Review of Gastrointestinal Carcinoid Tumors: Latest Therapies Arvind Dasari, MD, MS Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, TX, USA
Neuroendocrine Tumors (NET) Incidence Incidence Trends 1973-2012 1.09 6.98 Incidence Trends of NETs and all malignant neoplasms from 1973 2012 (age adjusted to 2000 US Standard Population) Incidence Trends of NETs and all malignant neoplasms from 1973 2012 (age adjusted to 2000 US Standard Population) Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) ver November 2014 Dasari et al. JAMA Oncol. 2017 Oct 1;3(10):1335-1342
NETs : Prevalence Incidence Trends of NETs and all malignant neoplasms from 1973 2012 (age adjusted to 2000 US Standard Population) 20-year Limited Duration Prevalence projected into US Population on 1/1/2014 : 171,321 Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) ver November 2014 Dasari et al. JAMA Oncol. 2017 Oct 1;3(10):1335-1342
NETs : Evolving Classification 2010 Grade 1 Grade 2 Grade 3 Ki-67 <3% 3-20% >20% Mitotic Index (10HPF) <2 2-20 >20 Differentiation Well Poor 2017 Ki-67 Grade 1 Grade 2 Grade 3 <3% 3-20% >20% >20% Mitotic Index (/10 HPF) <2/10 2-20 >20 >20 Differentiation Well Well Well Poor Small Cell Large Cell Sorbye et al, Cancer 2014 Sept 15; 120(18):2814-23 Kim et al, Ann Diagn Path 2017 Aug;29:11-16
Somatostatin Physiology Found in CNS and peripheral tissues Binds to five somatostatin receptors: sst1-5 Inhibitory effects on secretion & growth Aliment Pharmacol Ther. 2010 Jan 15;31(2):169-88
Hormone Control Somatostatin Analogues Compound Peptide size (#Amino Acids) t 1/2, Delivery Long Acting Formula, Delivery Binding Affinity Somatostatin 14 / 28 2-3min, iv All receptors FDA Approved Indications Octreotide 8 2 hrs, sc Octreotide LAR, IM q 4 wks Lanreotide 8 2 hrs, sc Lanreotide PR: IM q 2 wks Lanreotide AG: SC q4 wks Pasireotide 6 12 hrs, sc Pasireotide LAR: IM sst2 >> sst5 sst2 >> sst5 sst 1,2,3,5 Acromegaly Carcinoid syndrome VIPomas Acromegaly Gastroenter opancreatic NETs Carcinoid Syndrome Acromegaly Enzler et al, Semin Oncol, 2017 April;44(2):11-156 Octreotide, Lanreotide & Pasireotide Package Inserts.
Lanreotide ELECT Trial Advanced NETs with carcinoid syndrome, n = 115 R Lanreotide 120 mg sc q28 d + sc octreotide Placebo + sc octreotide Primary Endpoint: Adjusted mean percent of days sc octreotide used over 16-weeks Percent of days of sc octreotide Number of days of sc octreotide use Complete Success: No use Partial success : 1-3 days Treatment Failure: > 3 days Odds of full / partial success: 2.4; p = 0.036 Vinik et al Endocr Pract. 2016;22:1068-1080
Diarrhea Control Telotristat 4 BM (Mean 5-6) Rescue sc octreotide and anti-diarrheals allowed Baseline Characteristics: Mean BM = 5-6 / day Flushing = 2-3 / day Urine 5-HIAA = 81-90 (58% with elevation) Adapted from Dr. Kulke s presentation at 18 th ECCO-40 th ESMO European Cancer Congress, Sept 29, 2015
Diarrhea Control Telotristat Mean reduction in BM# Placebo Telotristat 250 tid Telotristat 500 tid 0.9 1.7 2.1 Responders* 20 44 42 Urine 5-HIAA +11.5-40.1-57.7 #Hodges-Lehman estimator for reduction in BM: -0.81 (250 mg) & -0.69 (500 mg) *Defined as 30% reduction in BM for 50% days **Small number of patients with significant flushing and abdominal pain at baseline and no change during study period Adapted from Dr. Kulke s presentation at 18 th ECCO-40 th ESMO European Cancer Congress, Sept 29, 2015
Tumor Control Drug Approvals Approved agents for oncologic control before 2011 pnets: Streptozocin GI NETs: None Approved agents for oncologic control pnets: Everolimus, sunitinib, lanreotide GI NETs: Lanreotide, everolimus Lung Nets: Everolimus Other active agents pnets: Temozolomide GI NETs: Octreotide, (177)Lu-DOTATATE 1900 1980 2000 2005 2010 2015 1988/89 1998 2009 2014/15 2015-17 OCT SC CS 25,30 LAN symptom control 24 PROMID OCT LAR: Antitumor activity 9,31 CLARINET LAN GEP NET 16,17,29 RADIANT-4 EVE NF GI and lung NET 15,19 Treatments 1982 STZ pnet 36 1992 STZ combination: Survival benefit pnet 2 OCT LAR carcinoid tumors 23,26,28 2010/11 RADIANT-3 EVE in pnet 11,12,32,33 Sunitinib phase III pnet 13,31,34 ELECT LAN: Symptom control 27 2015 TELESTAR telotristat etiprate CS 20 NDA filed 3/30/16 US approval US/EU approval EU approval RADIANT-2 EVE + OCT, LAR in mnet w/cs 14 NETTER-1 177 Lu-Dotatate midgut NET 18 AC, atypical carcinoid; AJCC; American Joint Committee on Cancer; CS, carcinoid syndrome; ENETS, European Neuroendocrine Tumor Society; ESMO; European Society for Medical Oncology; EVE, everolimus; GEP, gastroenteropancreatic; GI NETs, gastrointestinal neuroendocrine tumors; LAN, lanreotide; LAR, long-acting repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF, nonfunctional; OCT, octreotide; pnet, pancreatic NET; SC, subcutaneous; STZ, streptozocin; TC, typical carcinoid; UICC, Union for International Cancer Control; WHO, World Health Organization LAN symptom control
NETs : Pancreatic (pnet) vs Carcinoids 70 65 Median overall survival (months) 60 50 40 30 20 10 17 13 27 55 7 26 0 Lung Stomach Pancreas Small Intestine 1988-2004 Cecum Colon Rectum Yao et al, 2008 J Clin Oncol 26(18):3063-3072
pnet - Temozolomide Advanced pnet n = 143 Capecitabine 750 mg/m 2 BID Days 1-14 Temozolomide 200 mg/m 2 QD Days 10-14 Median # of cycles = 9 Overall Survival 73.2 (95% CI 51.9 81.1) months PFS 17 (95% CI 15 25) months Response Rate = 54% Cives et al. Endocr Relat Cancer 2016;23:759-767
pnet - Temozolomide Advanced pnet n = 143 Capecitabine 750 mg/m 2 BID Days 1-14 Temozolomide 200 mg/m 2 QD Days 10-14 Median # of cycles = 9 E2211: PI Pamela Kunz, MD Phase II Temozolomide + / - Capecitabine n = 138, Primary End Point: PFS Accrual Completed Overall Survival 73.2 (95% CI 51.9 81.1) months PFS 17 (95% CI 15 25) months Response Rate = 54% Cives et al. Endocr Relat Cancer 2016;23:759-767
pnet - Sunitinib Updated OS (2017) Sunitinib 38.6 mo Placebo 29.1 mo* HR 0.73, p = 0.094 * 69% crossover Raymond et al. N Engl J Med 2011; Feb 10;364(6):501-13 Faivre et al. Ann Oncol 2017 Feb 1;28(2):339-343
pnet Everolimus (RADIANT-3) *89% crossover Yao et al, 2011, N Engl J Med, Feb 10;364(6):514-23 Yao et al, 2016, J Clin Oncol Sep 12
Carcinoids Everolimus (RADIANT-4) Advanced, nonfunctioning, GI or Lung NETs N=302 R (2:1) Everolimus 10 mg QD Placebo Baseline Characteristics Variable Everolimus Placebo Male - n(%) 89 (43) 53 (55) Age - yr 65 60 Time since diagnosis (median, mo) 29.9 28.9 Prior SSA Therapy 109 (53%) 54 (56%) Origin n (%) Lung Midgut Hindgut Unknown/Other 63 (31) 72 (35) 34 (17) 36 (18) 27 (28) 32 (32) 19 (20) 19 (20) Yao et al. Lancet 2016 Mar 5;387(1022)968-977
Carcinoids Everolimus (RADIANT-4) Yao et al. Lancet 2016 Mar 5;387(1022)968-977
Everolimus Stomatitis (SWISH TRIAL) Rugo et al. J Clin Oncol.2016;34(suppl):Abstract 525
SSA for Tumor Control : PROMID Trial Advanced, mid-gut NETs N=85 R Octreotide 30 mg IM q28 d Placebo Overall Survival Time to Progression Rinke et al, Neuroendocrinology 2017;104(1):26-32 Rinke et al, J Clin Oncol 2009 Oct 1;27(28);4656-63
SSA for Tumor Control : CLARINET Trial Advanced, nonfunctioning Gastroenteropanc reatic NETs N=204 R Lanreotide 120 mg sc q28 d Placebo Baseline Characteristics Variable Lanreotide Placebo Male - n(%) 53 (52) 54 (52) Age - yr 63.3 62.2 Time since diagnosis (median, mo) 13.2 16.5 Origin n (%) Pancreas Midgut Hindgut Unknown/Other 42 (42) 33 (33) 11 (11) 15 (15) 49 (48) 40 (39) 3 (3) 11 (11) Tumor Progression: n (%) 4 (4) 5 (5) Caplin et al, N Engl J Med 2014;Jul 17;371(3)224-33
SSA for Tumor Control : CLARINET Trial Lanreotide Not reached Placebo 18.0 mo HR 0.47, p < 0.001 Caplin et al, N Engl J Med 2014;Jul 17;371(3)224-33 Caplin et al. Endocr Relat Cancer 2016;23:191-199
Peptide Receptor Radionuclide Therapy (PRRT) [ 111 In-DTPA 0 ]Octreotide [ 90 Y-DOTA 0,Tyr 3 ]Octreotide [ 177 Lu-DOTA0,Tyr 3 ]Octreotide [ 177 Lu-DOTA0,Tyr 3 ]Octreotate Bergsma et al, Best Practice & Research Clinical Gastroenterology 2012; 26:6, 867-881
PRRT Peptides and Radionuclides Affinity Profiles of Peptides, IC 50 (SEM) Profiles of Key Radionuclides Peptide sstr2 sstr5 Somatostatin 2.7 (0.3) 4 (0.30) Octreotide 2 (0.7) 22(6) Nuclide Indium-111 2.81 t 1/2 days Emission Depth Electrons γ 10 μm 550 μm DOTA- [Tyr3]Octreotide DOTA- [Tyr3]Octreotate 14(2.6) 393(84) 1.5(0.4) 547(160) Yttrium-90 2.67 β 12 mm Lutetium- 177 6.65 β, γ 3 mm Dash et al, 2015, Cancer Biotherapy and Radiopharmaceuticals, 2014, 30:47-70.
Kwekkeboom, JCO, 2008:2124 PRRT: Retrospective Data
NETTER-1 Study Design SSR +ve, progressive midgut carcinoids, n = 229 177 Lu-DOTA- Octreotate x 4 cycles Octreotide LAR 60 mg IM every 4 weeks 177 Lu-DOTATE Therapy: - 7.4 Gbq (200mCi) iv over 30 min every 8 weeks - Amino Acid solution iv for 4 hours - Octreotide 30 mg LAR 24 hours after therapy, continued monthly Median Time Since Diagnosis (years) 177 Lu-Dotate (n = 116) Octreotide LAR 60 mg (n = 113) 3.8 4.8 Ileum 86 (73%) 82 (73%) SRS, Krenning scale grade 2/3/4 (%) 9%/29%/61% 11%/30%/59% Grade 1 76 (66%) 81 (72%) Non-SSA Systemic Therapy 5-HIAA (mg/24 h), mean, SD* 41% 45% 100 (183) 77 (83) No. of PRRT of administrations = 4 78/102 (77%) Not applicable Strosberg et al, New Eng J Med. 2017 Jan 12;376(2):125-135
NETTER-1 Results: PFS Median PFS 8.4 m vs not reached (estimate 40 m); HR 0.21, p < 0.0001 Strosberg et al, New Eng J Med. 2017 Jan 12;376(2):125-135
NETTER-1 Results HR for death = 0.40; p = 0.004 (O-Brien-Fleming threshold for significance = 0.000085) Strosberg et al, New Eng J Med. 2017 Jan 12;376(2):125-135
NETTER-1 Grade 3 / 4 Toxicities 177 Lu-Dotate* Control* p Value Nausea / Vomiting 12 (11) 3 < 0.001 Lymphopenia 10 (9) 0 < 0.001 Thrombocytopenia 2 (2) 1(1) <0.001 Leukopenia 1 (1) 0 0.005 *n(%) Strosberg et al, New Eng J Med. 2017 Jan 12;376(2):125-135
NETTER-1 Grade 3 / 4 Toxicities 177 Lu-Dotate* Control* p Value Long term risk of MDS: ~ 2-3% AML: ~ 1% Nausea / Vomiting 12 (11) 3 < 0.001 Lymphopenia 10 (9) 0 < 0.001 Thrombocytopenia 2 (2) 1(1) <0.001 Leukopenia 1 (1) 0 0.005 *n(%) Strosberg et al, New Eng J Med. 2017 Jan 12;376(2):125-135
NETTER-1 Grade 3 / 4 Toxicities Toxicity Traditional Therapy PRRT p Liver 23 (31%) 10(59%) <0.001 Bone Marrow 54 (71%) 12(71%) 0.97 Kidney 27(36%) 5(29%) 0.63 Riff et al. Clin Nucl Med. 2015 Nov;40(11):845-50
Treatment Landscape of Advanced NETs Site Octreotide Lanreotide 177 Lu- DOTATATE Streptozocin Sunitinib Everolimus Disease status Tx naïve Stable Progressive over 3 yrs Historical Progressive over 12 mo Progressive over 6 mo* Lung RADIANT4 Stomach CLARINET RADIANT4 Pancreas CLARINET Historical Phase III RADIANT3* Small bowel Appendix PROMID CLARINET NETTER-1 RADIANT4 Colon CLARINET RADIANT4 Rectum CLARINET RADIANT4 Unknown 1 RADIANT4 *RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months. RADIANT-4 requires documentation of PD during prior 6 months. Rinke A, et al. J Clin Oncol. 2009. Caplin ME, et al. N Engl J Med. 2014. Strosberg J, et al. N Engl J Med. 2017. Raymond E, et al. N Engl J Med. 2011. Yao JC, et al. J Clin Oncol. 2008. Yao JC, et al. N Engl J Med. 2011. Yao JC, et al. Lancet. 2016.
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