the landscape of neuroendocrine tumors in 2019 speaker presentations/session 1a 1b...clinical trial...

The Landscape of Neuroendocrine Tumors in

2019

Daniel Rayson MD FRCPC

Attending Medical Oncologist, QEII HSC

Professor of Medicine, Dalhousie University

Halifax, Nova Scotia

CANM, Ville de Quebec

Feb 8 2019

Disclosures

▪ Honoraria for advisory meetings/CME lectures

▪ Clinical trial as PI/sub-I (funding to institution only)

▪ Ipsen, Novartis, Roche, Pfizer

I/You have a what???

Incidence v Prevalence

Rate

Per

100,000

%

Since

1994

Absolute*

New Cases

2009

All Cancers 611.42 13% 62,174

All NETS 5.86 138% 596

Small Intestine

NETS1.01 140% 103

*Hallet J et al. Cancer 2014.

Diagnostic difficulties

▪Many cases grow very slowly without any symptoms, or

hormonal syndrome, over years

▪Those with symptoms are often diagnosed and treated

for other benign conditions before anyone thinks of NET

▪Some NET specific tests are not readily available, or

considered, across Canada

▪Historically, medical hoofbeats means horses, not

zebras

Variable presentations and symptoms

TTF1 CDX1

The Spectrum of Neuroendocrine

tumors of _____ origin

Appendiceal

Carcinoids

Small

Incidental

Neuroendocrine

Carcinoma

‘Indolently’Metastatic

Potential

Poorly

Differentiated

Variably

ProliferativeCarcinoid/

Other Syndromes

Functional

(~20-30%)

Non-Functional

Ki-67 Index

Proliferation and NETS

New 2017 WHO classification of NETs

• G3 NET and G3 NEC have distinct molecular signatures

Mitoses

(per 10

HPF)

Ki67

indexMorphology

G1 NET <2 <3% Well differentiated

G2 NET 2–20 3–20% Well differentiated

G3 NET >20 >20% Well differentiated

G3 NEC

• Small cell type

• Large cell type

>20 >20%Poorly

differentiated

DAXX/ATRX/

MEN1

p53/Rb1

Pathologic features1

(mutant genotype / loss of

nuclear labelling)

NET, neuroendocrine tumour; NEC, neuroendocrine carcinoma

1. Yachida et al. Am J Surg Pathol. 2012;36(2):173–84.

2. Tang et al. Clin Cancer Res. 2016;22(4):1011–7.ENETS 2017A. Perren, Session 3A: Aggressive NEN,

March 9, 2017.

Functional imaging and NET therapeutics

• Patients with lesions showing high SSTRI uptake are obvious candidates for PRRT

• Lesion(s) showing both FDG and SSTRI avidity, suggesting intermediate-grade clinical behaviour, may also benefit from PRRT

• Further validation is neededG1 Ki67<2% G2 Ki67 2–20% G3 Ki67 20–55% G3 Ki67 >55%

Unsuitable for PRRTSuitable for PRRT

“Sweet spot” for PRRT

FD

G-P

ET

++

SS

TR

-Octr

eo

scan

++

PRRT, peptide receptor radionuclide therapy; SSTRI, somatostatin receptor imaging

R. Hicks. Workshop: Imaging Update, March 10, 2017.

Functional Disease

▪ Insert Ostry Slide #3: EM

Clinical Characteristics of functional pNETS

Tumor Type SyndromeMetastatic

Incidence

Extrapancreatic

Location?

Insulinomasymptomatic

hypoglycemia<15% rare

Glucagonoma

rash-NEM

diabetes

cachexia

most rare

VIPoma WDHA syndrome most ~10%

Gastrinoma

refractory peptic

ulcers

diarrhea

<50% often duodenal

Somatostatinomadiabetes

diarrheamost rare

Spectrum of Symptoms Associated with

Carcinoid Syndrome

Creutzfeldt W. Carcinoid tumors: development of our knowledge. World J Surg. 1996;20:126-131

Serotonin

metabolism

and carcinoid

syndrome

Telotristat Etiprate

Somatostatin Analogues

AM: 24hr urinary 5-

HIAA: 407umol/L

(N < 50)


▪ First-line therapy due to efficacy in controlling functional syndrome, prolonging disease stability, tolerability, excellent patient support programs

▪ Two options:

▪ Sandostatin LAR 30mg

▪ Somatuline Autogel 120mg

▪ Both given by injection: IM v SC

▪ Both very well tolerated in general:

▪ Minimal discomfort

▪ Transient stool changes: fat malabsorption

▪ Slight longer term increased risk of gall bladder sludge/stones

Phase II data: Octreotide LAR

Rubin J et al J Clin Oncol 1999

SSAs as anti-proliferative agents

Median OS 84.7m; NS

Clarinet: Prespecified PFS Analysis by Tumor Origin

HR derived from Cox proportional hazards model. CI, confidence interval; HR, hazard ratio; NETs, neuroendocrine tumors; PBO, placebo; PD, progressive disease; PFS, progression-free survival; PNETs, pancreatic neuroendocrine tumors.

Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.

0 3 6 9 12 18 24 27

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts a

live

and w

ith n

o p

rogre

ssio

n (

%)

Time (months)P

atie

nts

ali

ve

and w

ith n

o p

rogre

ssio

n (

%)

Lanreotide

8 events / 33 patients

Median PFS not reached

Placebo


Median PFS = 21.1 months [95% CI: 17.0, NC]0

10

20

30

40

50

60

70

80

90

100

Time (months)

0 3 6 9 12 18 24 27

Lanreotide


Median PFS not reached

Placebo


Median PFS = 12.1 months [95% CI: 9.4, 18.3]

PNETs (n=91)

Lanreotide 120 mg vs

PBO: HR=0.58

[95% CI: 0.32, 1.04]

Midgut NETs (n=73)

Lanreotide 120 mg vs

PBO: HR=0.35

[95% CI: 0.16, 0.80]

42 39 32 29 24 20

49 48 38 33 23 17

13

Numbers of patients at risk of death or PD

8 0

033 33 32 30 28 24

40 39 36 32 28 20

16

Numbers of patients at risk of death or PD

13 0

0

PROMID HR = 0.34 95% CI 0.20, 0.59

CLARINET: Safety – Adverse Events

*Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed.

**Defined as hazardous to well-being, or significant impairment of function or incapacitation.Somatuline Depot (lanreotide) injection [Prescribing Information]. Basking Ridge, NJ: Ipsen Biopharmaceuticals, Inc; 2014.

Any (%) Severe** (%) Any (%) Severe** (%)

Any adverse reactions 88 26 90 31

Abdominal pain 34* 6* 24* 4

Musculoskeletal pain 19* 2* 13 2

Vomiting 19* 2* 9* 2*

Headache 16 0 11 1

Injection site reaction 15 0 7 0

Hyperglycemia 14* 0 5 0

Hypertension 14* 1* 5 0

Cholelithiasis 14* 1* 7 0

Dizziness 9 0 2* 0

Depression 7 0 1 0

Dyspnea 6 0 1 0

> 5% incidence with > 5% diff c/w placebo

Key Questions at each decision point

▪Does this patient need treatment at this time?

▪ Is this change on the scan significant enough to pose a

threat or to change/add treatment?

▪Are there new/progressive functional symptoms?

▪ Is there something we can do to target the specific area of

disease?

▪ Is there a surgical option for significant debulking?

▪ Is the tumor somatostatin-avid and do we have access to

PRRT?

Inadequate control of carcinoid syndrome:

more than just dose escalation

Unmet medical need in poorly controlled

carcinoid syndrome

▪Daily symptoms impacting QOL, functional capacity,

work status, social interactions

▪Prolonged survival times therefore long duration of

symptom burden

▪Polypharmacy and/or invasive intervention required for

symptom control in absence of syndrome-specific

therapy

▪Carcinoid heart disease risk is a function of persistent

syndrome and elevated 5-HIAA and a major source of

mortality

Lanreotide PRO study: SSA dose is not always

the issue

▪30% had other potential causes of diarrhea.

▪Of these:

▪44%: small bowel resection

▪ bile salt malabsorption : Questran

▪ bacterial overgrowth: ? role of abx ?

▪32%: pancreatic insufficiency ***

▪ Pancreatic enzymes

▪24%: Ileocecal valve/colonic resection:

▪ Immodium/Loperamide

SSA Dose Escalation

Uncontrolled

symptom prior to

escalation

Number of

patients reporting

% reporting

improvement or

resolution

Flushing 90 81%

Diarrhea 107 79%

• Major limitations include retrospective nature of the data, uncertain follow-up time,

no standardized reporting, potential reporting bias, no control for concomittant Rx

• Max dose 133 mg q 4 wk; 21 patients received at least 1 dose escalation > 60mg

Strosberg J et al The Oncologist 2014

Serotonin

metabolism

and carcinoid

syndrome

Telotristat Etiprate


NET of small intestinal origin: disease

progression after SSA

NETTER-1: Lu-177 PRRT in progressive disease

177Lu-Dotatate

(n = 101)

Control

(n = 100) P Value†

Complete

response (%)1 0 N/A

Partial

response (%)17 3 N/A

Response

Rate % (95%

CI)

18 (10–25) 3 (0–6) <0.001

Objective response rates to LU-177 and high

dose SSA

Strosberg J et al, NEJM 2017

Any (%) Gr3/4 (%) Any (%) Gr 3/4(%)

Nausea 59 4 12 2

Vomiting 47 7 10 1

Fatigue 40 2 25 2

Appetite 18 0 8 3

Headache 16 0 5 0

Alopecia 11 0 2 0

Platelets 25 2 1 0

Anemia 14 0 5 0

Lymphos 18 9 2 0

Significant toxicity differences in

Netter-1

Strosberg J et al NEJM 2017

RADIANT-4 Study Design

Everolimus 10 mg/d +

best supportive care*

n = 207

Placebo +

best supportive care*

n = 203

Multi-phasic CT or MRI performed every 12 weeks

Treatment

until disease

progression

• N = 302

•2:1 randomization

•Non-functional

•Within 6 m of

radiologic

progression

Crossover

1:1

* Concurrent somatostatin analogs allowed

R

A

N

D

O

M

I

Z

E

Primary endpoint:• PFS (central review)

Randomization August 2007 - May 2009

Progressive, non-functional NET of GI (non-pancreatic)and lung origin

Yao et al. NEJM 2011, Lancet 2016.

PFS: 11m v 3.9m;

HR 0.48 (CI: 0.35-0.67)

P < 0.00001

> 24 m improvement

in median PFS in

Netter-1

▪Other systemic options –

approach with caution in

functional disease

Hepatic-Directed Therapy

Resection

Hepatic arterial ligation

Hepatic arterial embolization +/- chemotherapy

Hormonal response: 50% - 100%

Tumor response: 27% - 86%

Radioembolization

ischemia

radiation

Source: Bilbao, JI. Interventional Radiologist, Pamplona, Spain

Systemic Options for pNET

Systemic options in pNET

ORR Δ PFS ΔOS Comment

Somatuline 0%Not reached v

12 m-

90% non-

progressing at

study entry

Everolimus 5% v 2% 11m v 3.9 m -

Toxicity profile

can be difficult/

hyperglycemia

Sunitinib 9.3% v 0% 11.4 v 5.5m -

Stopped early-

? Over-

optimistic PFS

impact

CapTem*** 70%

(21/30)Median = 18 m -

Retrospective

data

NETTER 1: midgut NETS only

CAPTEM

▪Oral combination chemotherapy regimen

▪Capecitabine 750mg/m2 BID

▪Temozolomide 150-200mg/m2 daily

CapTem meta-analysis (15 studies; n = 384)

Lu Y et. Al Medicine 2018

CapTem meta-analysis (15 studies; n = 384)

Disease control rates (CR/PR/SD)

Lu Y, Medicine 2018

NET challenges and opportunities

▪ Integration of PRRT into Canadian NET landscape

▪Sequencing of multiple potentially efficacious therapies:

▪Toxicities

▪Cost

▪ Individualization not just precision

▪ ? Role for Immunotherapies in Grade 3 NEC ?

▪ Optimization of syndromic control

▪ Decrease risk/incidence of carcinoid heart disease

▪ Improve QOL

▪ Defining role of hepatic-directed therapies in the new

era of NET clinical trials and need for level 1 evidence

The importance of multidisciplinary,

interprovincial collaborative care

KK

53 yo man witn no comorbidities

▪ March/2011: acute hemorrhagic left-sided CVA

▪ Full cerebrovascular and neurologic w/u negative except for new onset insulin-

controlled diabetes mellitus diagnosed ~ 6 months prior

▪ As part of evaluation: CT scan

▪7 cm duodenal mass in context of iron-definiciency anemia

▪ Laparatomy: 7 cm duodenal paraganglioma, 1 of 2 nodes +, CgA/Syn +

Ki-67 index: 10%

▪ 6 weeks post-op: complete resolution of DM, off all medications

▪ Discharged from active F/U

KK

▪June-July 2015: recurrent issues with glycemic control

▪August 2015: acute onset upper abdominal

pain/diaphoresis

ECG- acute STEMI with elevated troponins

coronary angiogram: negative for CAD, treated medically

▪December 2015: new onset constipation: CT

CT shows several abdominal masses

123I-MIBG: uptake in the masses,

but more intense in the anterior mass

Scan 1 week after 200mCi 131I-MIBG: almost all of the activity went into

the anterior mass (2 of the other foci are just the normal adrenals). This

happened twice (ie we treated twice with 200mCi, and post therapy

scan showed almost all activity went to the one mass).

Cross sectional imaging: Jan 9/2017 c/w

July/22/2016:

Anterior abdominal mass: minor

response

All other masses: minor

progression/stable

Therapeutic MIBG: 200 mCi of I131 MIBG- 2

cycles: April and Sept 2016

KK

▪Therapeutic MIBG: 200 mCi of I131 MIBG- 2 cycles:

April and Sept 2016

Amine Feb/16/2016 Jan/29/2017

U Norepinephrine

(N: 0-591 nmol/TV 8706 10675

U Norepinephrine

(N: 0-30 umol/molC 864.5 897.8

U Dopamine

(N: 392-2500 nmol/TV) 3682 12728

U Dopamine

(N: 0-185 umol/molC) 365.7 1070.5

18F-FDG PET:

- all lesions are ++ hot, including a few previously unknown

- less in anterior mass: ? d/t 131I-MIBG Rx. ? Different biology.

18F-FDG PET

111In-Octreotide:

~ per FDG (allowing for lower resolution,

sensitivity)

KK

▪Wrong target or intratumoral heterogeneity?

▪Octreoscan: avid disease, Krenning 3

KK

▪Therapeutic Lu-177: May/July/Sept/November 2017

▪Tolerated without toxicity

▪He learned a few words of French

Amine Jan/29/2017 Sept/27/2018

U Norepinephrine

(N: 0-591 nmol/TV 10675 674

U Norepinephrine

(N: 0-30 umol/molC 897.8 57.3

U Dopamine

(N: 392-2500

nmol/TV)12728 1775

U Dopamine

(N: 0-185

umol/molC)1070.5 150.6

Cross Sectional

Imaging:

33.6% reduction in

X-sectional

diameter of target

lesions Oct 2018

c/w July 2016: PR

the landscape of neuroendocrine tumors in 2019 speaker presentations/session 1a 1b...clinical trial...

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