Recognition, Diagnosis, and Management of Neuroendocrine Tumors James C. Yao, MD Associate Professor and Deputy Chair, Gastrointestinal Medical Oncology University of Texas M. D. Anderson Cancer Center

Learning Objectives After completing this activity, participants should be able to: Outline patient signs and symptoms that should lead to an evaluation for NETs Describe the diagnostic work-up that can confirm a suspected diagnosis of NET Review current treatment approaches for NETs and expected patient outcomes Analyze recent clinical trial data demonstrating improved outcomes beyond symptom control in patients with advanced NETs Bullet 2:  ... confirm a suspected diagnosis of NET (delete s)? NET = neuroendocrine tumor

NETs: A Not-So-Rare Disease Epidemiology Signs and symptoms of NETs

Incidence of NETs Increasing 6.00 600 All malignant neoplasms 5.00 500 4.00 400 Incidence per 100,000 - NETs 3.00 Incidence per 100,000 – All malignant neoplasms 300 2.00 200 TO PURCHASE – USE AS IS 1.00 100 Neuroendocrine tumors 0.00 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Yao JC et al. J Clin Oncol. 2008;26:3063-3072. 4 4

NETs Are Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the US, 2004 1200 Median survival (1988 – 2004) Localized 203 months Regional 114 months Distant 39 months 103,312 cases (35/100,000) 1100 Cases (thousands) 100 RE-CREATE AS IS Note: the break in the colon cancer bar is correct, as it indicates a change in the scale used in the Y axis (because colon cancer is more common than the others by an order of magnitude Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary 29-year limited duration prevalence analysis based on SEER. Yao JC et al. J Clin Oncol. 2008;26:3063-3072. SEER = Surveillance, Epidemiology, and End Results 5 5 5

Autopsy Studies Carcinoid1,2 Islet cell3 2 studies 0.7% to 1.2% > 15,000 cases each 0.7% to 1.2% Islet cell3 > 11,000 cases from Hong Kong 0.1% 1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:322-330. 2. Moertel CG et al. Cancer. 1961;14:291-293. 3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.

NETs Are Often Diagnosed Late Vague abdominal symptoms Death Diarrhea Flushing Metastases RE-CREATE AS IS Primary tumor Time Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

Missed Symptoms and Late Diagnosis Flushing No sweating First sip of alcohol Diarrhea Especially nocturnal Wheezing Irritable bowel syndrome Bloating Keep as is 50% + 24% + 27% = 101% OK? [copyeditor note] Yes—these numbers are rounded from the original publication; keep as is.[SD note] Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

Diagnosis and Initial Work-Up Pathologic confirmation Assess disease burden Assess functional status

Anatomic Imaging: CT Std Arterial Venous Delayed Imaging studies property of James Yao, MD. CT: computed tomography.

Anatomic Imaging: MRI MRI = magnetic resonance imaging Imaging studies property of James Yao, MD.

Anatomic CT and Indium-111 Pentetreotide Scintigraphy Imaging studies property of James Yao, MD.

Tumor Markers General NET markers Chromogranin A Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function Neuron-specific enolase Midgut (small bowel, appendix, cecum) 5 HIAA (24-hr urine collection) Serotonin (blood, more variable) 5-HIAA = 5-hydroxyindoleacetic acid

Other Markers in Functional Tumors Fasting measurements when possible Gastrinoma Gastrin Glucagonoma Glucagon Insulinoma Insulin Pro-insulin C-peptide VIPoma Vasoactive intestinal peptide

Principles of Marker Assessment Lots of markers; expression can change over time Chromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, pancreatic polypeptide Take large panel of markers at key points Diagnosis or relapse Follow a few elevated markers over time Not necessary to check every marker at each visit

Current Treatment Approaches Somatostatin analogs Chemotherapy for pancreatic NETs Regional therapy approaches

Limited Options for Advanced NETs Functional Octreotide LAR + chemotherapy pNET Hepatic artery embolization Investigational agents (No approved therapies available) Nonfunctional Chemotherapy Carcinoid syndrome Octreotide LAR Disease progression Midgut No syndrome Carcinoid No standard RE-CREATE as is Non-midgut No syndrome No standard LAR = long-acting release; pNET = pancreatic NET

pNET: Streptozocin-Based Chemotherapy Imaging studies property of James Yao, MD.

Need for Tumor Control Agents Remains High Survival Patients with distant NET (1988-2004) Limited Options Carcinoid No approved drugs for tumor control pNET Streptozocin approved but perceived to be toxic No agreed-upon standard treatment for tumor control Carcinoid Pancreatic NET IMAGE ON THE LEFT – USE AS IS, NO PURCHASE Median survival Carcinoid 43 months pNET 27 months Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

Emerging Therapeutic Approaches Somatostatin receptor Peptide receptor radiotherapy Angiogenesis mTOR mTOR = mammalian target of rapamycin

Targeting NETs Somatostatin receptors highly expressed by NETs Targeting SST receptors can provide symptom and disease control New targets could change treatment paradigm : mTOR, PI3K, VEGF inhibitors Other antiangiogenic agents High potential for combinations Use image as is PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

PROMID: Octreotide LAR Slows Progression in Midgut NETs TTP in Midgut NET Octreotide LAR vs placebo P = .000072 HR = 0.34 [95% CI: 0.20–0.59] Octreotide LAR (n = 42) Median 14.3 months Placebo: (n = 43) Median 6.0 months Time (months) Proportion without progression 0.25 0.5 0.75 1 6 12 18 24 30 36 42 48 54 60 66 72 78 TO PURCHASE – USE AS IS Is the capitalization of the expanded form of PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors standard? (i.e. Capping Placebo, Octreotide, Randomized, MIDgut). [copyeditor note] Yes—the capitalized letters are those that spell out the acronym (in addition to LAR, which is always capped.) [SD note] Based on conservative ITT analysis HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP = time to progression Rinke A et al. J Clin Oncol. 2009;27:4656-4663.

Potential Management of Advanced NETs Post-PROMID Functional Octreotide LAR + chemotherapy pNET Nonfunctional Chemotherapy Investigational agents (No approved therapies available) Carcinoid syndrome Octreotide LAR Disease progression Midgut No syndrome Consider octreotide LAR Carcinoid No Standard Non-midgut No syndrome No standard

Peptide Receptor Radiotherapy (PRRT) 111In pentetreotide DTPA-CO-NH-D-Phe-Cys S Thr(ol)-Cys Phe D-Trp Lys Thr 111In DOTA-CO-NH-D-Phe-Cys Tyr 90Y DOTATOC 90Y 177Lu DOTATATE Thr-Cys 177Lu Systemic radiotherapy targeting somatostatin receptors Compounds vary by isotope and carrier molecule 177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies Insert semicolon after 2001 in reference 2. [done – SD] 177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.

90Y-DOTATOC, 90Y-Edotreotide Multiple studies Various doses: 6 GBq/m2, 7.4 GBq/m2, 13.3 GBq/m2 Various schedules of 3-4 treatments RRs from smaller studies: 23%1 & 24%2 RR from larger study (N = 90): 4.4%3 Semicolons are missing after 2001 and 2010 in references, and there’s an extra space after 43: in the first reference. [done – SD] Waldherr C et al. J Nucl Med. 2002;43:610-616. Waldherr C et al. Ann Oncol. 2001;12:941-944. Bushnell DL et al. J Clin Oncol. 2010;28:1652-1659.

177Lu DOTATATE Phase 2 Study N = 504 27.8-29.6 GBq in 4 cycles Efficacy in 310 pts, NOT ITT RR: 30% Median TTP: 40 months Does intent-to-treat need hyphens? [Yes – per SD] Add colon after TTP in the last bullet point? [done –SD] Missing graphics? [? Not sure what this means –SD] ITT = intent-to-treat; RR = response rate; TTP = time to progression Imaging studies property of James Yao, MD. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

177Lu DOTATATE: What Does It Mean? If ITT principle applied to response: 91 responses among 504 patients RR drops to 18% High reported TTP calculated only for 249 who did not have PD as best treatment outcome PRRT clearly active; strong need for rigorous phase 3 study If ITT principle is applied to response (add ‘is’) ? High reported TTP calculated only for the 249... (add ‘the’)? [note from SD: these changes not implemented b/c language is unambiguous as shown – this standard style is used to keep slide text brief] PD = progressive disease Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

NET: Bevacizumab fCT Baseline Day 2 after bevacizumab Move ‘MD’ up to same line as ‘Yao’ Imaging studies property of James Yao, MD. 28

Bevacizumab: Randomized Phase 2 Trial Stable dose of octreotide x 2 months Random assignment Bevacizumab + PEG interferon α-2b (+ octreotide) Protocol starts here Bevacizumab PEG interferon α-2b 18 wks ITT by assignment Bevacizumab (n = 22) PEG interferon PR (confirmed) 4 SD 17 16 PD 1 6 P = .019 (2-sided exact) Additional responses: 1 pt with PD on PEG interferon had PR after addition of bevacizumab 1 pt with SD on PEG interferon had PR after addition of bevacizumab delete space after 2008; PR = partial response; SD = stable disease Yao JC et al. J Clin Oncol. 2008;26:1316-1323. 29

Sunitinib: Phase 2 Open-Label Study Carcinoid, n (%) (n = 41) Islet cell, n (%) (n = 66) All pts, n (%) (N = 107) PR (confirmed) 1 (2) 11 (17) 12 (11) SD 34 (83) 45 (68) 78 (73) PD 5 (8) 6 (6) Not evaluable 5 (12) 10 (9) Kulke MH et al. J Clin Oncol. 2008;26:3403-3410.

Carcinoid: SWOG 0518 Phase 3 Study Octreotide + interferon Poor prognosis (N = 283) R Supported by CTSU Endorsed by ECOG, CALGB, NCCTG Added study # to title Octreotide + bevacizumab CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group 31

Sunitinib Phase 3 pNET Study Stopped early at unplanned time point March 12, 2009 Sunitinib 37.5 mg continuous dosing R Islet cell w/PD over prior 12 months (340 planned, 171 accrued) Placebo Clarified PFS rates and added reference. I’ve changed the word timepoint in the uber document; if those edits are accepted then the word should also be changed here. [SD note: made this change] Investigator-reported PFS: 11.4 mo with sunitinib vs 5.5 mo with placebo PFS = progression-free survival Raymond E et al. ASCO GI 2010; Abstract 127.

mTOR Signaling Pathways Receptor Tyrosine Kinase Nutrients & Metabolites RAS IRS-1 Grb SOS Protein Synthesis Cyclin D, p27 Glut 1 VEGF, PDGF-β P HIF-1α P P PI3K AKT TSC1/2 Rheb Everolimus mTORC1 Use as is Why ‘Receptor’ in bold? p70S6K 4EBP1 eIF4E Metabolism Angiogenesis Growth & Proliferation

Subependymal giant-cell astrocytoma Islet cell carcinoma Angiomyolipomas Imaging studies property of James Yao, MD.

MDACC: Everolimus + Octreotide LAR Response Per protocol Overall N = 60 Carcinoid n = 30 Islet cell n = 30 PR 13 (22%) 5 (17%) 8 (27%) SD 42 (70%) 24 (80%) 18 (60%) PD 5 (8%) 1 (3%) 4 (13%) PFS (median) 60 wks 63 wks 50 wks ITT RR: 20% MDACC = M. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318. 35

RADIANT-1: Study Design Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy Stratum 1: No octreotide LAR 60d before enrollment Received everolimus 10 mg/d Stratum 2: Octreotide LAR ≥ 3mo before enrollment Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d) Stratum 1 n = 115 SCREEN Stratum 2 n = 45 Everolimus + octreotide LAR Everolimus Primary endpoint RR stratum 1 Secondary endpoints RR stratum 2 Response duration Safety PFS Survival PK Why capping of all words in expanded form of RECIST? [SD note: Because those words spell out the acronym « RECIST »] Lowercase ‘e’ in ‘Primary endpoint’ and ‘Secondary endpoints’? Little horizontal line to the right of word ‘SCREEN’ overlaps vertical line slightly Treatment until progression; CT or MRI at baseline & q3mo PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors Yao JC et al. J Clin Oncol. 2010;28:69-76.

RADIANT-1: Best Change from Baseline Central Radiology Review Stratum 1: Everolimus (n = 115) Central radiology ITT, n (%) PR 11 (9.6) SD 78 (67.8) Clinical benefit (PR + SD) 89 (77.4) PD 16 (13.9) Unknown 10 (8.7) Stratum 2: Everolimus + Octreotide LAR (n = 45) Lowercase ‘f’ in ‘From’ in the title of this slide Central radiology ITT, n (%) PR 2 (4.4) SD 36 (80.0) Clinical benefit (PR + SD) 38 (84.4) PD 0 (0.0) Unknown 7 (15.6) Yao JC et al. J Clin Oncol. 2010;28:69-76.

RADIANT-1 PFS by Central Review Everolimus Everolimus + octreotide LAR 100 100 80 n = 115 80 n = 45 60 Probability (%) Probability (%) 60 40 40 20 20 Median PFS = 16.7 mo Median PFS = 9.7 mo TO PURCHASE BOTH IMAGES – USE AS IS 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, mo Time, mo Patients at risk Patients at risk 115 111 81 58 54 36 25 15 12 5 3 3 1 45 39 32 22 21 19 14 10 8 3 3 1 Yao JC et al. J Clin Oncol. 2010;28:69-76. 38

Pivotal Phase 3 Trials with Everolimus in NETs Accrual completed Octreotide LAR + Everolimus Advanced carcinoid with syndrome in progression (N = 429) R Octreotide LAR + placebo Accrual completed Lowercase w in with in title of slide What does the superscript 1 in placebo refer to? Is a footnote to this slide missing? Best supportive care + everolimus* Advanced pNET in progression (N = 410) R Best supportive care + placebo* *Octreotide LAR included as best supportive care. 39 39

Conclusions NETs not that rare Progress being made Somatostatin analogs effective in controlling hormonal syndrome PROMID suggests octreotide LAR controls tumor growth in midgut carcinoids Phase 2: VEGF and mTOR inhibitors have single-agent activity in NETs Confirmatory phase 3 studies ongoing