MOLECULAR TARGETED AGENTS IN GEP-NETS

Rocio Garcia-Carbonero

Medical Oncology Department

Hospital Universitario 12 de Octubre

Universidad Complutense de Madrid

rgcarbonero@gmail.com

DISCLOSURE OF INTEREST

• Travel and educational support from Ipsen, Pfizer, Novartis, Roche, Merck.

• Advisory/Speaker honoraria from Ipsen, Pfizer, Novartis, AAA, Roche, Merck, MSD, Sanofi,

Bayer, Lilly, PharmaMar, BMS, Servier.

• Research support from Pfizer and BMS.

SUCCESSFUL TARGETS

✓ SSTR: Octreotide, Lanreotide, PRRT

✓ Angiogenesis: Sunitinib

✓ PI3K-mTOR pathway: Everolimus

Singularities of NETs: SSTR

• 80-90% of well diff. NETs express Somatostatin Receptors

➢ relevant diagnostic and therapeutic implications

• Their natural ligand is Somatostatin, a physiological neuropeptide

involved in the regulation of neurotransmission, GI motility, nutrient and ion

absorption, exocrine and endocrine secretion.

• Somatostatin analogs were developed with a longer half-life to enable

clinical use

Inhibition of

angiogenesis

Modulation of

immune system

SMS Mechanism of Action

Antisecretory action Antiproliferative action

Guillermet-Guibert et al, Best Pract Res Clin Gastroenterol 2005.

Based on the ITT

analysis

67% reduction in the risk of tumour progression

HR=0.33; 95% CI: 0.19–0.55; P=0.000017

Time

(months)

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Pro

po

rtio

n w

ith

ou

t p

rog

ressio

n

Time (months)

Octreotide LAR: 42 pts / 27 events

Median 15.6 months [95% CI: 11.0–29.4]

Placebo: 43 patients / 41 events

Median 5.9 months [95% CI: 5.5–9.1]

Rinke A et al. J Clin Oncol 2009;27:4656

PROMIDOctreotide LAR vs Placebo in G1 Midgut NETs

Antiproliferative Effect of “cold” SSA in GEP-NETs

CLARINETLanreotide Autogel vs Placebo in GEP-NETs (ki67<10%)

Caplin M et al. NEJM 2014; 371: 224

Median PFS

• 177-Lu: 28.4 months

• Control: 8.4 months

HR=0.21

P<0.0001

NETTER-1 phase 3 trial of 177Lu-Dotatate

for midgut NETs progressive to SSA

Progression-free survival Overall survival (interim analysis)

HR=0.398 (0.21–0.77)

P=0.0043

Strosberg J et al. NETTER-1 Trial. N Engl J Med 2017;376:125-135.

Ki67 ≤20%

SST-R positive

IK ≥60%

F- & NF-NETs

Core Pathways in PanNETs

Scarpa, Nature 2017

Gene expression analysesidentified a subgroup of tumours associated with

hypoxia and HIF signalling

Raymond, NEJM 2011; Yao, NEJM 2011

Sunitinib: 11,5 monthsPlacebo: 5,5 months

HR 0.42P<0.001

Sunitinib ORR: 9%

Placebo ORR: 0%

SUN111: Sunitinib vs Placebo

(N=171)

RADIANT-3: Everolimus vs Placebo

(N=410)

Everolimus: 11,0 monthsPlacebo: 4.6 months

HR 0.35P<0.001

Everolimus ORR: 5%

Placebo ORR: 2%

Improved PFS in pts with progressive G1-G2

Pancreatic NETs

RADIANT-4: G1-G2 Lung or GI NETs

Everolimus 14.0 months

Placebo 5.5 months

HR 0.39

P<.00001

HR 0.64

P=0.037

Progression-Free Survival Overall Survival

Yao et al, Lancet 2016, 387:968-977

PFS HR by Primary Tumor Origin – Retrospective Analysis, Central Review

Lung

GI†

NET of unknown

primary

Hazard Ratio (95% CI)Subgroups*

90

175

36

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.56 (0.37-0.84)

0.60 (0.24-1.51)

Everolimus Better Placebo Better

Yao et al, Lancet 2016, 387:968-977

Midgut HR 0.71

Non-midgut HR 0.27

P

D

Pancreatic NEN: ENETS Guidelines for advanced disease

Pavel M et al, Neuroendocrinology 2016

SI-NEN: ENETS Guidelines for advanced disease

Pavel et al, Neuroendocrinology 2016

PROMISING NEW TARGETS

Emerging tyrosine kinase inhibitors in NETs

Grillo et al, Endocr-Rel Cancer 2018➢ RCTs ongoing with AXITINIB, CABOZANTINIB, SURUFATINIB

ORR (95 CI): 40.4% (27.3-54.9)

Pancreatic NETS

ORR (95 CI): 18.5% (9.7-31.9)

GI NETS

Median PFS: 14.2 months Median PFS: 17.6 months

Capdevila et al, ESMO 2018

TALENT Trial: A phase II Trial to Assess the efficacy of LENvatinib

in metastatic neuroendocrine Tumors (GETNE 1509)

Variable

Well-diff NETPoorly-diff

GEP NEC

N=21

Thoracic cohort

N=30

Pancreatic cohort

N=33

GI cohort

N=32

Overall

N=95

PR, n (%) 6 (20) 1 (3) 0 7 (7) 1 (5)

SD, n (%) 16 (53) 17 (52) 19 (59) 52 (55) 3 (14)

PD, n (%) 5 (17) 13 (39) 11 (34) 29 (31) 14 (67)

Unknown, n (%) 3 (10) 1 (3) 2 (6) 6 (6) 3 (14)

Confirmed ORR, n (%) 6 (20)* 1 (3) 0† 7 (7) 1 (5)

DCR, n (%) 22 (73) 19 (58) 19 (59) 60 (63) 4 (19)

*Among 6 responders in thoracic cohort, all were in patients with atypical carcinoids, 4 responses were ongoing with duration of response of 2-6 months. 2 other patients died after

confirmation of response due to respiratory failure (not treatment-related) and myasthenia gravis (treatment-related). †1 PR in the GI cohort with time to response of approx. 7 months

was unconfirmed at the time of the cut-off date.

Abbreviations: BICR, blinded-independent central review; DCR, disease control rate; diff, differentiated; GEP NEC, gastroenteropancreatic neuroendocrine carcinoma;

NET, neuroendocrine tumors; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Spartalizumab (PDR001) in Patients With Advanced NENs

Median follow-up, months (range): 8 (6.0-10.9) for NET and 6 (4.7-6.9) for NEC

Yao et al, ESMO 2018

% Change in Target Lesions Over Time (Thoracic Cohort)

0 1 2 3 4 5 6 7 8 9 10

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

Time in months

% c

han

ge

fro

m b

ase

lin

eOngoing treatment

SD PD UNK PR

Abbreviations: PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.

Yao et al, ESMO 2018

First-in-human phase I/IIa study of PEN-221 somatostatin analogue-DM1

conjugate for patients with advanced NETs or SCLC

SSTR2-targeting ligand

Optimised cleavable linker

DM1 cytotoxic payload

SST2 expressing NETs• Prior treatment permitted

• Exclude uncontrolled cardiovascular

factors, brain metastases, proteinuria at

baseline

PEN-221

1 hr IV

Once every

3 weeks

PEN-221 MOA

On binding, PEN-221 triggers SST2

internalisation resulting in the accumulation

of the DM1 payload in tumour cells followed

by cell cycle arrest and apoptosis.

Characteristic Data

Sex 13 M, 10 F

Age, median (range) 61 (27–74)

Tumour types

GI NET

pNET

Lung NET

Pheochromocytoma

NET of unknown primary

Small cell lung cancer

9

5

5

2

1

1

Prior therapies, median (range) 3 (1-8)Johnson ML, et al. ASCO 2018. Abstract 4097.

ClinicalTrials.gov ID: NCT02936323

N = 20

Phase I study of Rovalpituzumab in DLL3-expressing advanced solid tumors

• Rova-T is an antibody-drug conjugate

targeting delta-like protein 3 (DLL3)

❖ DLL3 is an atypical Notch receptor family ligand

expressed in high-grade NECs, with minimal to no

expression in normal tissues

Key Eligibility Criteria

▪ Histologically confirmed,unresectable, advanced solid tumor

▪ DLL3 positive

▪ PD after ≥ 1 prior systemic therapy

– No prior exposure to PBD-based drug

▪ ECOG PS 0-1

N=378

EIGHT COHORTS:

- Malignant melanoma

- Medullary thyroid cancer (MTC)

- Glioblastoma (GBM)

- Large-cell NEC of lung (LCNEC-lung)

- Neuroendocrine prostate cancer

- High-grade gastroenteropancreatic

NEC (GEP NEC)

- Other NEC

- Other solid tumors

Part A: Dose Escalation

- Rova-T 0.2-0.4 mg/kg q6w until PD

- N = 144

Part B: Dose Expansion

- Rova-T MTD or lower

1EP: MTD, safety, tolerability

2EP: ORR, DOR, PFS, OS, CBR, PK

Aggarwal et al, ESMO 2017

XmAb18087 - SST2 and CD3 bispecific antibody

Phase 1 study ongoing in NETs

Kill

CD3

NET

Cancer Cells

Effector

T Cells

SSTR2

PBS

XmAb18087

0 7 14 21 280

2

4

6

8

Tumor imaging

Days post PBMC engraftment

Mean tota

l flux (

p/s

10

10)

XmAb18087 (3 mg/kg

D28

D28

Lee et al. AACR 2017. Abstract 3633

AMG757 – DLL3 & CD3 bispecific T-cell

Engager Phase 1 study ongoing in SCLC

Bispecific Antibodies and BITEs

CONCLUSIONS

◆ Medical and non-medical therapeutic options are increasing:

✓ PNETs: Lanreotide, Sunitinib, Everolimus, Chemotherapy

✓ GI NETs: SSA, PRRT, Everolimus

✓ Lung NETs: Everolimus

◆ Promising new therapeutic strategies in development:

✓ Emerging antiangiogenic TKIs: axitinib, cabozantinib, sulfatinib, lenvatinib…

✓ Immunotherapy may play a role in certain subgroups of NENs, more likely in combination

✓ Novel strategies: ADC (PEN-221, Rova-T), bispecific MAbs or bites,..

• As treatment options expand, new challenges emerge: multiple pathway blockade, integration

with other therapeutic strategies, optimal sequence, new toxicities, …

• Pending issues: novel targets and strategies, precision medicine to improve efficacy