1. Optimal Sequence of Therapies for Advanced GI Neuroendocrine Tumors (NET) Tim Hobday M.D. Mayo Clinic Rochester, MN Tim Hobday M.D. Mayo Clinic Rochester, MN

3. Disclosure Research funding: Novartis

4. Off-label therapy discussed Octreotide for PNET Temozolomide and capecitabine for PNET Targeted therapy for carcinoid tumors Combined targeted therapies for PNET Octreotide for PNET Temozolomide and capecitabine for PNET Targeted therapy for carcinoid tumors Combined targeted therapies for PNET

5. What is the Scenario? Grade 1-2 NET with dominant hepatic metastases Progressive tumor Symptoms, or impending symptoms, of tumor bulk and/or endocrine syndrome despite Octreotide Not a candidate for hepatic resection Grade 1-2 NET with dominant hepatic metastases Progressive tumor Symptoms, or impending symptoms, of tumor bulk and/or endocrine syndrome despite Octreotide Not a candidate for hepatic resection

7. Rationale for Liver-Targeted Therapy “Selective” hepatic arterial blood supply to metastases “Concentrate” chemotherapy “Selective” internal radiotherapy “Less toxic, more effective” than systemic therapy Indolent disease: embolic therapies may take 3-5 months to complete “Selective” hepatic arterial blood supply to metastases “Concentrate” chemotherapy “Selective” internal radiotherapy “Less toxic, more effective” than systemic therapy Indolent disease: embolic therapies may take 3-5 months to complete

10. HEPATIC RESECTIONS Surgical control of sx 104/108 Recurrence of sx in 5 yrs 59 % (median 45.5 mos) Overall survival 5 yrs 61 % 10 yrs 35 % (median 81 months) Operative mortality 1% Sarmiento et al, J Amer Coll Surg 2003;197:29-37 Surgical control of sx 104/108 Recurrence of sx in 5 yrs 59 % (median 45.5 mos) Overall survival 5 yrs 61 % 10 yrs 35 % (median 81 months) Operative mortality 1% Sarmiento et al, J Amer Coll Surg 2003;197:29-37

11. Optimal Sequence of Therapies for GI NET Systemic therapy, followed by regional (liver-directed) therapy

12. Optimal Sequence of Therapies for GI NET Systemic therapy, followed by regional (liver-directed) therapy UNLESS… Systemic therapy, followed by regional (liver-directed) therapy UNLESS…

13. Progressive Carcinoid Syndrome on 40 mg octreotide LAR

14. GI NET not 1 disease “What is the best chemotherapy for esophagogastricpancreaticobiliarys mallintestinalcolorectal cancer”?

15. GI NET not 1 disease “What is the best chemotherapy for esophagogastricpancreaticobiliarys mallintestinalcolorectal cancer”? FOLFOX “What is the best chemotherapy for esophagogastricpancreaticobiliarys mallintestinalcolorectal cancer”? FOLFOX

16. GI NET not 1 disease Midgut Carcinoid Low grade (ki-67 1-2%) Indolent Syndrome is bothersome Rarely extrahepatic disease of significance Risk of carcinoid heart disease Systemic therapies do not cytoreduce Midgut Carcinoid Low grade (ki-67 1-2%) Indolent Syndrome is bothersome Rarely extrahepatic disease of significance Risk of carcinoid heart disease Systemic therapies do not cytoreduce

17. Systemic therapy for midgut carcinoid: Interferon Reports of tumor stabilization, hormonal suppression in octreotide naïve and pre-treated patients. Randomized trial (n = 83): Lanreotide vs interferon vs combination. No difference in response, PFS, symptom control Toxic Reports of tumor stabilization, hormonal suppression in octreotide naïve and pre-treated patients. Randomized trial (n = 83): Lanreotide vs interferon vs combination. No difference in response, PFS, symptom control Toxic Faiss et al, J Clin Oncol, 2003.

18. Chemotherapy for midgut carcinoid Minimal effect in carcinoid, PR = 15%, PFS 5 months with 5-FU/streptozocin or 5-FU/doxorubicin in Phase III. More recent studies that report separately on this group, PR 0-10%. Minimal effect in carcinoid, PR = 15%, PFS 5 months with 5-FU/streptozocin or 5-FU/doxorubicin in Phase III. More recent studies that report separately on this group, PR 0-10%. Sun et al, J Clin Oncol, 2005. Pavel et al Sem oncol 2013

19. Targeted therapy for midgut carcinoid No approved agents Everolimus vs placebo improved PFS (16.4 vs 11.3 m (p 0.026), response rate < 10%. Bevacizumab vs IFN in Phase III Pazopanib vs placebo: Alliance Lu-177-octreotate (PRRT) in phase III vs 60 mg octreotide LAR No approved agents Everolimus vs placebo improved PFS (16.4 vs 11.3 m (p 0.026), response rate < 10%. Bevacizumab vs IFN in Phase III Pazopanib vs placebo: Alliance Lu-177-octreotate (PRRT) in phase III vs 60 mg octreotide LAR Pavel et al, Lancet 2011

20. Results for HA(C)E and Radioembolization No clear advantage for either bland or chemo-embolization 50-90% with symptomatic response 3-12 months duration in most series? Toxicity Need for 2-3 procedures No clear advantage for either bland or chemo-embolization 50-90% with symptomatic response 3-12 months duration in most series? Toxicity Need for 2-3 procedures Wang et al Sem oncol 2013

21. Results for HA(C)E and Radioembolization Y-90 spheres frequently used, little good data. 40 patients, 99 procedures 10% grade 3-4 liver toxicity Responses per lesion, not patient Med OS < 3 years Conclusion: treat when healthy, low burden, normal LFTs Y-90 spheres frequently used, little good data. 40 patients, 99 procedures 10% grade 3-4 liver toxicity Responses per lesion, not patient Med OS < 3 years Conclusion: treat when healthy, low burden, normal LFTs Memon et al Int J Rad Onc 2011

22. Moertel Article: HAE alone vs HAE followed by chemotherapy Non-randomized, but prospective N = 111 Median time to progression PNET: 4 vs 22 months Carcinoid 10 vs 23 months Conclusion: Need chemo after HAE for PNET Non-randomized, but prospective N = 111 Median time to progression PNET: 4 vs 22 months Carcinoid 10 vs 23 months Conclusion: Need chemo after HAE for PNET Moertel et al Ann Int Med 1994

23. Progressive Carcinoid Syndrome on 40 mg octreotide LAR: BLAND HAE

24. Other NET Subsets Pancreatic (PNET) Often clinically non-functional Endocrine syndromes less responsive to octreotide Ki-67: Usually 5-30% Less Indolent than Midgut carcinoid Responsive to systemic therapies Pancreatic (PNET) Often clinically non-functional Endocrine syndromes less responsive to octreotide Ki-67: Usually 5-30% Less Indolent than Midgut carcinoid Responsive to systemic therapies

25. Other NET Subsets Gastric (type III), bronchial, hindgut, unknown primary “carcinoids” Atypical or no endocrine syndromes Use pathology, clinical behavior to asses…usually behave more like PNET when metastatic Gastric (type III), bronchial, hindgut, unknown primary “carcinoids” Atypical or no endocrine syndromes Use pathology, clinical behavior to asses…usually behave more like PNET when metastatic

26. Chemotherapy Active in PNET Streptozocin/Doxorubicin 69% “response”, OS advantage Temozolomide/Capecitabine 70% PR (retrospective) FOLFOX/CapeOx: PR 30-50% PFS approximately 18 months Streptozocin/Doxorubicin 69% “response”, OS advantage Temozolomide/Capecitabine 70% PR (retrospective) FOLFOX/CapeOx: PR 30-50% PFS approximately 18 months Moertel et al NEJM 1992. Strosberg et al Cancer 2011 Kulke Sem Ocol 2013

27. Case 1 63 yo woman with 3 months abdominal pain, 15 lb weight loss, fatigue, early satiety, ulceration CT: Mass tail of pancreas, multiple liver mets. Biopsy: Moderately differentiated NET; ki-67 30%. Gastrin > 20,000 Capecitabine/temozolomide 63 yo woman with 3 months abdominal pain, 15 lb weight loss, fatigue, early satiety, ulceration CT: Mass tail of pancreas, multiple liver mets. Biopsy: Moderately differentiated NET; ki-67 30%. Gastrin > 20,000 Capecitabine/temozolomide

28. Chemotherapy 3/2011 12/2011

29. Case 1 May 2012: resection liver mets path CR! September 2013: Regrowth of liver met at site of previous mass; resected. 3/2014: NED May 2012: resection liver mets path CR! September 2013: Regrowth of liver met at site of previous mass; resected. 3/2014: NED

30. Role of Targeted Therapy in PNET Everolimus and Sunitinib both improve PFS from 5 months to 11 months. PR < 10%. Combined mTOR/VEGF inhibition promising Temsirolimus and bevacizumab: PR 41%, PFS 13 months in phase II trial (n=56) Everolimus and Sunitinib both improve PFS from 5 months to 11 months. PR < 10%. Combined mTOR/VEGF inhibition promising Temsirolimus and bevacizumab: PR 41%, PFS 13 months in phase II trial (n=56) Raymond et al NEJM 2010. Yao et al NEJM 2010. Hobday et al ASCO 2013

31. Case 2 Glucagon secreting NET Response to Strep/Dox x 9 months HACE x 4, regrowth within 3-4 months Temsirolimus/bevacizumab Glucagon secreting NET Response to Strep/Dox x 9 months HACE x 4, regrowth within 3-4 months Temsirolimus/bevacizumab

32. Case 2: PR after 4 months

33. Case 3 2001: 59 yo with abdominal pain. Resection of 14 cm NET pancreatic tail. 2/2006: Progressing liver lesions over past few years. Asymptomatic, observed. March 2008: Progressive disease, Calcium 11.8 mg/dl, PTH-rp 13 pmol/L 2001: 59 yo with abdominal pain. Resection of 14 cm NET pancreatic tail. 2/2006: Progressing liver lesions over past few years. Asymptomatic, observed. March 2008: Progressive disease, Calcium 11.8 mg/dl, PTH-rp 13 pmol/L

34. Case Octreotide, IV bisphosphonate and everolimus vs placebo initiated (clinical trial) Initial improvement in Calcium, but by 9/08 up to 13. Disease progressed on placebo, crossover to everolimus. 5/09: Stable disease, Ca =14, osteoporosis, urine crystals Hepatic artery embolization Octreotide, IV bisphosphonate and everolimus vs placebo initiated (clinical trial) Initial improvement in Calcium, but by 9/08 up to 13. Disease progressed on placebo, crossover to everolimus. 5/09: Stable disease, Ca =14, osteoporosis, urine crystals Hepatic artery embolization

37. Case Post HAE, Ca = 9-10, off bisphosphonate. But…hepatic abscess requiring surgical resection 8/2009 6/2010 rising calcium, cholangitis from L biliary obstruction. Post HAE, Ca = 9-10, off bisphosphonate. But…hepatic abscess requiring surgical resection 8/2009 6/2010 rising calcium, cholangitis from L biliary obstruction.

38. Case 6/2010: initiated chemotherapy with temozolomide/capecitabine rapid normalization of calcium, disease response, decompressed L biliary system 9/2013 Stopped chemotherapy 4/2014: No disease progression, observed. 6/2010: initiated chemotherapy with temozolomide/capecitabine rapid normalization of calcium, disease response, decompressed L biliary system 9/2013 Stopped chemotherapy 4/2014: No disease progression, observed.

39. Thank you