Copyright 2017 American Medical Association. All rights reserved.
Arginine Deprivation With Pegylated Arginine Deiminase
in Patients With Argininosuccinate Synthetase 1–Deficient
Malignant Pleural Mesothelioma
A Randomized Clinical Trial
Peter W. Szlosarek, MD, PhD; Jeremy P. Steele, MD; Luke Nolan, MD, PhD; David Gilligan, MD; Paul Taylor, MD; James Spicer, MD, PhD; Michael Lind, MD;
Sankhasuvra Mitra, MD; Jonathan Shamash, MD; Melissa M. Phillips, MD, PhD; Phuong Luong, BSc; Sarah Payne, MD; Paul Hillman, RN; Stephen Ellis, MD;
Teresa Szyszko, MD; Gairin Dancey, MD; Lee Butcher, PhD; Stephan Beck, PhD; Norbert E. Avril, MD; Jim Thomson, PhD; Amanda Johnston, PhD;
Marianne Tomsa, BSc; Cheryl Lawrence, BPharm; Peter Schmid, MD, PhD; Timothy Crook, MD, PhD; Bor-Wen Wu, PhD; John S. Bomalaski, MD;
Nicholas Lemoine, MD, PhD; Michael T. Sheaff, MD; Robin M. Rudd, MD; Dean Fennell, MD, PhD; Allan Hackshaw, MSc
IMPORTANCE
Preclinical studies show that arginine deprivation is synthetically lethal in
argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of
the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been
evaluated in a randomized and biomarker-driven study among patients with cancer.
OBJECTIVE To assess the clinical impact of arginine depletion in patients with ASS1-deficient
malignant pleural mesothelioma.
DESIGN, SETTING, AND PARTICIPANTS A multicenter phase 2 randomized clinical trial, the Argi-
nine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and
May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients
(2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma.
INTERVENTIONS Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m
2
, weekly
intramuscular) plus best supportive care (BSC) or BSC alone.
MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS)
assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard
ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety,
and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline
levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by
18
F-fluorodeoxyglucose positron-emission tomography.
RESULTS Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19%
female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a
median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute
risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease:
12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves
crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the
BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic
adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in
the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia,
gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with
ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS.
CONCLUSIONS AND RELEVANCE In this trial, arginine deprivation with ADI-PEG20 improved
PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants
further clinical investigation in arginine-dependent cancers.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01279967
JAMA Oncol. 2017;3(1):58-66. doi:10.1001/jamaoncol.2016.3049
Published online September 1, 2016.
Invited Commentary page 66
Supplemental content at
jamaoncology.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Peter W.
Szlosarek, MD, PhD, Center for
Molecular Oncology, Barts Cancer
Institute, Queen Mary University of
London, Barts and the London
Medical School, John Vane Science
Center, Charterhouse Square, London
EC1M 6BQ, England (p.w.szlosarek
@qmul.ac.uk).
Research
JAMA Oncology | Original Investigation
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T
he incidence of malignant pleural mesothelioma is in-
creasing in many parts of the world, with a median sur-
vival from diagnosis of less than 12 months.
1
The US and
European mesothelioma incidence of 3000 and 5000 cases per
year, respectively, reflects a continuing population at risk.
Developing countries will be affected similarly as a result of
widespread use of asbestos.
2
Systemic treatment is by means
of platinum and antifolate chemotherapy.
3,4
Therapeutic
advances have stalled for more than a decade.
5
To our knowledge, we were the first to show that an ex-
ogenous supply of the amino acid arginine is critical for the
survival of mesothelioma cell lines displaying loss of the urea
cycle and arginine biosynthetic enzyme argininosuccinate syn-
thetase 1 (ASS1).
6
Arginine is essential for biosynthesis of pro-
teins, nitric oxide, and polyamines and contributes to proline
and glutamate production.
7
A wide therapeutic window ex-
ists because exogenous arginine is dispensable for normal cells
due to ASS1 expression, whereas its supply is essential for ASS1-
negative cancers.
8
Tumors deficient in ASS1 display in-
creased tumorigenesis due to diversion of the precursor as-
partate for enhanced pyrimidine synthesis.
9,10
Loss of the
tumor suppressor ASS1 in mesothelioma cell lines, due partly
to epigenetic silencing, was observed in 63% of archival me-
sotheliomas by immunohistochemical analysis, warranting
therapeutic stratification of an arginine–depleting agent.
6
Various ASS1-negative tumors have been shown to be sen-
sitive to the arginine depleters, mycoplasmal-derived peg-
ylated arginine deiminase (ADI-PEG20) and recombinant hu-
man arginases, in preclinical studies.
11,12
This led to several
arginine deprivation studies in patients with hepatocellular car-
cinoma and melanoma with single-agent ADI-PEG20, show-
ing low toxicity and evidence of efficacy.
13-16
A phase 3 regis-
tration trial in patients with hepatocellular cancer, a tumor with
frequent ASS1 deficiency, is ongoing.
17
We report the first prospectively biomarker-driven, ran-
domized trial of ADI-PEG20 in patients with cancer (mesothe-
lioma), the Arginine Deiminase and Mesothelioma (ADAM)
study. We hypothesized that exogenous arginine is a critical
amino acid for ASS1-deficient mesothelioma and that arginine
deprivation would improve progression-free survival (PFS).
Methods
Patients
From March 2, 2011, to May 21, 2013, we screened 201 pa-
tients. Eligible patients were at least 18 years old with histo-
logical evidence of advanced ASS1-deficient malignant pleu-
ral mesothelioma (defined by >50% low expressor cells; BD
Biosciences ASS1 antibody, 1:500 dilution with the BioGenex
Super Sensitive Polymer-IHC Detection System and human
liver controls); measurable disease by modified Response
Evaluation Criteria in Solid Tumors (RECIST) criteria
18
; East-
ern Cooperative Oncology Group (ECOG) performance status
of 0 or 1, and life expectancy of at least 3 months; adequate
bone marrow, hematologic, hepatic, and renal function; and
gave written, informed consent. Patients who had received
prior platinum-based chemotherapy were eligible after pro-
gression. A rebiopsy was permitted for ASS1 reassessment if a
prechemotherapy baseline biopsy was ASS1 positive (n = 13).
Study Design
Randomized phase 2 nonblinded trial conducted across 8 can-
cer centers in the UK Clinical Research Network, after multi-
center ethics approval (see trial protocol in Supplement 1).
Randomization
Patients were enrolled by research nurses. Randomization (2:1)
and allocation concealment was performed by telephoning the
Trials Center, where a computer program (generated by a pro-
grammer without further involvement in the trial) allocated
patients to a treatment arm using minimization, stratified ac-
cording to sex, sarcomatoid or nonsarcomatoid subtype, che-
monaive or prior chemotherapy, and hospital.
Treatment and Procedures
Sixty-eight patients were randomized to receive a weekly in-
tramuscular injection of ADI-PEG20 (36.8 mg/m
2
) for up to 6
months (cycles) into the buttock plus best supportive care (BSC),
or BSC alone. Patients continued to receive study treatment, with
regular blood sampling, until disease progression, withdrawal
of consent, or unacceptable toxic effects. ADI-PEG20–treated
patients with disease control were allowed to exceed 6 cycles.
Chemotherapy-naive patients were offered chemotherapy on
progression. Patients receiving BSC alone were not allowed to
cross over to ADI-PEG20. Computed tomographic scans were
scheduled at the end of month 2, 4, 6, end of treatment, and 6
months after finishing treatment. Quality-of-life question-
naires were scheduled at baseline, then at the end of 2 and 4
months, and end of treatment. We also collected survival data
on patients with low ASS1 expression who were not random-
ized, and from ASS1-positive patients (“high expressor”; ≤50%
low expressor cells) who were not eligible for randomization.
Outcomes
The primary end point was PFS, measured from the random-
ization date to first progression or death from any cause. Pro-
gression was assessed by means of imaging (modified RECIST)
and examined by blinded central review (which matched the
local review in 65 patients; in the other 3, the progression date
was judged to be earlier than the local review). Secondary end
points were overall survival (OS), response rate, toxicity, and
Key Points
Question What is the effect of arginine deprivation in patients
with argininosuccinate synthetase 1 (ASS1)-deficient malignant
pleural mesothelioma?
Findings In this phase 2 randomized clinical trial of 68 patients
with ASS1-deficient mesotheliomas, arginine deprivation with
pegylated arginine deiminase led to improved progression-free
survival compared with patients receiving best supportive care.
Meaning Arginine deprivation with pegylated arginine deiminase
warrants further clinical investigation in patients with
ASS1-deficient malignant mesothelioma.
Arginine Deprivation in ASS1-Deficient Malignant Pleural Mesothelioma Original Investigation Research
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quality of life using the Lung Cancer Symptom Scale.
19
Explor-
atory additional end points included plasma concentrations of
arginine (and duration of arginine deprivation), citrulline, and
anti–ADI-PEG20 antibodies, the methylation status of the ASS1
gene using the Illumina Infinium HumanMethylation450
BeadChip array, and metabolic response as assessed by
18
F-fluorodeoxyglucose positron-emission tomography
(FDG-PET) in patientsreceiving ADI-PEG20.
20-23
Plasma samples
were planned weekly during treatment for ADI-PEG20
patients and at weeks 9, 17, 25 for BSC-alone patients.
Statistical Analysis
The target sample size was 66 patients (2:1 allocation), based
on detecting a hazard ratio (HR) of 0.60, assuming a median PFS
of 4.5 months with BSC alone, 80% power, and 15% 1-sided sta-
tistical significance (phase 2 studies typically use 10%-20%).
Time-to-event end points were analyzed using Kaplan-Meier
curves, the log-rank test, and Cox regression, all measured from
the date of randomization, and by intention to treat (SAS, ver-
sion 9.3). P values for OS and PFS were either 1 sided (consis-
tent with the design; significance level, .15), or 2 sided (to be con-
servative) and are indicated throughout; all other P values were
2 sided. For PFS, an event was modified RECIST progression
(using the central review) or death from any cause, and those
without an event were censored when last seen alive (ie, seen
in clinic). Overall survival, but not PFS, violated the propor-
tional hazards assumption, so we also estimated the restricted
mean survival time, a measure of life expectancy or mean sur-
vival (calculated as the area under each Kaplan-Meier curve).
24
Overall survival was also compared (Kaplan-Meier curves, log-
rank test, and restricted mean survival times) between all reg-
istered patients who had BSC only and either low or high ASS1
expression, and the control group in the randomized trial, where
OS was measured from the date of study registration. The pur-
pose here was to examine the association between ASS1 expres-
sion as a prognostic marker for survival in patients receiving the
same care. Toxic effects were based on the maximum National
Cancer Institute Common Terminology Criteria for Adverse
Events toxicity grade for each patient and event. Quality of life
was examined as the difference in scores between baseline and
each of 2 and 3 months after randomization (Wilcoxon test). To
examine how within-patient arginine levels change over time
and how this correlates with PFS, a time-varying Cox regres-
sion was used (model containing only PFS and the individual
plasma levels for each patient where available). The Spearman
correlation was used to examine the relationship between the
duration of arginine depletion and PFS.
Results
A total of 201 patients were registered, with 97 (48%) identi-
fied as being ASS1 deficient; 70 were randomized, but 2 were
found to be ineligible (ECOG 2 and nonevaluable disease by
modified RECIST) (Figure 1). The main analyses were on 24 pa-
tients who received BSC alone and 44 who received ADI-
PEG20 + BSC; median follow-up was 38 months (range, 2.5-39
months). Overall, 4 of 9 (44%) patients with prior exposure to
platinum-antifolate chemotherapy were rescreened and dis-
played ASS1 deficiency on tumor rebiopsy compared with the
baseline tumor. Baseline patient characteristics were bal-
anced (Table 1).
Figure 1. Consolidated Standards of Reporting Trials Diagram
201 Patients registered
97 ASS1 negative
70 Randomized
46 Randomized to
ADI-PEG20 + BSC
24 Randomized to
BSC alone
22 Received BSC
as randomized
2 Withdrew from
study because
they wanted
chemotherapy
24 Analyzed for PFS
and OS (intent-
to-treat analysis)
2
Ineligible
1
1
ECOG 2
Nonmeasurable
disease
44 Received ADI-PEG20
+ BSC as randomized
44 Analyzed for PFS
and OS
27 ASS1-negative
patients not
randomized
25 ASS1-negative
patients analyzed
for OS
81 ASS1-positive
patients analyzed
for OS
83 ASS1
positive
21 ASS1 status
unknown
The trial protocol indicated that
patients who miss a dose of
pegylated arginine deiminase
(ADI-PEG20) could be withdrawn
from the study, unless the chief
investigator gave authorization to
continue based on clinical
information; this occurred for 2
patients. Follow-up information
(outcomes) was available on all
patients (ie, no trial withdrawals or
dropouts). ASS1 indicates
argininosuccinate synthetase 1;
BSC, best supportive care;
ECOG, Eastern Cooperative Oncology
Group; OS, overall survival; and
PFS, progression-free survival.
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Adherence to ADI-PEG20 Treatment
Nineteen of 44 (43%) patients completed 2 4-week cycles of
ADI-PEG20, and 10 (23%) had at least 6 cycles (eFigure 1 in
Supplement 2). Twenty-two (50%) patients had at least 9 in-
jections in total. Only 2 patients missed 1 week’s dose during
the treatment period; and 2 patients had a lower than target
dose based on their body surface area (1 patient had 51% of the
full dose for 1 injection out of 7 received in total; 1 patient had
49% of the full dose for 4 injections out of 8 in total. Eight pa-
tients stopped ADI-PEG20 treatment early: 4 due to toxic ef-
fects, 3 because of a clinical decision, and 1, a patient deci-
sion (unrelated to toxic effects).
Efficacy
No partial or complete radiological responses were observed.
Among patients who had evaluable disease at 4 months (using
modified RECIST), the best response was stable disease assessed
by central review: 12 of 23 (52%) in the ADI-PEG20 + BSC group
vs 2 of 9 (22%) in the BSC group (Fisher exact 2-tailed P = .23).
Twenty-one of 44 patients (48%) receiving ADI-PEG20 expe-
rienced disease progression by the first 8-week scan. Also, using
baseline
18
F-FDG-PET imaging and during the first cycle of treat-
ment in the ADI-PEG20 + BSC group only, 18 of 39 patients ex-
hibited partial metabolic responses (46%),with stable maximum
standardized uptake value in 12 (31%), mixed (ie, a decrease and
an increase in maximum standardized uptake value in the same
patient) in 3 (8%), and progression in 6 (15%) patients.
Sixty-six of 68 (97%) patients had a PFS event. Two
patients allocated to BSC alone withdrew soon after random-
ization because they wanted chemotherapy and so were cen-
sored at the date of withdrawal. The median PFS in the ADI-
PEG20 group was 3.2 (interquartile range, 1.8-5.5) months vs
2.0 (interquartile range, 1.8-3.6) months in the BSC-alone group,
with HR of 0.56 (95% CI, 0.33-0.96; P = .03 [1-sided P = .02]),
which was close to our target of 0.60 (Figure 2). The 6-month
PFS rate was 18% vs 0%, acknowledging the small number of
patients (10 patients at risk at this time point).
Sixty-four of 68 (94%) patients had died at the time of data-
lock (June 26, 2015). Three BSC-alone patients lived beyond 2
years, before dying between 27 and 29 months, compared with
10 ADI-PEG20 patients, of whom 4 were still alive as of
August 2015 (survived 32-38 months). The median OS in the
ADI-PEG20 group was 11.5 (IQR, 4.2-22.9) months vs 11.1 (IQR,
Table 1. Baseline Characteristics of Patients Receiving Pegylated Arginine
Deiminase (ADI-PEG20) Plus Be st Supportive Care (BSC) vs BSC Alone
Characteristic
No. (%)
BSC Alone
(n = 24)
ADI-PEG20 + BSC
(n = 44)
Age, median (range), y 64 (48-83) 67 (54-79)
Sex
Male 19 (79) 36 (82)
Female 5 (21) 8 (18)
Eastern Cooperative Oncology
Group performance status
0 7 (29) 9 (20)
1 17 (71) 35 (80)
Smoking history
Never smoker 7 (29) 18 (41)
Current smoker 1 (4) 1 (2)
Ex-smoker 16 (67) 25 (57)
Time since stopping,
median (range), y
20 (0.5-71) 25 (0.5-50)
Histological subtype
Sarcomatoid 1 (4) 1 (2)
Nonsarcomatoid 23 (96) 43 (98)
Prior chemotherapy
None 11 (46) 17 (39)
Platinum doublet 13 (54) 27 (61)
Figure 2. Progression-Free Survival (PFS) and Overall Survival (OS) According to Trial Group
100
80
60
40
20
90
70
50
30
10
0
0 3 6 9 12 2118
Alive and Progression-Free, %
Time Since Randomization, mo
15
Alive and progression-free
A
No. at risk
BSC
ADI-PEG20
24
44
9
24
1
9
0
4
0
2
0
2
0
1
BSC
ADI-PEG20 + BSC
Median survival, mo
2.0
3.2
100
80
60
40
20
90
70
50
30
10
0
0 6 12 18 24 4236
Alive, %
Time Since Randomization, mo
30
Alive
B
No. at risk
BSC
ADI-PEG20
24
44
21
31
11
22
4
17
3
10
1
8
0
4
BSC
ADI-PEG20 + BSC
Median survival, mo
11.1
11.5
Hazard ratio, 0.56 (95% CI, 0.33-0.96)
Log rank P
=
.03 (1-sided P
=
.02)
Hazard ratio, 0.68 (95% CI, 0.39-1.16)
Log rank P
=
.15 (1-sided P
=
.08)
The PFS hazard ratio adjusted for the randomization stratification factors (sex,
hospital, and prior chemotherapy; histologic subtype was excluded because
only 2 patients had sarcomatoid) was 0.47 (95% CI, 0.25-0.86). A test for
proportional hazards produced P = .30 for PFS and P = .02 for OS. The
restricted mean survival times (life expectancy) for PFS were 4.1 months for the
pegylated arginine deiminase (ADI-PEG20) group vs 2.7 months for the best
supportive care (BSC) group, for a difference of 1.4 months (95% CI, 0.2 to 2.6
months; P = .02 [1-sided P = .01]). For OS, they were 15.7 months for the
ADI-PEG20 group vs 12.1 months for the BSC group, for a difference of 3.6
months (95% CI, −1.0 to 8.1 months; P = .13 [1-sided P = .06]).
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6.9-14.2) months in the BSC-alone group, with HR of 0.68 (95%
CI, 0.39-1.16; P = .15 [1-sided P = .08]) (Figure 2). However, the
proportional hazards assumption failed (P = .02), and an analy-
sis of restricted mean survival times produced a measure of
life expectancy of 15.7 months in the ADI-PEG20 group and 12.1
months in the BSC group, that is, an increase of 3.6 months
(95% CI, −1.0 to 8.1 months; P = .13 [1-sided P = .06]). We could
not explain why the curves crossed; it could be a spurious fea-
ture within a phase 2 trial of limited size.
Prespecified subgroup analyses for sex and prior chemo-
therapy did not show a differential treatment effect for either
PFS or OS (eFigures 2 and 3 in Supplement 2). Among patients
who had prior chemotherapy, the PFS HR for ADI-PEG20 treat-
ment was 0.54 (95% CI, 0.26-1.14), compared with 0.60 (95%
CI, 0.27-1.37) for chemotherapy-naive patients, with corre-
sponding OS HRs of 0.68 (95% CI, 0.33-1.43) vs 0.60 (95% CI,
0.26-1.40) (interaction P = .95 for PFS and .56 for OS).
The beneficial effect of ADI-PEG20 treatment seemed
greatest for patients with an ASS1 loss of greater than 75%, vs
50% to 75% (PFS HRs of 0.25 [95% CI, 0.09-0.70] vs 0.72 [95%
CI, 0.34-1.49], interaction P = .21; and OS HRs of 0.25 [95% CI,
0.08-0.82] vs 0.64 [95% CI, 0.30-1.37], interaction P = .16)
(Figure 3); statistical significance of the interaction was not
reached because of insufficient power for this particular analy-
sis. Moreover, ASS1 loss of expression was associated with sig-
nificant hypomethylation (P = .02; regularized t test) at a single
CpG site of the ASS1 gene in intron 1, whereas methylation
changes were not detected at the ASS1 promoter in the clini-
cal samples (eFigure 4 in Supplement 2).
We compared OS from the BSC-alone patients (ASS1 nega-
tive/“low expressors”) in the randomized trial with nonran-
domized ASS1-positive (“high expressors”) or ASS1-negative
patients (eFigure 5 in Supplement 2). The nonrandomized ASS1-
negative patients had worse OS, whereas the OS curves for the
Figure 3. Progression-Free Survival (PFS) and Overall Survival (OS) by Degree of Argininosuccinate Synthetase 1 (ASS1) Loss
100
80
60
40
20
90
70
50
30
10
0
0 3 6 9 12 2118
Alive and Progression-Free, %
Time Since Randomization, mo
15
ASS1 loss 50% to 75%
A
No. at risk
BSC
ADI-PEG20
12
34
5
15
1
6
1
3
BSC
ADI-PEG20 + BSC
100
80
60
40
20
90
70
50
30
10
0
0 6 12 18 24 4236
Alive, %
Time Since Randomization, mo
30
No. at risk
BSC
ADI-PEG20
12
34
10
22
4
15
1
11
1
6
1
3
100
80
60
40
20
90
70
50
30
10
0
0 3 6 9 12 2118
Alive and Progression-Free, %
Time Since Randomization, mo
15
ASS1 loss greater than 75%
B
No. at risk
BSC
ADI-PEG20
11
9
5
9
1
4
1
2
100
80
60
40
20
90
70
50
30
10
0
0 6 12 18 24 4236
Alive, %
Time Since Randomization, mo
30
No. at risk
BSC
ADI-PEG20
11
9
11
9
7
8
4
7
3
6
1
6
Hazard ratio, 0.72
(95% CI, 0.34-1.49)
P = .37
Hazard ratio, 0.64
(95% CI, 0.30-1.37)
P = .25
Hazard ratio, 0.25
(95% CI, 0.08-0.82)
P = .02
Hazard ratio, 0.25
(95% CI, 0.09-0.70)
P = .008
There were 46 patients with 50% to 75% loss and 20 with 76% to 100% loss;
data were unavailable for 2 patients. Interaction test between ASS1 loss group
and treatment group resulted in P = .21 for PFS and 0.16 for OS. Restricted mean
survival times (OS) for ASS1 loss of 75% or less were 12.8 months in the
pegylated arginine deiminase (ADI-PEG20) group and 10.5 months in the best
supportive care (BSC) group. The P values in the figure are all 2 sided (1-sided P
values are half of these).
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