Advanced Pancreatic and GI Neuroendocrine Cancer Presenter Presented at: Thomas M. O’Dorisio, M.D. Professor of Medicine 5th Annual GI Cancer Symposium at Emory University Director, Carcinoid & Neuroendocrine Tumor Program November 8, 2014 Y Y = Somatostatin receptor subtype 2 Hypervascular In memory of Stephen Qualman, Pathology The Ohio State University Children’s Hospital 2008 Diffuse (Neuro)Endocrine System (DES) Diffuse (Neuro)Endocrine System (DES) Enrico Solcia Professor of Pathology University of Pavia, Pavia, Italy 2008 General WHO Neuroendocrine Tumor Categories *1. Well-differentiated endocrine tumor (+) chromogranin A, synatophysin, earlier term, “carcinoid” (Ki67 < 2%) *2. Well-differentiated endocrine carcinoma earlier term “atypical carcinoid” (Ki67 2-20%) *3. Poorly-differentiated endocrine (small cell) carcinoma scant CgA high mitotic index (Ki67 > 20%) 4. Mixed exocrine – endocrine tumor 5. Tumor-like lesions Solcia E, et al. Clin Endocrin. 2000;53:259. Well-differentiated Neuroendocrine Tumor “Salt and pepper chromatin” (carcinoid) Chromogranin + Well-Differentiated Endocrine Carcinoma, Ileum Tumor cells invading muscularis propria Serotonin tumor cell nests Solcia E, et al. Clin Endocrin. 2000;53:259. Ki67 • Is a antibody that recognizes an antigen Mr, 345 and 395 kDa Encoded by single gene (chromosome 10) Expression tightly associated with cell cycle Excellent indicator of tumor proliferation • MIBI is an monoclonal antibody raised against a Ki67 c DNA fragment and perpetuated in E. Coli • Ki67 is also a antibody, but recognizes a different epitope of the Ki-67 fragment than MIBI Cross SS. Histopathol. 1993;22:355-360. MIB1 Nuclear staining MIB1 (Ki-67) – a marker of increased proliferation A. Kaplan-Meier Curve Overall survival in 31 patients according to degree of differentiation: (A) Log Rank (p<0.001) and Ki67 score (B) Log Rank (p<0.001) B. Faggiano A, et al. J Endocrinol Invest. 2008;31:216-223. TTP = 3-5 yrs TTP = 17 mo TTP = 3-4 yrs TTP = 7 mo TTP = 4-5 yrs Pancreastatin Predicts Survival in Neuroendocrine Tumors Scott K. Sherman, MD, Jessica E. Maxwell, MD, MBA, M. Sue O’Dorisio, MD, PhD, Thomas M. O’Dorisio, MD, and James R. Howe, MD Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980. Overall Survival 5 yr. OS=79.9% 5 yr. OS=79.3% 10 yr. OS=57.4% Median not reached SEER 88 mos. 10 yr. OS=52.9% Median 126 mos. SEER 42 mos. Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980. Overall Survival-M1 Disease 5 yr. OS=75.8% 10 yr. OS=50.9% Median not reached SEER 56 mos. 5 yr. OS=71.0% 10 yr. OS=45.6% Median 90 mos. SEER 24 mos. Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980. Zollinger-Ellison I-131 Therapy Syndrome 1930 1955 Gastrin SecretinInsulin Purified 1902 1921 1961 Gastrin 1905 CCK 1925 VernerRIA Morrison 1960 1958 “Karzinoide” 1907 Endocrine Cell Radio-Peptide (Helle Zellen) Receptor (RPR) 1938 1967 Evolution of Neuroendocrine Medical Therapy Courtesy of Teresa Ruggle and Dawn Wray © University of Iowa GIP Zollinger-Ellison I-131 Therapy Syndrome 1971 1930 1955 Gastrin SecretinInsulin Purified 1902 1921 1961 Gastrin 1905 CCK 1925 VernerRIA Morrison 1960 1958 “Karzinoide” 1907 Endocrine Cell Radio-Peptide (Helle Zellen) Receptor (RPR) 1938 1967 Evolution of Neuroendocrine Medical Therapy Courtesy of Teresa Ruggle and Dawn Wray © University of Iowa GIP Zollinger-Ellison I-131 Therapy Syndrome 1971 1930 1955 Gastrin SecretinInsulin Purified 1902 1921 1961 Gastrin 1905 CCK 1925 VernerRIA Morrison 1960 1958 VIP “Karzinoide” 1972 1907 Endocrine Cell Radio-Peptide (Helle Zellen) Receptor (RPR) 1938 1967 Evolution of Neuroendocrine Medical Therapy Courtesy of Teresa Ruggle and Dawn Wray © University of Iowa GIP Zollinger-Ellison I-131 Therapy Syndrome 1971 1930 1955 Somatostatin Gastrin SecretinInsulin 1973 Purified 1902 1921 1961 Gastrin 1905 CCK 1925 VernerRIA Morrison 1960 1958 VIP “Karzinoide” 1972 1907 Endocrine Cell Radio-Peptide (Helle Zellen) Receptor (RPR) 1938 1967 Evolution of Neuroendocrine Medical Therapy Courtesy of Teresa Ruggle and Dawn Wray © University of Iowa GIP Zollinger-Ellison I-131 Therapy Syndrome 1971 1930 1955 Somatostatin Gastrin SecretinInsulin 1973 Purified 1902 1921 Octreotide 1961 1980 Gastrin 1905 CCK 1925 VernerRIA Morrison 1960 1958 VIP “Karzinoide” 1972 1907 Endocrine Cell Radio-Peptide (Helle Zellen) Receptor (RPR) 1938 1967 Evolution of Neuroendocrine Medical Therapy Courtesy of Teresa Ruggle and Dawn Wray © University of Iowa Somatostatin and its Congeners Ala-Gly-Cys-Lys-Asn-Phe- Phe s Trp s Lys Somatostatin Thr Cys-Ser-Thr-PheD Phe-Cys- Tyr DTrp s s Thr -Cys-OL D Nal-Cys- Modified Octreotide Courtesy of Dawn Wray s DTrp s Lys Thr Tyr Thr -Cys-NH2 Lys Val Lanreotide SST2 Receptor Staining Courtesy of Barry De Young, M.D. Sandostatin and Gastroenteropancreatic Endocrine Tumor – Therapeutic Characteristics M.J. Dunne, R. Elton, T. Fletcher, P. Hofkur, J. Shui Chapter 14; pp. 93-117. Im: Sandostatin in the Treatment of GEP Endocrine Tumors (ed: T.M. O’Dorisio) pp. 1-146, 1987. SPRINGER VERLAG (Berlin, Heidelberg, N.Y.) Duane MJ, et al. Springer. Berlin, Heidelberg. 1989:93-113. OCTREOTIDE Registration for Europe (1988) and U.S. (1989) was determined from a TOTAL of 173 subjects submitted by 38 investigators (from Europe) and 40 investigators (from U.S.) TUMOR U.S. Europe TOTAL Carcinoid VIPoma Glucagonoma Gastrinoma Insulinoma GRF-oma PP-oma 47 12 9 14 3 4 2 38 13 7 12 12 - 85 25 16 26 15 4 2_ 173 Duane MJ, et al. Springer. Berlin, Heidelberg. 1989:93-113. Carcinoid Syndrome Response to Octreotide (n = 73) Dunne R, et al. FDA Registration, 1989. Carcinoid Response to Octreotide (n = 74) Dunne R, et al. FDA Registration, 1989. First VIPoma Patient (H.T.) Treated in U.S. Maton PN, et al. N Engl J Med. 1985;312(1):17-21. First VIPoma Patient (H.T.) Treated in U.S. Maton PN, et al. N Engl J Med. 1985;312(1):17-21. Placebo-Controlled, Double-blind, Prospective, Randomized study on the effect of Octreotide – LAR in the control in patients with metastatic neuroendocrine mid-gut tumors: A Report from the PROMID Study Group  85 patients (well-differentiated midguts);ki-67 < 2%  Placebo versus Sandostatin-LAR 30 mg monthly  Median time to tumor progression (TTP) 6 months = placebo 14.3 mo Octreotide-LAR (29.4 mo; Liver < 10%) (Non-Crossover) Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors (CLARINET Study Group)  107 Patients (well-differentiated midgut & hindgut) ki-67<10%  Placebo versus Lanreotide Depot 120mg monthly  Median time to progressive (TTP) 18 months = Placebo LAN-DEP median not reached (Cross-over Study) Caplin ME, et at. N Engl J Med. 2014;371(3):224-233. Anti-Angiogenics for N/E Tumors (FDA Approved) Pancreatic (FDA approved) Everolimus (Afinitor) mTOR inhibitor Sunitinib (Sutent) TKI* Medullary Thyroid Cancer Vandetanib (ZD 6474) TKI* Cabozantinib (XL 184) TKI* * TKI – Tyrosine Kinase Inhibitor Courtesy of Nancy Sharma, MD Everolimus for Advanced Pancreatic Neuroendocrine Tumors J.C. Yao, M. Shah, T. Ito… K. Oberg (NEJM 2011; 364:514-522)    410 patients; Grade 1 or 2; RECIST 1.1 progression Placebo versus 10mg daily Everolimus & Octreotide Median progression-free survival (PFS): 4-6 month = placebo 11 month = Everolimus (Cross-Over Study) Yao JC, et al. N Engl J Med. 2011;364(6):514-522. Sunitinib Malate For the Treatment of Pancreatic Neuroendocrine Tumors  171 Patients; Grade 1 or 2; RECIST 1.1 Progression  Placebo versus 37.5 mg daily Sunitinib & Octreotide  Median progression-free survival (PFS): 5.5 month = placebo (Non-cross over study) Raymond E, et al. N Engl J Med. 2011;364(6):501-513. 11.4 month = Sunitinib Theranostics “Molecular targeting of VECTORS which can be used for both therapies and diagnosis, when modified accordingly… (it) embodies both molecular and personalized medicine.” Rösch F, et al. Dalton Trans. 2011;40(23):6104-6111. DOTA-DPhe1-Tyr3-Octreotide (DOTA-TOC) Theranostic Application D Isotope-DOTA- Phe-Cys- Tyr s DTrp s Lys Thr-OL-Cys- Thr (SMS 204-090) Isotope (Radiometal): • Ga68-DOTA-TOC-PET: sensitive; quantifiable • Y90-DOTA-TOC: hard beta; 7-9 mm range “kill” • Lu177-DOTA-TOC: soft beta; 3-5 mm range “kill” Current Targeting Paradigm One Receptor – One Ligand Target Somatostatin Receptor Subtype 2 Vector (TOC) Modified Somatostatin  High receptor expression  Native peptide sequence known  High affinity/specificity/avidity for target  Synthetically feasible (<50 residues) Concept & design by M Schultz Linker (DOTA) Ga-68 GA-68 DOTATOC Imaging at the University of Iowa Y Menda, M Schultz, L Watkins, D Bushnell, T O’Dorisio, M Graham, L Ponto, J Sunderland, M Sue O’Dorisio FDA IND held by M. Sue O’Dorisio and Yusuf Menda Subject 1 Menda Y, et al. Ga-68 DOTATOC Subject 2 In-111 Octreotide Menda Y, et al. Ga-68 DOTATOC Subject 3 MIP In-111 Octreotide Menda Y, et al. Ga-68 DOTATOC Subject 4 MIP In-111 Octreotide Menda Y, et al. Ga-68 DOTATOC Subject 5 In-111 Octreotide Menda Y, et al. Ga-68 DOTATOC Outcome of Peptide Receptor Radionuclide Therapy (PRRT) in Patients with Metastatic Low Grade Neuroendocrine Tumors Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract. Methods • 108 Metastatic Neuroendocrine tumors: Small Bowel (Mid Gut, 44%) Pancreas (PNET 28%) Lung (Foregut 5%) • Peptide Receptor Radio-Nuclide Therapy (PRRNT), 72% Basel, 26% Iowa • 86% y90-DOTA-TOC and 13% Lu177 DOTATOC • ALL followed up for 10 years in NETC Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract. OS from Diagnosis (years) OS from PRRT #1 (months) TTP from PRRT #1 (months) All sites 9.9 40.6 39.6 SNETs 13.7 96.7 60.3 PNETs 5.7 39.4 63.1 Lung 2.7 22.7 4.5 Unknown Primary 4.1 20.7 24.1 Other 7.2 52.0 26.6 P<0.0001 P=0.1 P<0.0001 Site OS: Median overall survival Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract. TP: Median Time to Progression Conclusion “PRRNT appears to be a valuable treatment option for mNETs, especially SBNETs, and its role earlier in the disease course warrants investigation” Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract. Neuroendocrine Tumor Faculty Thomas M O’Dorisio, MD, Director James R Howe, MD, co-Director Nuclear Medicine David Bushnell, MD Yusuf Menda, MD Michael Schultz, PhD Michael Graham, MD Internal Medicine Daniel Berg, MD Joseph Dillon, MD Henning Gerke, MD Daniel Vaena, MD Interventional Radioology Schilang Sun, MD Surgery Mark Iannatoni, MD Joel Shilyansky, MD Pediatrics M Sue O’Dorisio, MD, PhD