Phase 3 Trial (NGR015) with NGR-hTNF Plus Best

Phase 3 Trial (NGR015) with NGR-hTNF
Plus Best Investigator Choice (BIC) Versus
Placebo Plus BIC in Previously Treated Patients
with Advanced Malignant Pleural Mesothelioma
Abstract # 7501
Rabab Gaafar, Adolfo Favaretto, Vanesa Gregorc, Francesco
Grossi, Jacek Jassem, Andreas Polychronis, Paolo Bidoli,
Marcello Tiseo, Mary O’Brien, Ryaz Shah, Paul Taylor, Silvia
Novello, Alberto Muzio, Alessandra Bearz, Pawel Badurak,
Laurent Greillier, Antonio Lambiase, Claudio Bordignon
1) National Cancer Institute, Cairo University, Egypt; 2) Istituto Oncologico Veneto, Padua, Italy; 3) Ospedale San
Raffaele, Milan, Italy; 4) Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 5) Medical University, Gdansk, Poland;
6) Mount Vernon Cancer Centre, Northwood, UK; 7) Ospedale San Gerardo, Monza, Italy; 8) Azienda OspedalieroUniversitaria, Parma, Italy; 9) The Royal Marsden Hospital, Sutton, UK; 10) Kent Oncology Centre, Maidstone, UK; 11)
Wythenshawe Hospital, Manchester, UK; 12) Università di Torino, AOU San Luigi, Orbassano, Italy; 13) Ospedale S
Spirito, Casale Monferrato, Italy; 14) Centro di Riferimento Oncologico, Aviano, Italy; 15) Maria Sklodowska Memorial
Cancer Center, Warsaw, Poland; 16) Hôpitaux de Marseille, Marseille, France; 17) MolMed, Milan, Italy
Disclosure information

Consultant/Advisory role: no

Other: no
Disease background

Advanced malignant pleural mesothelioma (MPM) is a devastating disease mostly related to
asbestos exposure, with an increasing incidence worldwide

MPM is a highly vascularized tumor, with increased angiogenesis independently associated
with poor prognosis1

In the first-line MPM setting, pemetrexed/cisplatin is standard of care with a median OS of 12.1
months compared with 9.3 months with cisplatin alone2

However, patients failing a front-line therapy have an aggressive disease, with median PFS of
1.4 months and median OS of 6.2 to 7.1 months recently reported in a second-line phase 3 trial3

Neither regulatory-approved nor widely-accepted second-line therapy are currently available,
though gemcitabine, vinorelbine and doxorubicin are routinely used as salvage treatments
1 Chest
2003, 124:1916-1923 ; 2 JCO 2003, 21:2636-2644 ; 3Lancet Oncol 2015, 16: 447-456
NGR-hTNF

NGR-hTNF (the tumor-homing peptide asparagine-glycine-arginine fused with human tumor
necrosis factor α) is an antivascular agent that selectively binds to CD13-expressing blood
vessels.4,5 CD13 expression is upregulated in response to tumor hypoxia/angiogenesis6
Recombinant fusion protein
NGR binding to
tumor blood vessels
NGR peptide
CD13 on tumor
neo-vasculature
hTNF
TNF-receptors 1&2
4Science
1998; 279: 377-380; 5Nat Biotechnol 2000; 18: 1185-1190; 6Cancer Sci 2011; 102: 501-508
CD13-expressing
mesothelioma
NGR-hTNF background
7JCI

NGR-hTNF displays a biphasic dose-response curve with activity driven at low doses by an early
vessel stabilization that improves intratumor chemotherapy uptake and T-cell infiltration and at
high doses by a rapid vessel disruption7,8

At low doses, synergistic effects noted especially with cisplatin, gemcitabine and doxorubicin9

Optimal low dose of NGR-hTNF was defined at 0.8 µg/m2 by TNF-receptor shedding kinetics and
dynamic imaging10

In a randomized phase 2 trial in untreated squamous lung cancer, NGR-hTNF plus cisplatin and
gemcitabine significantly improved OS over chemotherapy alone11

In a single arm phase 2 trial in pemetrexed-pretreated MPM, NGR-hTNF induced a 46% disease
control rate, maintained for a median of 4.7 months, and a median OS of 12.1 months12

This phase 3 trial aimed at assessing the efficacy of NGR-hTNF in the second-line MPM setting
2002, 110: 475-482; 8PNAS 2012; 20: 7841-7846; 9CCR 2006, 12: 175-82;
2010, 46:198-206; 11ASCO 2013 Abs 8035; 12JCO 2010, 28: 2604-2611
10EJC
Key eligibility criteria

Age ≥ 18 years

Histologically or cytologically confirmed MPM (epithelial, sarcomatoid or mixed)

No more than one pemetrexed-based regimen for advanced or metastatic disease

Radiologically-confirmed disease progression after first-line therapy

ECOG performance status (PS) of 0 to 2

Measurable or nonmeasurable disease according to MPM-modified RECIST criteria

Adequate baseline bone marrow, hepatic and renal function

No serious cardiac events, uncontrolled hypertension or QTc interval > 450 ms

Written informed consent
Study design
 Primary endpoint
 overall survival (OS)
 Key secondary endpoint
 progression-free survival (PFS)
 Stratification factors
 performance status (0 or 1-2)
 chemotherapy (yes or no)
 chemotherapy agent
 Statistical considerations
 α=0.05; 1-β=0.80; HR=0.72; n=390 (306 events)
 data cut-off: April, 2014 (accrual time, 33 months)
 subgroup analysis by 8 baseline risk factors: age,
sex, PS, histology, EORTC score, best response
to prior therapy, neutrophil-to-lymphocyte ratio
(NLR) and treatment-free interval (TFI)
Multicenter, double-blind, placebo-controlled,
2-arm, randomized (1:1) phase 3 trial
n=200
NGR-hTNF
+ BIC
R
n=200
Placebo
+ BIC
NGR-hTNF/placebo
 0.8 µg/m2 weekly until progressive disease (PD)
BIC (Best Investigator Choice)
 Supportive care only
 Single-agent chemotherapy (up to max 6 cycles)
 gemcitabine (1,000-1,250 mg/m2 iv d1+8 q3w)
 vinorelbine (25 iv or 60 os mg/m2 d1+8 q3w)
 doxorubicin (60-75 mg/m2 iv d1 q3w)
 Investigational sites: 41 in EU (Italy, UK, Poland, Belgium, France,
Spain, Sweden, Ireland and Netherlands), USA, Canada and Egypt
Baseline characteristics
NGR-hTNF
plus BIC (n=200)
Placebo
plus BIC (n=200)
Median age in years (range)
65 (25-89)
67 (32-81)
Gender (male)
156 (78%)
145 (72%)
PS (1 or 2)
143 (72%)
138 (69%)
Histology (nonepithelial)
30 (15%)
37 (19%)
EORTC prognostic score (poor)
59 (30%)
45 (23%)
Best response to prior therapy (PD)
35 (17%)
43 (21%)
NLR (> median of 4)
113 (56%)
106 (53%)
TFI (< median of 4.8 months)
93 (47%)
105 (53%)
Prior pemetrexed (399 patients, 99%), surgery (143, 36%) and radiotherapy (125, 31%)
Investigator-selected therapy before randomization




gemcitabine
vinorelbine
doxorubicin
supportive care only
104 (52%)
82 (41%)
5 (2%)
9 (5%)
107 (53%)
77 (39%)
6 (3%)
10 (5%)
Treatment exposure and safety overview
NGR-hTNF
plus BIC (n=193)
Placebo
plus BIC (n=193)
4 (3 - 5)
3 (2 - 4)
41%
32%
10 (7 - 14)
10 (7 - 12)
36%
28%
Serious adverse events (AEs)
25%
24%
Grade 4 AEs
12%
10%
AEs leading to drug discontinuation
15%
11%
AEs with outcome of death#
6%
7%
-
-
Chemotherapy cycles, median (95% CI)
6 cycles*
NGR-hTNF/placebo infusions (95% CI)
≥ 18 infusions^
Treatment-related deaths
Safety population (n=386): 14 randomized patients did not receive any study drug
*p=0.08; ^p=0.15; #Including death due to disease progression
Treatment-emergent adverse events
NGR-hTNF
plus BIC (n=193)
Placebo
plus BIC (n=193)
All grades
Grade 3/4
All grades
Grade 3/4
Neutropenia
29%
18%
30%
19%
Anemia
16%
2%
19%
2%
Thrombocytopenia
7%
2%
7%
3%
Chills
56%
5%
11%
-
Fatigue
46%
5%
46%
7%
Pain
44%
5%
42%
7%
Nausea
32%
<1%
32%
<1%
Dyspnea
31%
4%
27%
2%
Appetite loss
20%
<1%
25%
1%
Cough
18%
<1%
19%
-
Vomiting
16%
1%
21%
<1%
Overall survival (primary endpoint)
Treatment-by-covariate
interaction test for OS



13NEJM
Interaction
p-value
Treatment * Age (median)
0.20
Treatment * Gender (male vs female)
0.23
Treatment * PS (0 vs 1/2)
0.12
Treatment * Histology (epithelial vs non)
0.85
Treatment * EORTC score (> vs < 1.27)
0.79
Treatment * Response to prior therapy
0.39
Treatment * NLR (median)
0.15
Treatment * TFI (median)
0.008
Primary study endpoint not met in the ITT population
By prespecified subgroup analyses13 for OS, an interaction test was significant between
treatment group and prior treatment-free interval (TFI), which is the time from the end of firstline therapy to the start of second-line therapy
TFI data splitted at the sample median value (4.8 months)
2007; 357: 2189-2194
Poor prognostic effects of short TFI
Short TFI
(n=198)
Long TFI
(n=201)
p-value
Time from diagnosis (median, months)
7.4
16.1
<0.0001
PFS on prior therapy (median, months)
4.9
10.2
<0.0001
Nonepithelial histology
23%
10%
0.001
Prior surgery
25%
46%
<0.0001
PD as best response on prior therapy
35%
4%
<0.0001
Prior treatment and disease history

Short TFI associated with worse OS and PFS on second-line therapy compared with long TFI
 median OS, 6.3 vs 11.7 months (HR=1.81, p<0.0001; multivariate HR=2.01, p<0.0001)
 median PFS, 2.1 vs 4.0 months (HR=1.69, p=0.001; multivariate HR=1.63, p=0.003)
OS by treatment in the short TFI subset



Median follow-up: 18.4 vs 18.3 months (events/patients: 67/93, 72% vs 86/105, 82%)
Similar difference in HR for OS with cutoff for short TFI moved at 6 months (HR=0.73; p=0.04)
In the long TFI subset, there was no significant difference between arms (HR=1.29; p=0.16)
OS by baseline factors in the short TFI subset
NGR-hTNF
plus BIC
Placebo
plus BIC
64
66
Gender (male)
76%
72%
PS (1 or 2)
75%
67%
Baseline characteristics
Median age in years
Histology (nonepithelial)
25%
22%
EORTC prognostic score (poor)
34%
23%
Response to prior therapy (PD)
31%
38%
NLR (> median)
57%
48%
Post-progression therapy (3rd line)
Subsequent chemotherapy
21%
20%
 Vinorelbine
40%
71%
 Gemcitabine
25%
19%
 Pemetrexed
20%
10%
 Others
15%
-
OS by chemotherapy agent in the short TFI subset

Median follow-up time of 24.1 months (gemcitabine, n=107) and 16.9 months (vinorelbine, n=77)
PFS in the short TFI subset
 Treatment-by-TFI interaction for PFS (p=0.002)
 Events/patients: 83/93 (89%) vs 98/105 (93%)
 Similar differences in PFS according to the chemotherapy agent
 gemcitabine: HR=0.74 (95% CI, 0.50-1.11); vinorelbine: HR=0.66 (95% CI 0.41-1.19)
Best response in the short TFI subset
Best overall response
Measurable disease at baseline &
NGR-hTNF
plus BIC
Placebo
plus BIC
p-value
60%
47%
0.07
complete/partial response (CR/PR)
2%
2%
stable disease (SD)
58%
45%
Progressive disease (PD) *
23%
42%
Not evaluated
17%
11%
Duration of disease control (median, months)
5.7
4.5
0.15
OS in patients with disease control (median, months) ^
10.4
6.3
0.04
Disease control rate (CR/PR/SD)
& 184
patients with measurable disease at baseline (84 for NGR-hTNF, 100 for placebo)
* PD rate at the first tumor assessment performed after 6 weeks
^ Landmark analysis with landmark time set at 6 weeks
0.007
Exploratory analyses in the short TFI subset




14JCO
LDH serum levels significantly higher in the short than in the long TFI subset (p<0.0001)
 high serum LDH associated with increased tumor hypoxia/angiogenesis14
High blood lymphocytes associated with improved outcomes after NGR-hTNF plus chemo15
Increased NGR-hTNF effects with high LDH and lymphocytes
Consistent results in the ITT population with high LDH and lymphocytes (n=198)
 median PFS, 4.1 vs 2.6 months (p=0.03); median OS, 10.9 vs 6.6 months (p=0.12)
2012; 30: 3402-3407;
15ASCO
2013 Abs 3038
Conclusions

NGR-hTNF was well tolerated in combination with chemotherapy in pretreated MPM patients

In the ITT population, there was no difference in survival outcome

By subgroup analysis, an interaction test was significant only between treatment group and
prior treatment-free interval (TFI)

Consistent increases in OS (HR=0.69) and PFS (HR=0.69) for NGR-hTNF plus chemotherapy
over chemotherapy alone were observed in patients with a short TFI after first-line therapy

Survival improvements were notably reported in very poor prognosis patients who presented
with a more aggressive and chemoresistant disease

Outcomes with NGR-hTNF in patients rapidly progressing after first-line therapy were plausibly
related to an augmented tumor hypoxia/angiogenesis (as assessed by high serum LDH), with
increasing treatment effects observed in presence of high baseline LDH and lymphocytes

These results with NGR-hTNF plus chemotherapy deserves a confirmatory first-line phase 3 trial
Acknowledgements (NGR015 Investigators)
ITALY
Vanesa Gregorc, Milan
Francesco Grossi, Genoa
Silvia Novello, Turin
Adolfo Favaretto, Padua
Marcello Tiseo, Parma
Alessandra Bearz, Aviano
Clelia Casartelli, Como
Paolo Bidoli, Monza
Alberto Muzio, Casale Monferrato
Federica Grosso, Alessandria
Claudio Dazzi, Ravenna
POLAND
Jacek Jassem, Gdansk
Pawel Badurak, Warsaw
BELGIUM
Thierry Pieters, Bruxelles
Lionel Bosquee, Liege
Florina Surmont, Ghent
Paul Germonpré, Antwerp
UK
Mary O’Brien, Sutton
Sanjay Popat, London
Rohit Lal, London
Michael Lind, Hull
Riyaz Shah, Maidstone
Andreas Polychronis, Northwood
Paul Taylor, Manchester
Samreen Ahmed, Leicester
Noelle O'Rourke, Glasgow
NETHERLANDS
Franz Schramel, Nieuwegein
Steven Gans, Hardewijk
FRANCE
Laurent Greillier, Marseille
SPAIN
Susana Cedres, Barcelona
IRELAND
Ken O’Byrne, Dublin
SWEDEN
Anders Vikstrom, Linkoping
USA
Robert Taub, New York
Julie Brahmer, Baltimore
Jonathan Dowell, Dallas
Marianna Koczywas, Duarte
Evan Alley, Philadelphia
Ben Ebrahimi, Corona
CANADA
Ronald Feld, Toronto
Quincy Chu, Edmonton
EGYPT
Rabab Gaafar, Cairo
MolMed, Milan, Italy
Floriana Fontana, Scialini Colombi,
Gloria Rossoni, Cristina Ammannati,
Giulia Salini, Veronica Savia, Emma
Redaelli, Manuela Ratti, Antonella
Troysi, Simona Santucci