Teresa Alonso GordoaServicio Oncología Médica

Hospital Universitario Ramón y Cajal

Incidence rates of neuroendocrine tumors by primary tumor site

Inci

den

ce p

er 1

00

,00

0

Year

Lung

Apendice

Gastric

Colon

Small intestine

Rectum

Cecum

Pancreas

NET Site

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

EPIDEMIOLOGY

EPIDEMIOLOGY

Grade III

Grade II

Sackstein P, et al. Seminars Oncology 2018, In press

Grade I

EPIDEMIOLOGY

Halperin D, et al. Lancet oncol 2017

EPIDEMIOLOGY

Halperin D, et al. Lancet oncol 2017; 18: 525–34.

Incidence of total NETs and carcinoid syndrome, 2000–2011

Percentage of patients with incident NETs diagnosed with carcinoid syndrome.

EPIDEMIOLOGY

Halperin D, et al. Lancet oncol 2017; 18: 525–34.

Metastatic grade 1–2 small bowel NETsEntire NET cohort

Overall survival of patients diagnosed with NET, 2000–2011

23/11/2018 9

SYMPTOMS AT DISEASE

PRESENTATION

Halperin DM, Kulke MH & Yao JC. Ann Rev Med 2015

CARCINOID SYNDROME

✓ Serotonin and other hormones play a central role.

✓ Incidence ≈ 8-35% of patients with NETs mainly with liver metastasis, butnot only.

✓ Symptoms are different among patients

Yao JC, Hassan M, Phan A et al. J Clin Oncol 2008;26: 3063–3072.Oberg K, Akerström G, Rindi G et al. Ann Oncol 2010;21(suppl 5): v223–v227Kulke, MH, Mayer RJ. Carcinoid tumors. NEJM 1999;340(11):858-868 .

THERAPEUTIC AGENTS THAT HAVE BEEN

EVALUATED IN PATIENTS WITH FUNCTIONING

NET

SYMPTOMS

CONTROL

AVOID

COMPLICATIONS

WINDOW OF

THERAPEUTIC

OPPORTUNITY

TUMOR GROWTH

CONTROL

QUALITY OF LIFE

SOCIAL/FAMILY/LAB

OR ENVIRONMENT

SURVIVAL

IMPROVEMENT

ENDPOINTS

HORMONE

SECRETION

CONTROL

SURGERY

CHEMOTHERAPY

SOMATOSTATIN

ANALOGUES

INTERFERONEVEROLIMUS/SUNITI

NIB

RADIONUCLIDES

LIVER DIRECTED

THERAPIES

TREATMENT FOR NETs

TELOTRISTAT

GαGβ Gγ

Ca 2+

Hormona

Secretion

Voltage

Ca 2+ channel K+ channel

K+

cAMP

AC PTPaseSHP-1

SHP-2

PTP-γ

Caspase 8

Wild type p53

Bax

pHi

Endonuclease

Apoptosis

ERK 1/2

P27kip1

ERK 1/2

Cell Growth Secretion

Ca 2+

Ca 2+ channel

PLCβ

IP3

SSTR1-

5

SRIF

IGF-1R

IGF-1

Signaling

Toumpanakis C, Caplin ME. Update on the Role of Somatostatin Analogs for the Treatment of Patients With GEP NET. Semin Oncol 2013

SOMATOSTATIN ANALOGES

Rindi G & Wiedenmann B. Nature Reviews Endocrinology, 2012Modlin IM, Latich I, Kidd M et al. Clin Gastroenterol Hepatol 2006;4:526–547.

SOMATOSTATIN ANALOGES

SOMATOSTATIN ANALOGES

Rubin J, Ajani J, Schirmer W et al. J Clin Oncol.1999;17:600–606.

SOMATOSTATIN ANALOGES

Caplin ME, et al. N Engl J Med 2014;371:224-33

mTTP= 14.3 (O) vs 6.0m (P) (HR0,34; p<0.001

-Phase III-Well-differentiated metastatic midgut NETs (Ki67 1-2%)-Functioning and non functioning

SOMATOSTATIN ANALOGES

Caplin ME, et al. N Engl J Med 2014;371:224-33

-Phase III-Well-differentiated metastatic midgut NETs (Ki67 1-2%)-Functioning and non functioning

Rinke A et al. J Clin Oncol 2009;27:4656–4663 mPFS= NR(L) vs 18.0m (P) (HR0.47, p<0.001)

-Phase III-Well-differentiated metastatic NETs (Ki67 <10%)-Non functioning

SOMATOSTATIN ANALOGES

Fisher GA, et al. Endocr Practice 2018

SOMATOSTATIN ANALOGES

-Phase III-Well-differentiated metastatic NETs (Ki67 <10%)-Stable Carcinoid Syndrome

OPEN LABEL (IOB) PHASE (32 weeks)

LONG TERM OPEN LABEL EXTENSION (≥2 years)

Fisher GA, et al. Endocr Practice 2018

SOMATOSTATIN ANALOGES

-Phase III-Well-differentiated metastatic NETs (Ki67 <10%)-Stable Carcinoid Syndrome

RESISTANCE TO SSA

Octreotide fails in carcinoid syndrome control in approx 71% of patients after 36 moths of treatment.

% of patients still responding over time (months)

86%74%

50%

29%

0%

20%

40%

60%

80%

100%

0-6 6-12 12-24 24-36

Courtesy of Dr E. Grande. Presented at ESMO 2015.Beaumont JL, et al. Pancreas 2012Kvols L, et al. Endocr Relat Cancer 2012

RESISTANCE TO SSA

Molina-Cerrillo J, Alonso-Gordoa T, Saez O & Grande E. The Oncologist. 2016

Mechanisms of resistance Observations

Different phosphorylation patterns In SSTR2 different phosphorylation patterns have been described over

4 threonine residues (Thr353, Thr354, Thr356, and Thr359) with

octreotide and only 2 threonine residues (Thr356 and Thr359) with

pasireotide. This phosphorylation is mediated by G protein-coupled

receptor kinases (GRK) 2 and 3, whose intracellular levels are

variable. The inhibition of these enzymes results in a reduction of

approximately 40% of SSTR2 phosphorylation.

Type of β-arrestins There are two major subtypes of β-arrestins, A and B. Replacement of

SSTR2 on the cell surface depends on β-arrestin (Type B)

internalization, once bound to the phosphorylated endosomal vesicle,

produces rapid receptor internalization. SSTR3 and SSTR5 are also β-

arrestin (Type A) dependent receptors, but their junction is less stable

so the internalization is less efficient. On the contrary, SSTR1 and

SSTR4 are not depending on this molecule for internalization.

Homo/Heterodimers Different types of receptors co-exist in the same cell surface, enabling

the formation of homo- and heterodimers between them, such as the

heterodimerization between SSTR5 and SSTR1

Antibody formation Creation of antibodies against somatostatin analogs, decreasing their

effectiveness.

ENETS GUIDELINES

Pavel M, et al. Neuroendocrinology, 2016

LOCAL TREATMENTS:

SURGERY AND LOCOREGIONAL TREATMENT

✓ Surgery can be curative if it reaches R0.

✓ Arterial hepatic embolization/radioembolization can be usefullin selected patients

✓ Use of those techniques depends on tumoral size, number of metastases, anatomic viability and surgeon/radiologistexperience.

✓ May help in symptoms relief.

Toumpanakis C, et al. Brest Pract Res Clin Endocrinol Metab. 2007Eriksson B, et al. World Surg. 2008

INCREASE SSA DOSE

Strosberg J. Gastrointest Cancer Res 6:81– 85

INTERFERON

Symtomatic hormone response: 40-70%.

Disease control rate: 50-60%, OR= 10-15%.

Alonso-Gordoa T, et al E. Eur J Endocrinol 2015

Pavel ME, Lancet 2011Yao JC, J Clin Oncol 2012 (Abstr 157)

Patients with advanced NET and history of carcinoid syndrome (N=429)- G1 or G2 histology- rDP within 12

months- Prior therapy

allowed- WHO PS ≤ 2

RA

ND

OM

IZED

Everolimus 10 mg/day + Octreotide LAR 30 mg q28d (N=216)

Placebo + Octreotide LAR 30 mg q28d (N=213)

Everolimus 10 mg/day + Octreotide LAR 30 mg q28d (N=143)

Double-blind phasePrimary analysis

Open-label everolimus at progresssion and unblinding

PD

RADIANT-2

1:1

EVEROLIMUS

EVEROLIMUS

Pavel ME, Lancet 2011Yao JC, J Clin Oncol 2012 (Abstr 157)

Changes in biomarker concentrations over time by treatment group

Cromogranin A

24 hour urine 5HIAA

RADIANT-2

RADIONUCLIDES

RADIONUCLIDES

Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

Aim

Design International, multicenter, randomized, comparator-controlled, parallel-group

Evaluate the efficacy and safety of 177Lu-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)

Baseline

and

Randomization

n = 115

Dose 1

n = 115

Treatment and AssessmentsProgression free survival (Recist criteria) every 12 weeks

5

Years

follow

up

Dose 2 Dose 3 Dose 4

1. FDA and EMA recommendation

4 administrations of 7.4 GBq of 177Lu-Dotatate

every 8 weeks + Octreotide30 mg

Octreotide LAR 60mg every 4 weeks

NETTER-1

RADIONUCLIDES

Strosberg J, et al. JCO 2018

RADIONUCLIDES

Strosberg J, et al. JCO 2018

TTD was significantly longer in the 177Lu-Dotatate arm compared with the octreotidearm in diarrhea

TELOTRISTAT

Molina-Cerrillo J, Alonso-Gordoa T, Saez O & Grande E. The Oncologist. 2016

TELOTRISTAT

Kulke M. ESMO 2015.Kulke M. et al. J Clin Oncol 2016

TELOTRISTAT

Kulke M. et al. J Clin Oncol 2016

TELOTRISTAT

Pavel et al. Presented NANETS 2016

✓ Similar design that TELESTAR, but including patients with less-severe gastrointestinal symptoms.

✓ Endpoints: Efficacy an safety.

CONCLUSIONS: BUILDING ON SUCCESS

✓ Carcinoid syndrome is lead by serotonin activity and can significantly deteriorate the quality of life of patients.

✓ Treatment with SSA is effective but the symptomatology of patients “resist” along the treatment.

✓ There are some drugs potentially effective in carcinoid syndrome, but further research is required: involvement in antitumor effect.

✓ Telotristat is a drug which inhibits peripherally secretion of serotonin, effective in refractory carcinoid syndrome.

✓ Pending questions: Adequate dose, antitumor effect, long term efficacy and safety (TELEPATH), durability of responses, prevention of fibrosis...

MUCHAS GRACIAS POR VUESTRA ATENCIÓN

talonso@oncologiahrc.com