molecular targeted agents in gep-nets · novel strategies: adc (pen-221, rova-t), bispecific mabs...
TRANSCRIPT
MOLECULAR TARGETED AGENTS IN GEP-NETS
Rocio Garcia-Carbonero
Medical Oncology Department
Hospital Universitario 12 de Octubre
Universidad Complutense de Madrid
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