novedades en neoplasias neuroendocrinas · functional neuroendocrine tumours of gastrointestinal or...
TRANSCRIPT
NOVEDADES EN NEOPLASIAS NEUROENDOCRINAS
V. ALONSO
SERVICIO DE ONCOLOGIA MEDICA
H. U. MIGUEL SERVET
LASTEST PROGRESS IN NENs
✓NEW CLASSIFICATION WHO PanNENs 2017
✓EPIDEMIOLOGY
✓DIAGNOSIS.- 68Ga PET-TC
✓TREATMENT OF NENs
LASTEST PROGRESS IN NENs
✓NEW CLASSIFICATION WHO PanNENs 2017
✓EPIDEMIOLOGY
✓DIAGNOSIS.- 68Ga PET-TC
✓TREATMENT OF NENs
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
ANTI-TUMOR EFFECTS OF LANREOTIDE FOR PANCREATIC AND INTESTINAL NEUROENDOCRINE TUMOURS: THE CLARINET OPEN-LABEL EXTENSION STUDY
Caplin M et al. Endocrine-Related Cancer 2016; 23: 191-99
ANTI-TUMOR EFFECTS OF LANREOTIDE FOR PANCREATIC AND INTESTINAL NEUROENDOCRINE TUMOURS: THE CLARINET OPEN-LABEL EXTENSION STUDY
Caplin M et al. Endocrine-Related Cancer 2016; 23: 191-99
138 p eligible - 88 p included41 LAN-----LAN47 PBO -----LAN
Treatment exposureLAN----------LAN-----------40 monthsPBO (SD)----LAN-----------18 monthsPBO (PD)----LAN-----------13 months
ANTI-TUMOR EFFECTS OF LANREOTIDE FOR PANCREATIC AND INTESTINAL NEUROENDOCRINE TUMOURS: THE CLARINET OPEN-LABEL EXTENSION STUDY
Placebo (PD)---------LAN
Caplin M et al. Endocrine-Related Cancer 2016; 23: 191-99
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
≥4 BM per day while stabledose SSAs for 3 months
<12 BM, no dehydration
IK>60%
Liver function tests
RECOMMENDED DOSE 250 mg TID
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
ObjectiveResponse
PFS/OS
Heterogenous Studies
• Retrospective studies – Introduce bias
• ORR 0-38% mPFS 15-36 months mOS 25-50 months
• Overestimation of results
Van der Zwan W et al. Eur J Endocrinol 2015
PRIMARY ENDOPOINT: PROGRESSION-FREE SURVIVAL
TTD was significantly longer in the 177Lu-Dotatate arm vs control: Global health status (HR 0.406), physical functioning (HR 0.518), role functioning (HR 0.580), fatigue (HR 0.621), pain (HR 0.566), diarrhea(HR 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425).Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning.
This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
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
• Enrolled within 6 months
from radiologic
progression
Everolimus 10 mg/day
N = 205
Treated until PD,
intolerable AE, or
consent withdrawal
2:1
R
A
N
D
O
M
I
Z
E
Placebo
N = 97
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 (worse 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
RADIANT-4 Study Design
Primary Endpoint: PFS by Central Review Interim Overall Survival Analysis
Neuroendocrine tumours of gastrointestinal orlung origin Afinitor is indicated for thetreatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours ofgastrointestinal or lung origin in adults withprogressive disease
APRIL 2016
On February 26, 2016, the U. S. Food and DrugAdministration approved everolimus (Afinitor ,Novartis) for the treatment of adult patientswith progressive, well-differentiated non-functional, neuroendocrine tumors (NET) ofgastrointestinal (GI) or lung origin withunresectable, locally advanced or metastaticdisease.
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
Yao C et al. JCO 2017
Treatment-NaiveN: 61
Previously-treatedN: 45
Overall Survival NA 33.8 months
Response Rate 21.3% 28.9%
Median durationResponse
19,1 months 14.7 months
Toxicity Grade 3-4
Neutropenia 20.8%
Diarrhoea 5,7%
HFS 6.6%
Thrombocytopenia 7.5%
Hypertension 5.7%
Raymond E et al. Neuroendocrinol 2018
Primary Endpoint: Progression-free survival by central review
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
CATEGORIES OF TREATMENT
✓SOMATOSTATIN ANALOGUES✓Octreotide✓ Lanreotide
✓TELOTRISTAT
✓PEPTIDE RECEPTOR RADIONUCLIDE THERAPY✓
90Y-DOTATE/DOTATOC✓
177Lu-DOTATE
✓mTOR inhibitors✓ Everolimus✓ Temsirolimus
✓TKI – Angiogenesis✓ Sunitinib✓Bevacizumab
✓CYTOTOXIC CHEMOTHERAPY✓ Streptozocin-based✓ Temozolomide-based
✓IMMUNOTHERAPY✓ Interferon✓PD-1 inh.
✓LIVER-DIRECTED THERAPY✓ TAE/TACE✓ SIRT
NENs have lower mutation rates than other cancers
Lawrence et al. Nature 2013
RR 12% RR 6%
Median age 59 years45% ECOG 1
≥2 lines – 67%PD-L1+ 16%
Median follow-up 18.6 months
Response Rate.- 3.7% (4 PR) – All PD-L1 -61 SD
mPFS 4.1 months6-months OS – 84.6%
20% G3-4 Toxicity (Fatigue + common)
Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in pts with previously treated advanced NET
Strosberg J. ASCO-GI 2019
Zhang et al. ESMO 2018
Zhang et al. ESMO 2018
Yao JC et al. ESMO 2018
Durvalumab plus Tremelimumab for the Treatment of Patients(pts) with Advanced Neuroendocrine Neoplasms (NENs) ofLung or Gastroenteropancreatic (GEP) Origin. A Phase IIMulticohort Trial (DUNE Trial / GETNE 1601)
DURVALUMAB 1500 mg every 28 days for 12
months
TREMELIMUMAB 75 mg every 28 days up to 4
doses
Efficacy and safety of Durvalumab plus Tremelimumab within four different cohorts: • Well-moderately differentiated lung NENs• Grade 1-2 gastrointestinal NENs• Grade 1-2 pancreatic NENs• Grade 3 GEP NENs
Primary endpoint for cohorts 1-3 is disease control rate at 9 months Primary endpoint for cohort 4 is median overall survivalCENTRAL RADIOLOGICAL REVIEW
Secondary endpoints: mPFS, survival, safety and tolerability and a wide panel of biomarkers in blood and tumor samples.
PI: J. Capdevila
➢ SSA strengthen their long-term antiproliferative effect even in patients in progression
➢ Telotristat is useful in the control of diarrhea in carcinoid syndrome
➢ Radionuclide therapy (PRRT) increase efficacy in NENs maintaining QoL
➢ mTOR inhibitors (Everolimus) has shown efficacy in all types of NENs
➢ New TKI drugs in development (Pazopanib, Cabozantinib, Lenvatinib, Axitinib,
Sulfanitinib) with excellent results in phase II trials
➢ Combination TMZ + CAP > TMZ in panNENs (Phase IIR)
➢ Immunotherapy (antiPD1) fails to show activity in most of NENs
CONCLUSIONS
