibVatalanib

PertuzumabBevacizumab