novedades en neoplasias neuroendocrinas · functional neuroendocrine tumours of gastrointestinal or...

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