New Treatments for Neuroendocrine Cancers George Fisher, MD, PhD - - PDF document

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New Treatments for Neuroendocrine Cancers George Fisher, MD, PhD - - PDF document

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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

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1 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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3 Stanford Cancer Center 3 Stanford Cancer Center 3 Stanford Cancer Center

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

Octreotide Approved

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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-differentiated 2-20 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 PET

111In-octreotide

Octreoscan

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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.1

References: 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: Octreotide

PROMID STUDY IN MIDGUT CARCINOID

 Primary Endpoint

Time to Progression

 Secondary Endpoints

Overall Survival Response Rates Arnold, GI ASCO 2009, abstract #121.

85 patients with well-differentiated metastatic midgut NETs R A N D O M I Z E Octreotide LAR 30 mg IM q4wks N=42 Placebo IM q4wks N=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: Lanreotide

CLARINET 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 mg 32 events / 101 patients median, not reached Placebo 60 events / 103 patients median, 18.0 months [95% CI: 12.1, 24.0] Lanreotide Autogel vs. placebo p=0.0002 HR=0.47 [95% CI: 0.30, 0.73] 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) 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 Progressive n (%) 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-DOTA Phase 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 VEGF Production Reduced Cell Growth Reduced Proliferation

Nutrients Amino 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 RAD001 mTOR PI3-K Akt/ PKB Energy LKB1 AMPK S6

P

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 NETs n=410

R

Everolimus 10 mg qd N=207 Placebo N=203 Median PFS Everolimus11.0 mo Placebo 4.6 mo P<0.001

FDA approved for Pancreatic NET

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Targeting mTOR in non-pancreatic NETs: Ph III Everolimus (RADIANT 2)

  • Pavel. Lancet,

2011

Advanced carcinoid n=429

R

Everolimus 10 mg

+ Octreotide LAR

N=216 Placebo +

Octreotide LAR

N=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

R

Best 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

Angiogenic Factors

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 P P PLC 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 P P PLC 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 P P PLC 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 P P PLC 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 P P PLC VEGF-C VEGF-D

Sunitinib Sorafenib Pazopanib Axitinib, 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 Scans

Yao 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

R A N D O M I Z E

*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 Sunitinib, n 74 32 14 2 Survival probability 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 5 10 15 20

Raymond E, et al. N Engl J Med. 2011

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Carcinoid Trials targeting angiogenesis

Advanced, progressive carcinoids

R

Interferon + Octreotide LAR Bevacizumab + Octreotide LAR SWOG Trial (Yao PI)

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Carcinoid Trials targeting angiogenesis

Advanced, progressive carcinoids

R

Interferon + 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 NETs

R

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-FU

  • vs. STZ/Dox

105

PNET

45% 69% Moertal et al NEJM ‘92

***STZ/5-FU/Dox

84

PNET

39% Kouvaraki et al JCO ‘04

STZ/Dox

  • vs. Dox/5-FU

176

carcinoid

16% 16% Sun et al JCO ‘05

STZ/5-FU

  • vs. Interferon

64

carcinoid

3% 9% Dahan et al Endocr 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

  • r 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

N Tumor Type Response Rate Reference TMZ 36 PNET Carcinoid 8% **30% Ekeblad et al Clin Cancer Res ’07 TMZ + Thalidomide 29 PNET Carcinoid 45% 7% Kulke et al JCO ‘06 TMZ+Bev 34 PNET Carcinoid 24% 0% Kulke, et al Clin Cancer Res ‘09 TMZ + Capecitabine 33 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

R

Temozolomide / 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