Pancreatic NeuroEndocrine Tumors Prof Eric Van Cutsem, MD, PhD Gastroenterology/Digestive Oncology Leuven, Belgium
Epidemiology Overall incidence 1.8 to 2.6 SEER, Europe Peak in 5 th and 6 th decade Incidence of Non Functional pnets increasing 47% (Japan) 60-90% (SEER) Incidental detection Pose particular challenges Will have impact on outcome?
Pancreatic NET: Survival and Stage Stage at diagnosis 1 Survival by stage 2 Localized > 10 years Regional Distant 111 months 27 months Unknown 1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data, Nov 2008 Sub (1973-2006) released April 2009, based on the November 2008 submission; 2. Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
Classification WHO 2000 Histological Differentiation Size Metastases WHO 2010 Ki67-Index (%) WDET Well differentiated 1-2 cm NeuroEndocrine Tumor - G1 2 WDEC Well to moderately differentiated > 2 cm + NeuroEndocrine Tumor - G2 3-20 - Well to moderately differentiated any +/- NeuroEndocrine Carcinoma, G3 Large cell or small cell type > 20 PDEC Poorly differentiated large and small cell any +/- Mixed AdenoNeuroEndocrine Carcinoma (MANEC)
Prognostic value of grading in Neuroendocrine neoplasms (NEN) Foregut NEN * (n=202) Pancreatic NEN (n=425) 75% 62% 7% * Gastric, duodenal, pancreatic Pape et al, Cancer 2008 Strosberg et al JCO 2011
Ki-67 Range within G2 tumours is large
Ki-67 cut-off: 5% appears better for pnets ENETS: Ki-67 G1 vs G2 Cut-off: 2%, no significant distinction Ki 67 <= 5%, significant distinction between G1 and G2 Panzuto et al, J Clin Oncol, 2011
J Natl Cancer Inst 2012;104:1 14
UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability N=891 Rindi et al J Natl Cancer Inst 2012;104:1 14
Molecular imaging (staging) Functional imaging results based on Proliferation Index SRS, % 18 F-FDG, % Ki-67 positive negative positive negative < 2% 87 13 41 59 2-15% 96 4 73 27 >15% 69 31 92 8 Binderup et al J Nucl Med 2010 WDEC with Ki-67 >10% (n=18): -100% FDG/PET + -83% SRS + Abgral et al, JCEM 2011
Survival according to metabolic activity
Therapy localised disease Surgery OF COURSE But 1. What about small tumours...? Most small tumours (<2 cm)» Benign or intermediate-risk lesions» 6% of Non Functional pancreatic NETs <2 cm are malignant when incidentally discovered Incidentally discovered in bad places... 2. Can we safely use limited resection methods? Enucleation?» Balance functional outcome vs oncological completeness
Therapy advanced disease (surgery, loco-regional) Radio-embolisation Falconi et al Neuroendocrinology 2012:95:120-34
Medical therapy for pnet Functional tumours Somatostatin analogues (PPI ) Anti-proliferative measures Somatostatin analogues Systemic chemotherapy Poorly differentiated tumors: cisplatin/etoposide Good/moderately diffenentiated: strepto/dox or 5FU; temozolamide ± capecitabine; FOLFOX Molecular targeted therapies Sunitinib Everolimus Peptide Receptor Targeted Therapy (PRRT)
SSA FOR GROWING CONTROL OF pnets Promid in non pnet ANTIPROLIFERATIVE EFFECT OF SSA IN PTS WITHOUT DOCUMENTED PD ANTIPROLIFERATIVE EFFECT OF SSA IN PTS WITH DOCUMENTED PD OR ~5% SD 40-45% OR ~5% SD 60-70% Clarinet Toumpanakis C, et al. Semin Oncol. 2013 Delavault P, et al. ASCO 2012
Systemic Chemotherapy p NET Author Chemotherapy Pt. (n) RR (%) mos (mo) Moertel et al.(1980) STZ + 5-FU STZ 42 42 63 36 26 16.5 Moertel et al.(1992) STZ + DOX STX + 5-FU CLZ 36 33 33 69 45 30 26.4 16.8 18 Bukowski et al.(1992) CLZ + 5-FU 44 36 25 McCollum et al.(2004) STZ + DOX 16 6 20.2 Cheng & Saltz (1999) STZ + DOX 16 6* NA Kouvaraki et al.(2004) 5-FU + STZ + DOX 84 39 37 Fjällskog et al. (2009) STZ + DOXO liposomal 30 40** 52 Turner et al (2010) STZ+5-FU+Cispl. 47 38 31.5 * 56/ **57%/ 51% stable TTP: 9-18 months
Temozolomide no randomized trials Author Chemotherapy Pt. (n) RR (%) mos (mo) Ramanathan et al.(2001) DTIC 50 34 19 Ekeblad et al. (2007) Temozolomide 12 8* 67 SD NA Kulke et al. (2006) Temozolomide + Thalidomide 11 45 NA Kulke et al. (2006) ASCO Temozolomide + Bevacizumab 18 24 NA Isacoff et al (2006) ASCO Temozolomide + Capecitabine 17 6 CR 56 PR Strosberg J et (2011) Temozolomide + Capecitabine 30 21 PR 2Y surv: 92% MGMT deficiency better response? NA
Capecitabine and Temozolamide in Pancreatic NET N = 30 RR: 70 % PFS 18 mo Strosberg J et al, Cancer 2011
Anti-angiogenic Agents VEGF antibodies 1 Bevacizumab Inhibition of PDGF + VEGF receptors Sunitinib 2, sorafenib, vandetanib Inhibition of mtor which regulates HIF-1 impacting the transcription of VEGF-A 3 Everolimus VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor; HIF = hypoxia inducible factor 1. Jain RK, et al. Semin Oncol. 2002;29(6_Suppl 16):3-9. 2. Faivre S, et al. J Clin Oncol 2006;24(1):25-35. 3. Majumder PK, et al. Nature Medicine 2004;10(6):594-601.
Rationale for the Use of Angiogenesis Inhibitors in NET NET are highly vascularised and express VEGF and VEGF-R 1 IGF-1 EGF Endothelial Cell Angiogenesis VEGF expression correlates with decreased PFS duration 2 Tumour Cell IGF-1R EGFR HER2 VEGF VEGFR Angiogenesis inhibitors that target VEGF have been shown to have clinical activity in NET 3 RAF MEK Aberrantly activated PI3K/AKT/mTOR pathway ERK mtor PTEN TSC1/2 PDGFR PDGF Angiogenic factors Sunitinib showed efficacy in a phase II trial with superior efficacy in pnet compared to carcinoid 4 Survival Growth and proliferation Metabolism Angiogenesis 1 Yao JC, et al. J Clin Oncol. 2008;26(8)1316-1323. 2 Phan AT, et al. J Clin Oncol. 2006;24(18s suppl):abstract 4091. 3 Eriksson B. Curr Opin Oncol. 2010;22(4):381-386. 4 Kulke M, et al. J Clin Oncol. 2008;26(20):3403-3410.
Sunitinib vs Placebo in Advanced pnet Phase III randomised, placebo-controlled, double-blind trial Trial terminated after unplanned early analysis Well differentiated advanced pnet patients (N = 171 enrolled / 340 planned) Disease progression in past 12 months Not amenable to curative treatment R A N D O M I S E 1:1 Sunitinib 37.5 mg/day orally Continuous daily dosing* n = 86 Placebo* n = 85 * With best supportive care Somatostatin analogues were permitted Primary Endpoint: PFS Statistical significance required nominal critical z value 3.8809 Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364:501-513. Secondary Endpoints: OS ORR TTR Duration of response Safety Patient-reported outcomes
Baseline Characteristics Sunitinib n = 86 Placebo n = 85 Median age, yr (range) 56 (25 84) 57 (26 78) Male, n 42 40 Female, n 44 45 ECOG Performance Status, n 0/1/2 53/33/0 41/43/1 Number of disease sites, n 1/ 2/ 3 30/31/24 23/26/35 Presence of distant metastases, n Any, including hepatic 82 80 Extrahepatic 21 34 Prior Therapies, n Somatostatin analogues 30 32 Systemic chemotherapy 57 61 Streptozocin 24 28 Anthracyclines 27 35 Fluoropyrimidines 20 25 Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364:501-513.
Sunitinib Phase III Trial: PFS by Investigator Review Progression-Free Survival Probability, % 100 90 80 70 60 50 40 30 20 10 0 HR, 0.418 95% CI, 0.263-0.662 P = 0.000118 * *P-value might be misleading due to multiple early looks Sunitinib (n = 86) Median, 11.4 months Placebo (n = 85) Median, 5.5 months 0 3 6 9 12 15 18 21 Subjects at risk, n Time, months Sunitinib 86 52 34 20 15 4 2 0 Placebo 85 42 20 9 2 2 2 0 P-value did not cross adjusted efficacy boundary when accounting for early data looks by IDMC PFS at 6 months: 71.3% for sunitinib; 43.2% for placebo Further PFS analyses not performed due to early termination of study Hazard ratio is obtained from Cox proportional hazards model Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364:501-513. Blumenthal GM, et al. The Oncologist. 2012;17(8):1108-13.
Sunitinib Phase III Trial: Summary of PFS Analyses PFS Analysis Events n Events Censored n Median Difference in PFS months HR P Value Cross- Efficacy Boundary? * Investigator 81 90 5.9 0.42 No Central radiology 61 110 6.8 0.32 N/A FDA 2 82 89 4.8 0.43 No *When accounting for early data looks by DMC. 2 The FDA did an additional analysis and found a median PFS of 10.2 months for sunitinib and 5.4 months for placebo. These data were used in the Sutent prescribing information. 1. Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364(6):501-513. 2. Blumenthal GM, et al. The Oncologist. 2012;17(8):1108-13.
Sunitinib Phase III Trial: PFS by Investigator Subgroup Analysis All Patients N 171 HR 0.418 95% CI (0.263, 0.662) Age <65 years Age 65 years White Non-White Male Female ECOG PS 0 ECOG PS 1/2 2 disease sites 3 disease sites Extrahepatic distant disease Pancreas/liver only disease No somatostatin analogs used Somatostatin analogs used* 0 or 1 previous systemic regimens 2 previous systemic regimens Non-functioning tumour Functioning tumour Ki-67 5% Ki-67 >5% Time from diagnosis <3 years Time from diagnosis 3 years 126 45 101 70 82 89 94 77 112 59 55 114 103 68 121 50 86 46 43 29 89 82 0.474 0.223 0.487 0.353 0.374 0.477 0.404 0.455 0.435 0.428 0.536 0.414 0.409 0.428 0.334 0.607 0.264 0.747 0.378 0.634 0.433 0.292 (0.284, 0.793) (0.071, 0.702) (0.257, 0.923) (0.179, 0.695) (0.200, 0.701) (0.242, 0.939) (0.222, 0.735) (0.219, 0.943) (0.245, 0.772) (0.195, 0.941) (0.245, 1.170) (0.233, 0.736) (0.222, 0.752) (0.206, 0.887) (0.188, 0.594) (0.269, 1.370) (0.129, 0.539) (0.303, 1.841) (0.155, 0.922) (0.235, 1.711) (0.239, 0.786) (0.130, 0.657) 0.1 Favours Sunitinib 1 Favours Placebo 10 *Includes all patients receiving somatostatin analogs at any time before and/or concomitant with study treatment. ECOG PS, Eastern Cooperative Oncology Group Performance Score; HR, hazard ratio. Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364:501-513.
Kaplan Meier estimates of OS Overall survival probability (%) 100 90 80 70 60 50 40 30 20 10 0 Hazard ratio: 0.737 95% CI: 0.465-1.168 P =0.1926 0 3 6 9 12 15 18 21 24 27 30 33 36 Number of subjects at risk Sunitinib Placebo 86 85 83 75 77 68 73 61 69 55 Time (months) 59 49 49 39 Raymond E, Van Cutsem E et al J Clin Oncol. 2011; 29(15): Abstract 4008. 41 32 31 24 Sunitinib (N=86, death=34)) Median: 30.5 months Placebo (N=85, death=39)) Median: 24.4 months 18 18 10 11 5 4 1
Sunitinib: Treatment-Related Adverse Events >20% Treatment duration: median (range) Sunitinib: 4.6 mos (0.4-17.5) Placebo : 3.7 mos (0.03-20.2) Sunitinib (n=83) Placebo (n=82) All Grades Grade 3 or 4 All Grades Grade 3 or 4 no of patients (%) Diarrhoea 49 (59) 4 (5) 32 (39) 2 (2) Nausea 37 (45) 1 (1) 24 (29) 1(1) Asthenia 28 (34) 4 (5) 22 (27) 3 (4) Vomiting 28 (34) 0 25 (30) 2 (2) Fatigue 27 (32) 4 (5) 22 (27) 7 (8) Hair-colour changes 24 (29) 1 (1) 1 (1) 0 Neutropenia 24 (29) 10 (12) 3 (4) 0 Abdominal pain 23 (28) 4 (5) 26 (32) 8 (10) Hypertension 22 (26) 8 (10) 4 (5) 1 (1) Palmar-plantar erythrodysesthesia 19 (23) 5 (6) 2 (2) 0 Anorexia 18 (22) 2 (2) 17 (21) 1 (1) Stomatitis 18 (22) 3 (4) 2 (2) 0 Dysgeusia 17 (20) 0 4 (5) 0 Epistaxis 17 (20) 1 (1) 4 (5) 0 *Cardiac failure leading to death was reported in 2/83 (2%) patients on Sunitinib and no patients on placebo.
Summary Sunitinib Sunitinib provided a clinically meaningful 5.9 month improvement in median PFS compared with placebo in patients with advanced pnet in all subgroups Due to the early termination of the study, the FDA performed an additional analysis, and found a mean difference in PFS of 4.8 months 2 6-month survival for patients treated with sunitinib was 92.6% Toxicities were consistent with those observed in other trials of sunitinib 1. Raymond E, Van Cutsem E et al. N Engl J Med. 2011;364:501-513. 2. Blumenthal GM, et al. The Oncologist. 2012;17(8):1108-13.
RADIANT-3 Study Design Patients with progressive advanced pnet, N=410 Advanced low- or intermediategrade pnet Radiologic progression 12 months Prior anti-tumour therapy allowed WHO PS 2 Stratified by: WHO PS Prior chemotherapy Randomisation: August 2007-May 2009 * Concurrent somatostatin analogues allowed Phase III Double-Blind, Placebo-Controlled Trial R A N D O M I S E 1:1 Primary Endpoint: PFS Statistical boundary.025 Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523. Everolimus 10 mg/d + best supportive care* n = 207 Crossover allowed at time of PD Placebo + best supportive care 1 n = 203 Multiphasic CT or MRI performed every 12 weeks Secondary Endpoints: OS ORR Biomarkers Safety PK Treatment until disease progression
RADIANT-3: Baseline Characteristics Everolimus (n = 207) Placebo (n = 203) Median age, years (range) 58 (23-87) 57 (20-82) Male : Female (%) 53 : 47 58 : 42 WHO PS (%) 0 / 1 / 2 67 / 30 / 3 66 / 32 / 3 No. of disease sites(%) 1 25 31 2 41 32 3 34 38 Histological Differentiation (%) Well differentiated 82 84 Moderately differentiated 17 15 Unknown 1 1 Prior Treatment (%) Somatostatin analogues 49 50 Chemotherapy 50 50 Radiotherapy 23 20 Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523.
Progression Free Survival by Investigator Review % Event-free 100 80 60 40 Kaplan-Meier median PFS Everolimus: Placebo: 11.0 months 4.6 months Hazard ratio = 0.35; 95% CI 0.27-0.45 P value: <.0001 20 0 Censoring times Everolimus (n/n = 109/207) Placebo (n/n = 165/203) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (months) 148 placebo patients crossed over to everolimus at the time of progression P value obtained from stratified 1-sided log-rank test Hazard ratio is obtained from stratified unadjusted Cox model Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523.
Everolimus Provided a Durable PFS Benefit PFS; Kaplan-Meier estimates [95% CI] Everolimus 10 mg n = 207 Placebo n = 203 3 months 84.0 [78.0-88.4] 58.5 [51.2-65.0] 6 months 69.5 [62.4-75.5] 31.9 [25.4-38.5] 12 months 45.6 [37.7-53.1] 15.4 [10.5-21.2] 18 months 34.2 [25.9-42.7] 8.9 [4.0-16.3] Median treatment duration (months) 8.79 3.74 Median follow-up 17 months Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523.
RADIANT-3: Overall Survival Percentage event free 100 80 60 40 20 0 Patients still at risk, n Everolimus 207 Placebo 203 Censoring Times Everolimus (n/n = 68/207) Placebo (n/n = 78/203) Kaplan-Meier Median OS Everolimus NR Placebo 36.63 months HR (95% CI), 0.89 (0.64-1.23) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time, months 203 199 195 195 189 183 182 175 174 163 168 162 159 151 157 150 147 144 142 140 119 118 91 93 70 77 53 59 39 44 27 31 16 20 36 38 40 42 44 7 13 3 3 0 2 0 1 0 0 Lombard-Bohas C, Van Cutsem E et al. 2011 European Multidisciplinary Cancer Congress; Stockholm, Sweden. Abstract 6561
Subgroup PFS Analysis Subgroups (N) Favours Everolimus Favours Placebo Median PFS (mos.) HR E P Investigator review (410) 0.35 11.0 4.6 Central review * (410) 0.34 11.4 5.4 Prior chemotherapy Yes (189) 0.34 11.0 3.0 No (221) 0.41 11.1 5.5 WHO Performance Status 0 (279) 0.39 13.8 5.4 1 or 2 (131) 0.30 8.3 3.0 Age Group <65 years (299) 0.39 11.0 4.5 65 years (111) 0.36 11.1 4.9 Gender Male (227) 0.41 11.0 4.6 Female (183) 0.33 11.0 3.3 Race Caucasian (322) 0.41 10.8 4.6 Asian (74) 0.29 19.5 3.8 Region America (185) 0.36 11.0 4.6 Europe (156) 0.47 10.8 4.6 Asia (69) 0.29 19.5 2.9 Prior long-acting SSA Yes (203) 0.40 11.2 3.7 No (207) 0.36 10.8 4.9 Tumour grade Well diff. (341) 0.41 10.9 4.6 Moderately diff.(65) 0.21 16.6 3.0 0 0.4 0.8 1 Hazard Ratio * Independent adjudicated central review E = Everolimus 10 mg PO daily; P = Placebo
Everolimus in pnet Patients is Clinically Beneficial Regardless of Prior Chemotherapy Use p value is obtained from the unstratified one-sided log-rank test. Hazard ratio is obtained from unstratified unadjusted Cox model. In the everolimus arm, median PFS did not significantly differ in patients who did and did not receive prior chemotherapy In the placebo arm, a trend toward shorter median PFS was observed in patients who had received prior chemotherapy compared with chemo-naive patients Lombard-Bohas C, Van Cutsem E et al. J Clin Oncol. 2012; 30 suppl. 34; abstract # 224.
Everolimus versus Placebo: Best Response of Target Lesions (% Change) Objective Tumour remissions (Everolimus/ Placebo): 5% versus 2% Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523. Any tumour shrinkage: 64 versus 21%
RADIANT-3: Treatment-Related Adverse Events >20% Treatment duration: median (range) Everolimus (n=204) Placebo (n=203) Everolimus: 8.79 mos (0.25 - All Grades Grade 3 or 4 All Grades Grade 3 or 4 27.47) Placebo : 3.74 mos (0.01 37.79) no. of patients (%) Stomatitis* 131 (64) 14 (7) 34 (17) 0 Rash 99 (49) 1 (<1) 21 (10 0 Diarrhoea 69 (34) 7 (3) 20 (10) 0 Fatigue 64 (31) 5 (2) 29 (14) 1 (<1) Infections 46 (23) 5 (2) 12 (6) 1 (<1) Nausea 41 (20) 5 (2) 37 (18) 0 Peripheral oedema 41 (20) 1 (<1) 7 (3) 0 Decreased appetite 40 (20) 0 14 (7) 2 (1) * Included in this category are stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration All types of infection are included Included in this category are pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523.
RADIANT- 3 Summary RADIANT-3 enrolled 410 patients with advanced pnet, the largest-ever placebo-controlled phase III clinical trial in this patient population Everolimus provided a statistically and clinically significant improvement in median PFS by 6.4 month compared to placebo Everolimus provided a durable benefit; 18-mo PFS rate of 34% vs. 9% placebo Consistent benefit seen with everolimus across all subgroups Everolimus has an acceptable safety profile Yao, JC. Van Cutsem E et al. N Engl J Med. 2011;364:514-523.
Treatment Selection for pnet Patients Favour Everolimus Disease factors Functional tumours Co-morbidities Heart disease Uncontrolled HTN Bleeding risk Varices Favour Sunitinib Disease factors Co-morbidities Severe lung disease Uncontrolled DM
Targeted therapies in pnet Everolimus and sunitinib Both significantly prolong PFS (11 vs 6 months) Despite positive Phase III data When to start? Which one? Combination with other agents Lack of predictive markers
Advanced pnets 2014 pnet Hormonal syndrome Oncologic control Somatostatin analogues Everolimus Sunitinib Disease progression Investigational agents Regional therapy PRRT (No approved therapies are available) High tumor burden Chemotherapy combination Somatostatin analogues
Therapy advanced disease (surgery, loco-regional) SIRT SIRT
Outstanding questions When and how long somatostatin analogues? Best 1 st line agent(s) Everolimus and sunitinib? PRRT? Phase III trial of PRRT in intestinal NETs Strategy with chemotherapy in GR 1 & 2 Place of temozolamide Adjuvant therapy? Neoadjuvant therapy?