NET

(1)

Lorenzo Antonuzzo

SC Oncologia Medica

Azienda Ospedaliero Universitaria Careggi Firenze

(2)

Dasari et al. JAMA ONCOL 2017

(3)

Slide 4

Presented By Nicola Fazio at 2018 ASCO Annual Meeting

(4)

PANCREAS

Dasari et al. JAMA ONCOL 2017

(5)

2010 to 2017 WHO classif ication

• NETumor, G1

• NETumor, G2

• NECarcinoma, G3

• Small cell type

• Large cell type

Well differentiated NET

Poorly

Differentiated = NEC G3-NET not included in the last (2010) WHO

First report of G3-NET: 2013 Velyoudom-Cephise, ERC

2010 t o 2017 WHO classif icat ion

• NETumor, G1

• NETumor, G2

• NETumor, G3

• NECarcinoma, G3

• Small cell type

• Large cell type

Well differentiated NET

Poorly

Differentiated=NEC Well-diff NET of grade 3 are included in the 2017 WHO for Pan-NEN

Evaluation of the grade does not change in the new WHO

≤ 2%

2 – 20%

> 20%

≤ 2%

2 – 20%

> 20%

Ki 67

(6)

TACE TAE RF

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

Paziente Endocri nologia

Oncolo gia

Chir urgia

Gastroent erologia Medi

cina Nucle

are Radiol

ogia Gene

tica Anato

mia Patolo

gica

Primary resection Metastasectomy Debulking

OLT

Interventional Radiology Surgery

(7)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

(8)

Kulke et al. JCO 2017

(9)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

(10)

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

(11)

Additional SSA questions being addressed by ongoing studies Maintenance?

Dose-

intensification?

Combination?

CLARINET-Forte | Efficacy and Safety of Lanreotide 120 mg administered every 14 days in Pancreatic or Midgut NETs Having Progressed Radiologically While Previously Treated With Lanreotide 120 mg

[NCT02651987]

REMINET | A Study Evaluating Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno- Pancreatic Neuroendocrine Tumors [NCT02288377]

SONNET | Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET [NCT02231762]

SSAs | SELECTED ONGOING GEP NET STUDIES

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• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

(13)

Strosberg et al. NEJM Jan 2017

(14)

Strosberg et al. ASCO 2018

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Strosberg et al. NEJM Jan 2017

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Key Adverse Events: all grades and grades 3-4

Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium

(17)

MDS in 2.3% of pts Acute leukemia in 1.1%

Nephrotoxicity

Hematological toxicity

(18)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

(19)

Kaplan Meier median Sunitinib 11.4 mo Placebo 5.5 months

Everolimusis indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated

neuroendocrine tumours of pancreatic origin in adults with progressive disease.³

Sunitinibis indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic

neuroendocrine tumours (pNET) with disease progression in adults.⁴

1Yao et al NEJM 2011;364(6):514-23; ²Raymond et al NEJM 2011;364(6):501-13; ³Afinitor SPC (accessed 01/03/2016); ⁴Sutent SPC (accessed 01/03/2016)

RADIANT-3 (everolimus)

¹

SUN1111 (sunitinib)

²

TARGETED THERAPY | PRIMARY ENDPOINT

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21 Yao JC et al. Lancet 2015;

(21)

mPSF 6 mos mOS 28 mos

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STUDY DESIGN

TALENT Trial: A phase II T rial to Assess the efficacy of LENvatinib in metastatic neuroendocrine T umors (GETNE 1509)

Lenvatinib 24 mg qd

Patients with advanced/metastatic G1/G2 neuroendocrine tumors of the pancreas after progression to a previous targeted agent

N = 110 pts

Cohort A

Cohort B

Patients with advanced/metastatic G1/G2 neuroendocrine tumors of the gastrointestinal tract after progression to somatostatin

analogs

• Primary endpoint: Overall response rate (ORR) by RECIST v 1.1 upon central radiologic assessment Hip: Objective Response Rate with Lenvatinib up to 25%

• Secondary endpoints: safety, progression-free survival, overall survival, biomarkers

(23)

PRIMARY ENDPOINT: OVERALL RESPONSE RATE (CENTRAL RADIOLOGY REVIEW)

PanNETs (n=55)

GI-NETs (n=56)

Total (n=111) Patients with tumor

assessments

52 54 106

^*

Best overall response n(%)

Complete response (CR) 0 0 0

Partial response (PR) 21 (40.4%) 10 (18.5%) 31 ( 29.2%)

Stable disease (SD) 29 (55.8%) 41 (76%) 70 (66%)

Progressive disease (PD) 2 (3.8%) 0 2 (2%)

Not evaluable 0 3

^**

(5.5%) 3 (2.8%)

*Five patients withdrew the Informed Consent before the first post-basal tumor assessment.

**Central radiologist confirms that 3 patients did not have evaluable target lesions. They have been considered as not evaluable.

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PROGRESSION-FREE SURVIVAL

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Slide 4

Presented By Emily Bergsland at 2019 ASCO Annual Meeting

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Best Response & Waterfall Plots for RECIST Measurements (Central Review)

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Progression Free Survival (Central Review, ITT)

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• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

(29)

n RR PFS OS

(30)

Strosberg, Cancer, 2011

Advanced p-NETs N=30

Capecitabine 750 mg/m2 po BID days 1-14

Temozolomide 200 mg/m2 po QD days 10-14 q28 days X 3 cycles

• Study design - Retrospective - pNETs only

• Endpoints:

- RR 70%

- mPFS 18 mos

- Overall well tolerated No previous chemo

Grade:

16 low

9 intermediate 5 unspecified

(31)

E2211 Study Design

Presented By Pamela Kunz at 2018 ASCO Annual Meeting

(32)

Progression Free Survival

(33)

Response Rates

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*Response assessment: Every 8 weeks for first 6 months; every 12 weeks thereafter Primary endpoints: ORR per RECIST v1.1 (investigator review)

Secondary endpoints: PFS, OS, duration of response, and safety

KEYNOTE-028 (NCT02054806): Phase 1b Multicohort Study of Pembrolizumab for PD-L1+ Advanced Solid Tumors

Response Assessment*

Pembrolizumab 10 mg/kg IV

Q2W

CR, PR, or SD

Treat for 24 months or until

progression^b or intolerable toxicity

Confirmed PD^b or unacceptable

toxicity

Discontinue pembrolizumab Patients

• Carcinoid tumors or well or moderately differentiated pNETs

• Failure of or inability to receive standard

therapy

• ECOG PS 0 or 1

• ≥1measurable lesion

• PD-L1 positivity^a

• No autoimmune disease or interstitial lung disease

aAt least 1% modified proportion score or interface pattern (QualTek IHC using 22C3 antibody clone).

bIf SD or better when pembrolizumab discontinued and subsequently have PD,patients may be eligible to resume pembrolizumab for ≥1year.

cIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan perform ed ≥4 w eeks later.

(35)

Antitumor Activity

(RECIST v1.1, Investigator Review

^a

)

aOnly confirmed responses are included.

Data cutoff date: February 20, 2017.

Carcinoid (N = 25)

pNET (N = 16) Objective Response Rate, % (95% CI) 12% (3–31) 6% (0.2–30) Best overall response, n (%)

Complete response 0 0

Partial response 3 (12%) 1 (6%)

Stable disease 15 (60%) 14 (88%)

≥6 months 8 (32%) 5 (31%)

Progressive disease 7 (28%) 1 (6%)

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0 5 1 0 1 5 2 0 2 5 0

1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

T im e , m o n t h s

Progression-Free Survival, %

16 7 4 2 2 0

N o . a t r i s k

0 5 1 0 1 5 2 0 2 5

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

Progression-Free Survival, %

25 16 8 4 2 0

N o . a t r is k

Progression-Free Survival

(RECIST v1.1, Investigator Review)

Carcinoid pNET

40% 27%

44% 27%

Median (95% CI) 5.6 (3.5–10.7) Median (95% CI) 4.5 (3.6–8.3)

0 5 1 0 1 5 2 0 2 5 3 0

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

Overall Survival, %

N o . a t r i s k

16 14 14 12 7 0 0

0 5 1 0 1 5 2 0 2 5 3 0

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

Overall Survival, %

N o . a t r i s k

25 20 15 11 7 1 0

Overall Survival

83% 65% 93% 87%

Median (95% CI) 21.1 (9.1–22.4) Median (95% CI) 21.0 (20.2–NR)

Carcinoid pNET

Is PDL-1 the right biomarker?

Is G1-G2 NET the right disease?

(37)

KEYNOTE-158: Study Design<br />

Presented By Jonathan Strosberg at 2019 Gastrointestinal Cancer Symposium

(38)

Summary of Response<br />(RECIST v1.1, Central Review)

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Slide 7

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SSA

Locoregional treatments/

RT

Liver surgery

Primary tumor removal

Eve

PRRT Chemo

Clinical Trials

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SSA Eve/Su n

Locoregional treatments

Liver surgery

RT

Eve/Su

n PRRT Chemo

Clinical Trials

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SSA

Syndrome progression (diarrhea)

Telotris tat

SSA dose/schedu

le adjustment

Locoregional treatments

INF

PRRT

Everolimus