Nuevas alternativas en el manejo de TNE avanzados

Nuevas alternativas en el manejo de TNE avanzados Jaume Capdevila Hospital Universitari Vall d Hebron Barcelona Coordinación científica: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander Organizado por: Fundación para el progreso de la oncología en Cantabria

Treatments Classification/Guidelines PROGRESS IN THE LAND OF NENS 2009 2015/16 1907 1980 2000 AJCC/UICC TNM classification GI/pNET 10 2006/08 2010 2012 ENETS guidelines including TC/AC 21 2015 2017 Karzinoide coined by Oberndofer 1 WHO classification Carcinoids 3 WHO classification NET and NEC 6 ENETS guidelines 4 ; TNM staging 5,7 NANETS guidelines 8 ESMO guidelines 22, 27 WHO classification Lung NET/carcinoids 35 WHO classification GEP- NENs 1900 1980 2000 2005 2010 2015/2017 1988/89 1998 2009 2014/15 2015/16 1982 STZ pnet 36 OCT SC CS 25,30 1992 STZ combination: survival benefit pnet 2 LAN symptom control 24 OCT LAR carcinoid tumors 23,26,28 2010/11 PROMID OCT LAR: antitumor activity 9,31 RADIANT-3 EVE in pnet 11,12,32,33 Sunitinib phase 3 pnet 13,31,34 CLARINET LAN GEP NET 16,17,29 ELECT LAN: symptom control 27 RADIANT-4 EVE NF GI and lung NET 15,19 2015 TELESTAR telotristat etiprate CS 20 NDA filed 3/30/16 US Approv al US/EU Approv al EU Approv al RADIANT-2 EVE + OCT, LAR in mnet w/cs 14 NETTER-1 177 Lu-Dotatate midgut NET 18

Frilling A, et al Lancet Oncol 2014

ADVANCED NENS THERAPEUTIC ALGORITHM Unresectable NENs Si-NET pannet LUNG NET NEN G3 G1 G2 G1 G2 G1 G2 NETG3 NECG3 Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy Lanreotide (CLARINET) Somatostatin Analogues Somatostatin Analogues? Everolimus RADIANT-3 & RADIANT-4 Chemotherapy Targeted agents? PRRT NETTER-1 Interferon Sunitinib Chemotherapy

PROMID AND CLARINET STUDIES Screening period Treatment period 12 24 weeks* CT scan 1 CT scan 2 Lanreotide Autogel 120 mg s.c. every 28 days Randomization 1:1 Placebo s.c. every 28 days 1 (baseline) 12 24 36 48 72 96 Study visits (weeks)

RADIANT PROGRAM RAD001 IN NEUROENDOCRINE TUMORS RADIANT-1 Phase II Pancreatic NETs Everolimus w/wo Octreotide LAR E E+O ORR 9.6% PFS 9.7m ORR 4.4% PFS 16.7m RADIANT-2 Phase III Non- Pancreatic NETs Octreotide LAR + Everolimus vs Octreotide LAR + placebo 16.4 vs 11.3m HR 0.77 P=0.026 (one sided) RADIANT-3 Phase III Pancreatic NETs Everolimus vs Placebo 11 vs 4.6m HR 0.35 P<0.001 RADIANT-4 Phase III GI & Lung NETs Everolimus vs Placebo 11 vs 3.9m HR 0.48 P<0.00001

RADIANT-4 STUDY DESIGN Patients with welldifferentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N=302) Absence of active or any history of carcinoid syndrome Pathologically confirmed advanced disease Radiologic disease progression in 6 months R A N D O M I Z E 2:1 Everolimus 10 mg/day N=205 Placebo N=97 Treated until PD, intolerable AE, or consent withdrawal Endpoints: Primary: PFS (central) Key Secondary: OS Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Stratified by: Prior SSA treatment (yes vs. no) Tumor origin (stratum A vs. B)* WHO PS (0 vs. 1) *Based on prognostic level, grouped as: Stratum A (better prognosis) appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worst prognosis) lung, stomach, rectum, and colon except caecum. Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Yao JC, et al. Lancet 2016

Probability of Progression-free Survival (%) PRIMARY ENDPOINT: PFS BY CENTRAL REVIEW 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 15 18 21 24 27 30 No.of patients still at risk Censoring Times Everolimus (n/n = 113/205) Placebo (n/n = 65/97) Kaplan Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Months Everolimus Placebo 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0 P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. CI, confidence interval; HR, hazard ratio. Yao JC, et al. Lancet 2016

Probability of Overall Survival (%) INTERIM OVERALL SURVIVAL ANALYSIS First interim OS analysis performed with 37% of information fraction favored the everolimus arm 100 90 Everolimus vs Placebo HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)* 80 70 60 50 40 30 20 10 Censoring Times Everolimus (n/n = 42/205) Placebo (n/n = 28/97) Next interim analysis is expected in 2016 0 0 2 4 6 8 10 12 15 18 21 24 27 30 Months No. of patients still at risk Everolimus Placebo 205 195 184 179 172 170 158 143 100 59 31 5 0 97 94 86 80 75 70 67 61 42 21 13 5 0 *P-value boundary for significance = 0.0002. P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. NS, not significant. Yao JC, et al. Lancet 2016

PFS HR BY PRIMARY TUMOR ORIGIN RETROSPECTIVE ANALYSIS, CENTRAL REVIEW Subgroups* No. Hazard Ratio (95% CI) Lung 90 0.50 (0.28-0.88) GI 175 0.56 (0.37-0.84) NET of unknown primary 36 0.60 (0.24-1.51) 0.1 0.4 1 10 Everolimus Better Placebo Better *One patient with thymus as primary tumor origin was not included. Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI. Hazard ratio obtained from unstratified Cox model. GI, gastrointestinal; NET, neuroendocrine tumors. Yao JC, et al. Lancet 2016

Pavel M, et al. Lancet, 2011

NETTER -1 STUDY DESIGN Aim Design Evaluate the efficacy and safety of 177 Lu-Dotatate (Lutathera ) plus Octreotide30 mg compared to Novartis Octreotide LAR 60mg (off-label use) 1 in patients with inoperable, somatostatin receptor positive, midgut NET, progressive under Octreotide LAR 30mg (label use) International, multicenter, randomized, comparator-controlled, parallelgroup Treatment and Assessments Progression free survival (Recist criteria) every 12 weeks Dose 1 Dose 2 Dose 3 Dose 4 Baseline and Randomization n = 115 n = 115 4 administrations of 7.4 GBq of LUTATHERA every 8 weeks + Octreotide30 mg Octreotide LAR 60mg every 4 weeks 5 Years follow up Strosberg J, et al. N Engl J Med 2017

POPULATION CHARACTERISTICS AT ENROLLMENT (N=229) 177 Lu-Dotatate (n=116) Octreotide LAR 60mg (n=113) Age (years), mean (SD) 63 (±9) 64 (±10) Gender, n (%) Male Female Primary tumor site, n (%) Jejunum Ileum Appendix Right colon Other Site of metastasis, n (%) Liver Lymph nodes Bone Lungs Other 53 (46%) 63 (54%) 6 (5%) 86 (74%) 1 (1%) 3 (3%) 20 (17%) 97 (84%) 77 (66%) 13 (11%) 11 (10%) 40 (35%) 60 (53%) 53 (47%) 9 (8%) 82 (73%) 2 (2%) 1 (1%) 19 (17%) 94 (83%) 65 (58%) 12 (11%) 5 (4%) 37 (33%) Strosberg J, et al. N Engl J Med 2017

PRIMARY ENDPOINT: PROGRESSION-FREE SURVIVAL Strosberg J, et al. ENETS 2018

SECONDARY ENDPOINT: OVERALL SURVIVAL Strosberg J, et al. ENETS 2018

SWOG S0518 STUDY DESIGN Study population Advanced G1/2 NET with poor prognosis Progressive disease Refractory syndrome G2 with 6+ lesion Colorectal or gastric primary R A N D O M I Z E 1:1 Bevacizumab 15 mg/kg q21 d octreotide LAR 20 mg q21 d Treatment until disease progression Interferon α-2b 5 mu 3 d/wk octreotide LAR 20 mg q21 d Multiphasic CT or MRI performed every 9 wk Primary endpoint: PFS (Central radiology review) Stratification factors: Primary site: Midgut vs others PD since diagnosis Histologic grade: G1 vs G2 Octreotide 2 months prior to registration Yao JC, et al. ASCO 2015

TELOTRISTAT ETIPRATE THE PHASE III TELESTAR CLINICAL TRIAL Serotonin Hormonal syndrome Diarrhoea... 5-HIAA Urine 5-HIAA: 5-hydroxyindole acetic acid SSA somatostatin analogue SSTR somatostatin receptor Serotonin Tryptophanhydroxylase Tryptophan 5-Hydroxytryptophan (5- HTP) Serotonin (5-HT) NET-cell Telotristat etiprate SSTR SSA

TELESTAR PHASE 3 STUDY DESIGN 3- to 4-week run-in (n=135) Run in: Evaluation of bowel movement (BM) frequency 1:1:1 R Placebo TID (n=45) Telotristat etiprate 250 mg TID (n=45) Telotristat etiprate 500 mg TID* (n=45) Telotristat etiprate 500 mg TID Evaluation of primary endpoint: Reduction in number of daily BMs from baseline (averaged over 12- week double-blind treatment phase) All patients required to be on SSA at enrollment and continue SSA therapy throughout study period Kulke M, et al. J Clin Oncol 2017

TELESTAR: REDUCTION IN DAILY BOWEL MOVEMENT FREQUENCY AVERAGED OVER DOUBLE-BLIND TREATMENT PHASE Hodges Lehmann estimator of treatment differences showed a median reduction versus placebo of 0.81 BMs daily for telotristat etiprate 250 mg dose (P<0.001) 0.69 for telotristat etiprate 500 mg dose (P<0.001) BM, bowel movement. Kulke M, et al. J Clin Oncol 2017

TREATMENT ALGORITHM IN sinets 1 st Treatment option SOMATOSTATIN ANALOGUES: Functioning & non-functioning Octreoscan +ive & -ive Ki67 up to 10% 2 nd Treatment option 3 rd Treatment option 4 th Treatment option EVEROLIMUS (EVEROLIMUS + SSAs) Non-functioning (functioning) Octreoscan +ive & -ive High & low tumor burden 177 Lu-DOTATATE Functioning & non-functioning Octreoscan +ive INTERFERON Indication based on a negative trial & old trials

Patients Alive and With No Progression, % CLARINET PFS IN ENTEROPANCREATIC NET PFS in midgut vs pancreatic NET 100 Mi d g u t NE T s ( n = 7 3 ) La nr e ot i de Au t o g e l vs p l aceb o P =. 0 0 9 1 HR = 0. 3 5 [ 9 5 % C I : 0. 1 6, 0. 8 0 ] 100 pn E T s (n = 9 1 ) La nr e ot i de Au t o g e l vs p l aceb o P =. 0 6 3 7 HR = 0. 5 8 [ 9 5 % C I : 0. 3 2, 1. 0 4 ] 90 90 80 80 70 70 60 60 50 50 40 30 Lan r eot i de A u t ogel 120 m g 8 e v e n t s / 3 3 p a t i e n t s m e d i a n, n o t r e a ch e d 40 30 Lan r eot i de A u t ogel 120 m g 1 8 e v e n t s / 4 2 p a t i e n t s m e d i a n, n o t r e a ch e d 20 10 0 P l a ce b o 2 1 e v e n t s / 4 0 p a t i e n t s m e d i a n, 2 1. 1 m o n t h s [ 9 5 % C I : 1 7. 0, N C ] 0 3 6 9 12 18 24 27 20 10 0 P l a ce b o 3 1 e v e n t s / 4 9 p a t i e n t s m e d i a n, 1 2. 1 m o n t h s [ 9 5 % C I : 9. 4, 1 8. 3 ] 0 3 6 9 12 18 24 27 Ti m e, m o nt hs Ti m e, m o nt hs Caplin ME, et al. N Engl J Med. 2014

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 M I 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

% Event-free RADIANT-3 PFS BY CENTRAL REVIEW COMMITTEE 100 80 60 40 Kaplan-Meier median PFS Everolimus: 11.0 months Placebo: 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) Yao JC, et al. N Engl J Med. 2011

EVEROLIMUS 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, et al. J Clin Oncol. 2012; 30 suppl. 34; abstract # 224.

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

Percentage of event-free SUNITINIB VS PLACEBO IN ADVANCED PNET 100 80 60 Kaplan-Meier median PFS Sunitinib: 11.4 months Placebo: 5.5 months HR = 0.42 ; 95% CI [0.26-0.66] P value <.001; nominal critical z value = 3.8506 40 Number at risk: Sunitinib Placebo 20 0 Censoring times Sunitinib (n/n = 30/86) Placebo (n/n = 51/85) 0 5 10 15 20 25 Time (months) 86 85 39 28 19 7 4 2 0 1 0 0 * Local review Raymond E, et al. N Engl J Med. 2011

Change from baseline (%) DEGREE OF TUMOUR SHRINKAGE IN THE SUNITINIB PHASE III STUDY Maximum change from baseline of target lesions in patients from the sunitinib phase III study* 60 40 Sunitinib Placebo 20 0 20 40 SD PD: 20% increase PR: 30% decrease 60 80 100 Confirmed partial or complete response The RECIST-defined ORR in patients receiving sunitinib was 9.3%; however, the majority of patients had some degree of tumour shrinkage (Clinical Benefit Rate 72%) Raymond E, et al. N Engl J Med. 2011

ESTIMATES OF OVERALL SURVIVAL Faivre S, et al. Ann Oncol 2016

STZ-BASED CHEMOTHERAPY IN PNETS Moertel C, et al. N Engl J Med, 1992

TEMOZOLOMIDE + CAPECITABINE Crespo G, et al. Future Oncol 2016

TEMOZOLOMIDE + CAPECITABINE

TEMOZOLOMIDE + CAPECITABINE RR: 28% vs 33% (p=0.47) G3-4 AEs: 22% vs 44% (p=0.007)

THERAPEUTIC ALGORITHM FOR pannets 1 st Treatment option SOMATOSTATIN ANALOGUES: Functioning & non-functioning Octreoscan +ive Ki up to 10% Not too much liver involvement 2 nd Treatment option 1 st Treatment option EVEROLIMUS / SUNITINIB / CHT Progressive disease Higher tumor burden Symptoms related with tumor burden EVEROLIMUS / SUNITINIB / CHT Sequential therapies

PFS HR BY PRIMARY TUMOR ORIGIN RETROSPECTIVE ANALYSIS, CENTRAL REVIEW Subgroups No. Hazard Ratio (95% CI) Lung 90 0.50 (0.28-0.88) GI* 168 0.60 (0.39-0.91) NET of unknown primary (n=36) or Others (n=8) 44 0.50 (0.22-1.16) 0.1 0.4 1 10 Everolimus Better Placebo Better *Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI tract. Yao JC, et al. Lancet 2016

LOW EFFICACY EVIDENCE OF CHEMOTHERAPY IN G1/G2 LUNG NETS Granberg D, et al. Ann Oncol 2011

RETROSPECTIVE EFFICACY EVIDENCE OF SSAs IN LUNG NETS Sullivan I, et al. Eur J Cancer 2017

THERAPEUTIC ALGORITHM FOR LUNG NETS 1 st Treatment option SOMATOSTATIN ANALOGUES Functioning & non-functioning Octreoscan +ive (mainly) Typical (atypical) 2 nd Treatment option EVEROLIMUS 3 rd Treatment option CHT / PRRT

NET G3 (40%) Small cellnec G3 (95%) Ki-67

Nuñez-Valdovinos B, et al. The Oncologist 2018

SUGGESTED CHEMOTHERAPY IN FIRST-LINE REGARDING NEW CLASSIFICATION Fazio N & Milione M. Cancer Treatment Reviews 2016

Pellat A, et al. Neuroendocrinology 2017 SUNITINIB IN NET G3

PRRT IN NET G3 G1 & G2 tumors show comparable response to PRRT Up to Ki67 of 20%, no impaired response Potential cut-off for treatment failure >30-40% 1 (up to 55% last ENETS 2018 meeting 2 ) No differences of PRRT benefit comparing Ki67 index of 10, 15 and 20% 1 1.Ezziddin S, et al. Eur J Nucl Med 2011 2. Skovgaard D, et al. ENETS 2018

jacapdevila@vhebron.net jcapdevila@vhio.net