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Learning Objectives

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

JasminFlorian
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Learning Objectives

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  1. 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 NET = neuroendocrine tumor

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

  3. Incidence of NETs Increasing 6.00 600 All malignant neoplasms 5.00 500 4.00 400 Incidence per 100,000 – All malignant neoplasms Incidence per 100,000 - NETs 3.00 300 2.00 200 1.00 100 Neuroendocrine tumors 0.00 0 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1973 1974 1975 1976 1977 1978 1979 1980 1981 1999 2000 2001 2002 2003 2004 Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

  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 0 Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary 29-year limited duration prevalence analysis based on SEER. Yao JC et al. J ClinOncol. 2008;26:3063-3072. SEER = Surveillance, Epidemiology, and End Results

  5. Autopsy Studies • Carcinoid1,2 • 2 studies • > 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.

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

  7. Missed Symptoms and Late Diagnosis • Flushing • No sweating • First sip of alcohol • Diarrhea • Especially nocturnal • Wheezing • Irritable bowel syndrome • Bloating Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

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

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

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

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

  12. 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

  13. Other Markers in Functional Tumors Fasting measurements when possible

  14. 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

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

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

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

  18. Need for Tumor Control Agents Remains High SurvivalPatients with distant NET (1988-2004) Limited Options Carcinoid Pancreatic NET • Median survival • Carcinoid 43 months • pNET 27 months • Carcinoid • No approved drugs for tumor control • pNET • Streptozocin approved but perceived to be toxic • No agreed-upon standard treatment for tumor control Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

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

  20. 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 PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

  21. 1 Octreotide LAR (n = 42) Median 14.3 months Placebo: (n = 43) Median 6.0 months 0.75 Proportion without progression 0.5 0.25 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (months) 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] 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.

  22. 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

  23. Peptide Receptor Radiotherapy (PRRT) 111In pentetreotide • Systemic radiotherapy targeting somatostatin receptors • Compounds vary by isotope and carrier molecule • 177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies DTPA-CO-NH-D-Phe-Cys Phe 111In S D-Trp S Lys Thr(ol)-Cys Thr 90Y DOTATOC DOTA-CO-NH-D-Phe-Cys Tyr 90Y S D-Trp S Lys Thr(ol)-Cys Thr 177Lu DOTATATE DOTA-CO-NH-D-Phe-Cys Tyr 177Lu S D-Trp S Lys Thr Thr-Cys 177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraaceticacid0 (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.

  24. 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 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.

  25. 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 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.

  26. 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 PD = progressive disease Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

  27. NET: Bevacizumab fCT Baseline Day 2 after bevacizumab Imaging studies property of James Yao, MD.

  28. Stable dose of octreotide x 2 months Protocol starts here Random assignment 18 wks Bevacizumab (+ octreotide) PEG interferon α-2b (+ octreotide) Bevacizumab + PEG interferon α-2b (+ octreotide) Bevacizumab: Randomized Phase 2 Trial ITT by assignment • 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 PR = partial response; SD = stable disease Yao JC et al. J Clin Oncol. 2008;26:1316-1323.

  29. Sunitinib: Phase 2 Open-Label Study Kulke MH et al. J Clin Oncol. 2008;26:3403-3410.

  30. Poor prognosis (N = 283) Carcinoid: SWOG 0518 Phase 3 Study Octreotide + interferon R Supported by CTSU Endorsed by ECOG, CALGB, NCCTG 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. Islet cell w/PD over prior 12 months (340 planned, 171 accrued) R Sunitinib Phase 3 pNET Study Stopped early at unplanned time point March 12, 2009 Sunitinib 37.5 mg continuous dosing Placebo 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.

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

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

  34. MDACC: Everolimus + Octreotide LARResponse ITT RR: 20% MDACC = M. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318.

  35. 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) RADIANT-1: Study Design • Primary endpoint • RR stratum 1 • Secondary endpoints • RR stratum 2 • Response duration • Safety • PFS • Survival • PK Stratum 1 n = 115 Everolimus SCREEN Everolimus + octreotide LAR Stratum 2n = 45 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.

  36. RADIANT-1: Best Change from BaselineCentral Radiology Review Stratum 1: Everolimus (n = 115) Stratum 2: Everolimus + Octreotide LAR (n = 45) Yao JC et al. J Clin Oncol. 2010;28:69-76.

  37. RADIANT-1 PFS by Central Review Everolimus Everolimus + octreotide LAR 100 100 n = 115 80 n = 45 80 60 60 Probability (%) Probability (%) 40 40 20 20 Median PFS = 16.7 mo Median PFS = 9.7 mo 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, mo Time, mo Patientsat risk Patientsat risk 115 111 81 58 54 36 25 15 12 5 3 3 1 0 45 39 32 22 21 19 14 10 8 3 3 1 0 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 Best supportive care + everolimus* Advanced pNET in progression (N = 410) R Best supportive care + placebo* *Octreotide LAR included as best supportive care.

  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

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