TRACTAMENT ONCOLÒGIC DELS TUMORS NEUROENDOCRINS METASTÀSICS

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1 TRACTAMENT ONCOLÒGIC DELS TUMORS NEUROENDOCRINS METASTÀSICS Jaume Capdevila Unitat de Tumors GI i Endocrins Hospital Universitari Vall d Hebron Barcelona Experts, acollidors i solidaris

2 OUTLINE BACKGROUND AND DECISION MAKING CRITERIA MANAGEMENT OF GRADE 1/2 NETS MANAGEMENT OF GRADE 3 NECS GUIDELINES FOR THE MANAGEMENT OF ADVANCED NENS

3 OUTLINE BACKGROUND AND DECISION MAKING CRITERIA MANAGEMENT OF GRADE 1/2 NETS MANAGEMENT OF GRADE 3 NECS GUIDELINES FOR THE MANAGEMENT OF ADVANCED NENS

4 PARAMETERS WITH AN IMPACT ON THERAPEUTIC DECISION MAKING Histology Grading G1/G2 (NET) vs G3 (NEC) (WHO 2010) Well/moderately or poorly differentiated NET/NEC (US) Functionality Carcinoid syndrome, insulinoma, gastrinoma, VIPoma Primary tumor site Pancreatic vs intestinal Ø 5-year overall survival 40-50% vs 70-90% in metastatic disease Somatostatin receptor imaging Tumor burden/extrahepatic disease Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; WHO, World Health Organization.

5 CORRELATION OF TUMOUR GRADE AND CUMULATIVE SURVIVAL 1.0 Cumulative survival G1 G1 vs G2 G1 vs G3 G2 vs G3 G2 P =.040 P<.001 P<.001 Grade 1 Mitotic count Ki-67 index (10 HPF) 2 (%) 3 G1 <2 2 G G3 >20 > G Time (months) 1 ENETS grading system HPF = 2 mm 2 at least 40 fields (40 magnification) evaluated in areas of highest mitotic density. 3 Percentage of 2,000 tumour cells in areas of highest nuclear labeling with MIB1 antibody. Pape UF, et al. Cancer. 2008;113:

6 DISEASE STATE IMPLICATIONS FOR MANAGEMENT

7 OUTLINE BACKGROUND AND DECISION MAKING CRITERIA MANAGEMENT OF GRADE 1/2 NETS MANAGEMENT OF GRADE 3 NECS GUIDELINES FOR THE MANAGEMENT OF ADVANCED NENS

8 CURRENT ANTIPROLIFERATIVE THERAPY IN G1/G2 GEP-NETs Intestinal (Midgut) a NET G1/G2 Pancreatic NET G1/G2 " Somatostatin analogues PROMID: octreotide LAR vs placebo 1 TTP 14.3 mo vs 6 mo CLARINET: lanreotide vs placebo (ongoing trial) 2 " Interferon alpha " PPRT " Everolimus? RADIANT-2: everolimus + octreotide LAR vs placebo + octreotide LAR 3 RADIANT-4: everolimus vs placebo (ongoing trial) 4 " Chemotherapy Streptozotocin + 5-FU: RR ~40% 5 Temozolomide + capecitabine: RR up to 70% (retrospective trial) 5 " Everolimus, sunitinib RADIANT-3: everolimus vs placebo 6 Sunitinib trial: sunitinib vs placebo 7 " Somatostatin analogues? Octreotide/ lanreotide CLARINET: lanreotide vs placebo (ongoing trial) 2 " PRRT " Interferon alpha a Includes carcinoid tumors and tumors at other sites. 1. Rinke A, et al. J Clin Oncol. 2009; 2. ClinicalTrials.gov NCT Pavel M, et al. Lancet. 2011; 4. ClinicalTrials.gov NCT Frilling A, et al. Endocr Relat Cancer. 2012; 6. Yao J, et al. N Engl J Med. 2011; 7. Raymond E, et al. N Engl J Med. 2011; 8

9 CURRENT ANTIPROLIFERATIVE THERAPY IN G1/G2 GEP-NETs Intestinal (Midgut) a NET G1/G2 Pancreatic NET G1/G2 " Somatostatin analogues PROMID: octreotide LAR vs placebo 1 TTP 14.3 mo vs 6 mo CLARINET: lanreotide vs placebo (ongoing trial) 2 " Interferon alpha " PPRT " Everolimus? RADIANT-2: everolimus + octreotide LAR vs placebo + octreotide LAR 3 RADIANT-4: everolimus vs placebo (ongoing trial) 4 " Chemotherapy Streptozotocin + 5-FU: RR ~40% 5 Temozolomide + capecitabine: RR up to 70% (retrospective trial) 5 " Everolimus, sunitinib RADIANT-3: everolimus vs placebo 6 Sunitinib trial: sunitinib vs placebo 7 " Somatostatin analogues? Octreotide/ lanreotide CLARINET: lanreotide vs placebo (ongoing trial) 2 " PRRT " Interferon alpha a Includes carcinoid tumors and tumors at other sites. 1. Rinke A, et al. J Clin Oncol. 2009; 2. ClinicalTrials.gov NCT Pavel M, et al. Lancet. 2011; 4. ClinicalTrials.gov NCT Frilling A, et al. Endocr Relat Cancer. 2012; 6. Yao J, et al. N Engl J Med. 2011; 7. Raymond E, et al. N Engl J Med. 2011; 9

10 MOLECULAR PATHWAYS INVOLVED IN SOMATOSTATIN RECEPTOR ACTIVATION Öberg KE, et al. Gastroenterology 2010

11 MAJORITY OF PATIENTS ACHIEVE COMPLETE OR PARTIAL CONTROL OF SYMPTOMS ON SSA Symptomatic response 100 (74.2) (71) (77.3) (75) (63.0) (63) (67.5) (63) % of response Flushing n=53 Diarrhea n=49 25% 57% 74% 89% >50% Improvement Complete response 0 OCT OCT LAR LAN LAN SR+AG Studies n=11 n=7 n=1 n=7 Patients n=261 n=122 n=30 n=185 Octreotide Lanreotide 5-HIAA n=57 68% 5% Patients with improvement (%) Modlin IM et al. Aliment Pharmacol & Therap 2010 Moertel CG. J Clin Oncol 1987

12 ANTIPROLIFERATIVE EFFECT OF SSA IN PATIENTS WITH NETS ANTIPROLIFERATIVE EFFECT OF SSA IN PATIENTS WITHOUT DOCUMENTED PD ANTIPROLIFERATIVE EFFECT OF SSA IN PATIENTS WITH DOCUMENTED PD OR ~5% SD 60-70% OR ~5% SD 40-45% Toumpanakis C, et al. Semin Oncol 2013

13 CONTROLLED STUDY OF LANREOTIDE ANTIPROLIFERATIVE RESPONSE IN NET CLARINET STUDY Lanreotide Autogel 120 mg Advanced nonfunctioning NETs R Primary endpoint: PFS N = 204 pts Placebo Primary endpoint: Time to either disease progression (measured using RECIST criteria) or death, occurring within 96 weeks of the first injection Secondary endpoints: Tumor progression rate at 48 and 96 weeks, TTP, OS, QoL, PK, Safety, Biomarkers

14 CHEMOTHERAPY FOR CONTROLLING PANCREATIC NETS Vilar E, et al. Endocr Rel Cancer, 2007

15 RANDOMIZED CONTROLLED TRIALS WITH CHEMOTHERAPY There have been few randomized controlled trials Tumour type Regimen n Objective response (%) Overall survival (months) Response assessment Pancreatic NET 1 STZ + DOX STZ + 5-FU Radiologic GI NET 2 STZ + 5-FU DOX Clinical exam Early chemotherapy trials did not use RECIST criteria, nor did they report PFS STZ = streptozotocin; DOX = doxorubicin; 5-FU = fluorouracil 1 Moertel, et al. N Engl J Med. 1992;326(8): Engstrom, et al. J Clin Oncol. 1984;2(11):

16 PEPTIDE RECEPTOR RADIONUCLEOTIDE THERAPY (PRRT) Kaltsas GA, et al. End Relat Cancer 2005

17 PRRT FOR CONTROLLING NETS Kwekkeboom DJ, et al. J Clin Oncol. 2008

18 MOLECULAR TARGETS IN NETS Capdevila J, et al. Cancer Discovery 2011

19 NEW TARGETED AGENTS IN pnets Raymond E, et al. N Engl J Med. 2011; Yao J, et al. N Engl J Med. 2011;

20 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 mos 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 Secondary Endpoints: OS ORR TTR Duration of response Safety Patient-reported outcomes Raymond E, et al. N Engl J Med. 2011

21 SUNITINIB VS PLACEBO IN ADVANCED PNET Raymond E, et al. N Engl J Med Percentage of event-free Number at risk: Sunitinib Placebo Censoring times Sunitinib (n/n = 30/86) Placebo (n/n = 51/85) Kaplan-Meier median PFS Sunitinib: 11.4 months Placebo: 5.5 months HR = 0.42 ; 95% CI [ ] P value <.001; nominal critical z value = Time (months) * Local review

22 Raymond E, et al. N Engl J Med PHASE III SUNITINIB Best confirmed tumor response, n (%) Complete response Partial response Stable disease/no response Objective progression Not evaluable Objective response rate (95% CI) Two-sided p value for treatment difference Sunitinib (n=86) 2 (2.3) 6 (7.0) 54 (62.8) 12 (14.0) 12 (14.0) 9.3% (3.2%, 15.4%) Median (range) duration of response, months 8.1 ( ) Placebo (n=85) (60.0) 23 (27.1) 11 (12.9) Stable disease >6 months, n (%) 30 (34.9) 21 (24.7) 0

23 PHASE II-III STUDIES OF EVEROLIMUS IN NETS Study Population (n) Desig Primary End Point Study Status MDACC Islet cell tumors Single-arm, Response rate Results (Phase II) Carcinoids (30) stratified RADIANT TRIALS (RAD001 In Advanced Neuroendocrine Tumors) Study Population (n) Design Primary End Point Study Status RADIANT-1 (2239) Islet cell tumors failing chemotherapy (144) Single-arm, stratified (Phase II) Response rate Results RADIANT-2 (2237) Carcinoid (Sandostatin) (429) Randomized placebo- RAD (Phase III) PFS Results RADIANT-3 (2324) Islet cell tumors (410) Randomized placebo- RAD (Phase III) PFS Results

24 RADIANT-3: STUDY DESIGN Phase III, Double-Blind, Placebo-Controlled Trial Patients with advanced pnet (N = 410) Advanced well or moderately differentiated Radiologic progression 12 months Prior antitumour therapy allowed WHO PS 2 Stratified by: WHO PS Prior chemotherapy R A N D O MI S E 1:1 Everolimus 10 mg/d + best supportive care 1 n = 207 Crossover at disease progression Placebo + best supportive care 1 n = 203 Multiphasic CT or MRI performed every 12 weeks Treatment until disease progression Primary Endpoint: Progression-free survival By investigator review Secondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK) 1 Concurrent somatostatin analogues allowed Yao JC, et al. N Engl J Med. 2011

25 RADIANT-3 PFS BY CENTRAL REVIEW COMMITTEE % Event-free Kaplan-Meier median PFS Everolimus: 11.0 months Placebo: 4.6 months Hazard ratio = 0.35; 95% CI P value: < Censoring times Everolimus (n/n = 109/207) Placebo (n/n = 165/203) 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, et al. N Engl J Med. 2011

26 EVEROLIMUS PROVIDED A DURABLE PFS BENEFIT PFS; Kaplan-Meier estimates [95% CI] Everolimus 10 mg n = 207 Placebo n = months 84.0 [ ] 58.5 [ ] 6 months 69.5 [ ] 31.9 [ ] 12 months 45.6 [ ] 15.4 [ ] 18 months 34.2 [ ] 8.9 [ ] Median treatment duration (months) Median follow-up 17 months Yao JC, et al. N Engl J Med. 2011

27 RADIANT-3: PERCENTAGE CHANGE FROM BASELINE IN SIZE OF TARGET LESIONS RR by RECIST: 5% Yao JC, et al. N Engl J Med. 2011

28 OUTLINE BACKGROUND AND DECISION MAKING CRITERIA MANAGEMENT OF GRADE 1/2 NETS MANAGEMENT OF GRADE 3 NECS GUIDELINES FOR THE MANAGEMENT OF ADVANCED NENS

29 MANAGEMENT OF G3 NECS G1 G2 G3 Cumulative survival G3 G1 G1 vs G2 G1 vs G3 G2 vs G3 G2 P =.040 P<.001 P< Time (months) Pape UF, et al. Cancer. 2008;113:

30 MANAGEMENT OF G3 NECS The standard treatment for G3 NECs CISPLATIN + ETOPOSIDE Moertel 1991 pts OR Response duration (months) Median Survival (months) 18 67% 8 19 Mitry % 9 15 Fjallskog 2001 Welin 2011 (TMZ+CPC+BV) 36 47% % 19 22

31 Pharmacological Therapy in Metastatic Non-resectable Pancreatic NET ENETS Consensus Guidelines 2011 NEC G3 NET G1/G2 Functional NET G1/ G2 progressive Non-functional NET CTX contraindicated or not tolerated Cisplatin + Etoposide SSA IFN-α PPI Diazoxide STZ/Doxo + 5-FU G1 slowly progressive SRS + if high burden Everolimus Sunitinib PD Locoregional Tx Debulking; RFA Insulinoma Everolimus Sunitinib Everolimus PRRT SSA Further options: Loco-regional Tx TEM +/- CAP PRRT Modified from Pavel M, et al. Neuroendocrinology. 2012:95(2):

32 INTEGRATING GRADE AND TUMOR BURDEN IN PANCREATIC NETS Targeted Therapy Chemotherapy Targeted Therapy Surveillance SSA Targeted Therapy

33 TAKE HOME MESSAGES Grading G1/G2 (NETs) vs G3 (NEC) (WHO 2010) separates two different diseases and two different subgroups Surgery in metastatic setting, locoregional approaches, SSA constitute the main treatment approaches for G1 NETs (mainly carcinoids, few pnets )

34 TAKE HOME MESSAGES New targeted therapies have irrupted in the scenario of pancreatic NETs, where chemotherapy still has a role and should be integrated with SSA and locoregional approaches Advanced G3 NECs have a terrible prognosis where platinum-based chemotherapy is active but of short duration. New chemotherapy regimens with targeted therapies are warranted

35 GRÀCIES PER LA VOSTRA ATENCIÓ (I per la pressió, Carles )