Lorenzo Antonuzzo SC di Oncologia Medica
Azienda Ospedaliero Universitaria Careggi Firenze
Novità in tema di neoplasie
neuroendocrine
- (Brief) Introduction - Treatments overview
- Focus on new evidences (NETTER-1; RADIANT-4)
- Conclusions
ALL MALIGNANT NEOPLASMS
ALL NEUROENDOCRINE TUMORS
Yao et al. JCO 2008
Incidence: 5 / 100.000
Prevalence: 35 / 100.000
PANCREAS
• Median survival
– Carcinoid 43 months – pNET 27 months
Yao JC et al, J Clin Oncol 2008
Rindi, Wiedenmann. Nat Rev Endocrinol 2011
Jann et al, Cancer 2011; Rindi et al JNCI 2012
Intestinal NETs Pancreatic NETs
Pancreatic NETs Intestinal NETs
Rindi et al JNCI 2012, Jann et al Cancer 2011
Chemotherapy
Molecular targeted agents -mTOR
-Angiogenesis Ssa
Teloristat
Medical treatments
TACE TAE RF
Primary resection Metastasectomy Debulking
OLT
Interventional Radiology Surgery
Radiotherapy
PRRT
news
news
news
Tabella 2.1
Studi di legame in vitro della somatostatina-14 (SS-14), somatostatina-28 (SS-28) e dei principali analoghi agonisti ai diversi sottotipi dei recettori per lasomatostatina (SSTR). Modificata da Lamberts SWJ, Van der Lely AJ, de Herder W. Hofland LJ Octreotide. N. Engl. J. Med. 334: 246-254, 1996. *Modificata da Taylor JE, Coy DH.
The receptor pharmacology of somatostatin agonists and antagonists: implication for clinical utility.
J. Endocrinol. Invest. 20 (Suppl. 7): 8-10, 1997.
Reubi, J. C et al, Cancer Res 54, 3455– 3459
Kulke et al., ECC/ESMO 2015
13
*Including a blinded titration step of one week of 250 mg TID.
BM, bowel movement; SSA, somatostatin analog; TID, three times daily.
ClinicalTrials.gov. NCT01677910 TELESTAR. Available at: https://clinicaltrials.gov/ct2/show/NCT01677910. Accessed September 2015.
Telotristat etiprate 500 mg TID* (n=45) Telotristat etiprate 250 mg TID (n=45)
Placebo TID (n=45)
All patients required to be on SSA at enrollment and continue SSA therapy throughout study period 1:1:1
3- to 4-week run-in
(n=135) R
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)
Run in: Evaluation of bowel movement (BM)
frequency
© IEO 2011
All patients continue SSA therapy throughout study period
Placebo n=45
Telotristat etiprate 250 mg n=45 Telotristat etiprate 500 mg n=45
Hodges–Lehmann estimator of treatment differences estimated a 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)
(P<0.001)
204 entero-pancreatic NETs Lanreotide vs placebo 86 intestinal NETs
Octreotide vs placebo
Somatostatin analogs improves PFS in «low grade» digestive NETs
Rinke et al, J Clin Oncol 2009 – Caplin et al NEJM 2014
Caplin et al NEJM 2014
Caplin M et al. Endocr Relat Cancer 2016
CLARINET study: data from open label extension study
Caplin et al Endocr Related Cancer 2016
Mean LAN treatment exposure: 43.5 m in LAN-LAN and 18.8 m in PBO-LAN
Caplin M et al. Endocr Relat Cancer 201690 Y
177 Lu + DTPA
DOTA + ocreotate
Peptide Receptors Radiolabelled Therapy (PRRT)
Adapted from Kaltsas et al. Endocr Related Cancer 2005
Van der Zwan et al Eur J Endocrinol 2014
MDS in 2.3% of pts Acute leukemia in 1.1%
Nephrotoxicity
Hematological toxicity
Yao et al NEJM 2011
• Unresectable advanced and/or metastatic, Well differentiated pNET
• Documented disease
Progression in the last 12 Months*
(Target n= 340; n=171 Were recruited
before closure) Placebo + BSC
rand omised
N= 86 (170)
N= 85 (170)
37.5 mg
continuous daily sunitinib + BSC
Crossover to Sunitinib at disease progression
(n=38)
Raymond E et al NEJM 2011
Primary End point: PFS
EVE, compared with placebo, significantly improves PFS in patients with advanced progressive pancreatic able to prove efficacy for regulatory use
Yao et al NEJM 2011
Pavel M. et al ASCO 2015
SUN, compared with placebo, significantly improves PFS in patients with advanced progressive pNETs APPROVED for pancreatic NETs
Raymond et al. NEJM 2011
Raymond E. et al ASCO 2016
RADIANT-4 Study Design
*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.
Endpoints:
• Primary: PFS (central)
• Key Secondary: OS
• Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK
Everolimus 10 mg/day N=205
Treated until PD, intolerable AE, or consent withdrawal Patients with well-
differentiated (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
2:1
R A N D O M I Z E
Placebo N=97
Stratified by:
• Prior SSA treatment (yes vs. no)
• Tumor origin (stratum A vs. B)*
• WHO PS (0 vs. 1)
36
Yao JC et al. Lancet 2015;
37 Yao JC et al. Lancet 2015;
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. 38 Yao JC et al. Lancet 2015;
39 Yao JC et al. Lancet 2015;
Neuroendocrinology (DOI:10.1159/000443167) © 2016 S. Karger AG, Basel
22
Table 1. Therapeutic options and conditions for preferenti al use as first-line therapy in advaced NEN Drug Functionality Grading Primary site SSTR status Special considerations
Octreotide +/– G1 midgut + low tumor burden
Lanreotide +/– G1/G2 (–10%) midgut, pancreas
+ low and high (>25%) liver tumor burden
Interferon-alpha 2b
+/– G1/G2 midgut if SSTR negative
STZ/5-FU +/– G1/G2 pancreas progressive in short-term* or
high tumor burden or symptomatic
TEM / CAP +/– G2 pancreas progressive in short-term* or
high tumor burden or symptomatic;
if STZ is contraindicated or not available
Everolimus +/– G1/G2 lung
pancreas midgut
atypical carcinoid and/or SSTR negative;
insulinoma or
contr aindication for CTX if SSTR negative
Sunitinib +/– G1/G2 pancreas contraindication for CTX
PRRT +/– G1/G2 midgut + (requir ed) extended disease; extrahepatic disease, e.g. bone metastases Cisplatin§/
etoposide
+/– G3 any all poorly differentiated NEC
CTX = Chemotherapy; STZ = streptozotocin; 5-FU = 5 fluorouracil; TEM = temozolomide; CAP = capecitabine; SSTR = somatostatin receptor; * 6 months; §cisplatin can be replaced by carboplatin.
Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships)
Journal Editor:
Millar R.P. (Edinburgh)ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)
www.karger.com/NEN
Disclaimer: Accepted, unedited article not yet assigned to an issue. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
© 2016 S. Karger AG, Basel
Downloaded by: Ist.Europeo di Oncologia 198.143.49.33 - 2/17/2016 10:13:59 AM
Pavel M. Et al January 5, 2016 2016 Neuroendocrinology (DOI:10.1159/000443167)
42
Patients with GEP–LUNG NEC
11
