Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer

Baylor Charles A. Sammons Cancer Center, Dallas, TX 75246, USA.
New England Journal of Medicine (Impact Factor: 55.87). 01/2011; 364(3):205-14. DOI: 10.1056/NEJMoa1011418
Source: PubMed
ABSTRACT
Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition.
We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8--with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11--every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival.
The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P=0.01) and the rate of overall response from 32% to 52% (P=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P=0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events.
The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number, NCT00540358.).

Full-text

Available from: Cynthia Osborne, Jun 20, 2014
10.1056/nejmoa1011418  nejm.org
1
The new england
journal
of medicine
Iniparib plus Chemotherapy in Metastatic Triple-Negative
Breast Cancer
Joyce O’Shaughnessy, M.D., Cynthia Osborne, M.D., John E. Pippen, M.D., Mark Yoffe, M.D., Debra Patt, M.D.,
Christine Rocha, M.Sc., Ingrid Chou Koo, Ph.D., Barry M. Sherman, M.D., and Charles Bradley, Ph.D.*
Abstr act
From Baylor Charles A. Sammons Cancer
Center (J.O., C.O., J.E.P.), US Oncology
(J.O., C.O., J.E.P., M.Y., D.P.), and Texas
Oncology, Dallas (J.O., C.O., J.E.P.) — all
in Dallas; Cancer Centers of North Caro-
lina, Raleigh (M.Y.); Texas Oncology Can-
cer Center, Austin (D.P.); and BiPar Sci-
ences, South San Francisco, CA (C.R.,
I.C.K., B.M.S., C.B.). Address reprint re-
quests to Dr. O’Shaughnessy at Baylor
Charles A. Sammons Cancer Center,
3535 Worth St., Collins Building, Dallas,
TX 75246, or at joyce.oshaughnessy@
usoncology.com.
*Additional study investigators are listed
in the Supplementary Appendix, avail-
able at NEJM.org.
This article (10.1056/NEJMoa1011418) was
published on January 5, 2011, at NEJM.org.
N Engl J Med 2011.
Copyright © 2011 Massachusetts Medical Society.
Background
Triple-negative breast cancers have inherent defects in DNA repair, making this can-
cer a rational target for therapy based on poly(adenosine diphosphate–ribose) poly-
merase (PARP) inhibition.
Methods
We conducted an open-label, phase 2 study to compare the efficacy and safety of
gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-
inhibitory activity, in patients with metastatic triple-negative breast cancer. A total
of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square
meter of body-surface area) and carboplatin (at a dose equivalent to an area under
the concentration–time curve of 2) on days 1 and 8 with or without iniparib (at a
dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11 every 21 days.
Primary end points were the rate of clinical benefit (i.e., the rate of objective response
[complete or partial response] plus the rate of stable disease for ≥6 months) and
safety. Additional end points included the rate of objective response, progression-
free survival, and overall survival.
Results
The addition of iniparib to gemcitabine and carboplatin improved the rate of clini-
cal benefit from 34% to 56% (P = 0.01) and the rate of overall response from 32% to
52% (P = 0.02). The addition of iniparib also prolonged the median progression-free
survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P = 0.01)
and the median overall survival from 7.7 months to 12.3 months (hazard ratio for
death, 0.57; P = 0.01). The most frequent grade 3 or 4 adverse events in either treat-
ment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia,
leukopenia, and increased alanine aminotransferase level. No significant difference
was seen between the two groups in the rate of adverse events.
Conclusions
The addition of iniparib to chemotherapy improved the clinical benefit and survival
of patients with metastatic triple-negative breast cancer without significantly in-
creased toxic effects. On the basis of these results, a phase 3 trial adequately powered
to evaluate overall survival and progression-free survival is being conducted. (Fund-
ed by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number,
NCT00540358.)
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M
etastatic triple-negative breast
cancer which is estrogen-receptor
(ER)–negative and progesterone-recep-
tor (PR)–negative and has no overexpression of
human epidermal growth factor receptor type 2
(HER2) is an aggressive subtype of breast can-
cer marked by higher rates of visceral and central
nervous system metastases and poorer disease-
specific survival than hormone receptor–positive
subtypes.
1-4
Patients with triple-negative breast
cancer treated with preoperative chemotherapy
have higher rates of pathological complete re-
sponse than patients with hormone receptor–
positive breast cancer.
5,6
However, patients in
whom metastatic disease develops have a very
poor prognosis, with a median survival of ap-
proximately 1 year.
7
No standard-of-care therapy
exists for patients with metastatic triple-negative
breast cancer, and therefore they have an un-
met need.
Accounting for 15 to 20% of all cases of breast
cancer,
1,8,9
triple-negative breast cancer shares
clinical and pathological features with hereditary
BRCA1-related breast cancers. In sporadic triple-
negative breast cancer, dysregulation of BRCA1,
a protein with critical roles in the homologous-
recombination–dependent DNA-repair pathway,
has been attributed to a number of mechanisms,
including BRCA1-promoter methylation and over-
expression of the negative regulators ID4 and
HMG.
10-13
Other defects in homologous-recom-
bination pathways have also been implicated in
the tumorigenesis of triple-negative breast cancer
(including aberrations in MRE11–RAD50–NBS1,
ATM, p53, and PALB2),
14-17
providing a strong
rationale for developing new agents that exploit
DNA-repair defects in these cancers.
Poly(adenosine diphosphate–ribose) polymer-
ase 1 (PARP1), an important regulator of the
DNA base-excision–repair pathway, has emerged
as a therapeutic target for triple-negative breast
cancer. Preclinical studies have shown that com-
bining PARP1 inhibitors with platinum che-
motherapy agents, which induce DNA damage
through adducts and cross-linking, potentiates
chemotherapeutic cytotoxicity.
18,19
Iniparib (also
known as BSI-201) is an anticancer agent with
PARP inhibitory activity in preclinical models.
Although the full mechanism of its antitumor
activity is still under investigation, iniparib en-
hances the anti pro liferative and cytotoxic effects
of carboplatin and gemcitabine in in vitro mod-
els of triple-negative breast cancer.
19,20
In clini-
cal studies, the combination of gemcitabine and
carboplatin chemotherapy has demonstrated ac-
tivity in patients with metastatic breast cancer,
with rates of response ranging from 26 to
34%.
21-23
This phase 2 study was designed to
evaluate whether iniparib could potentiate the
antitumor effects of gem cita bine and carboplat-
in with acceptable toxicity levels.
Phase 11b studies of iniparib alone and ini-
parib in combination with chemotherapy in pa-
tients with advanced solid tumors have shown
iniparib to have mild toxicity, with no maximal
dose reached in terms of side effects.
24,25
In the
present study, we investigated the efficacy and
safety of iniparib in combination with gemcita-
bine and carboplatin chemotherapy in patients
with metastatic triple-negative breast cancer.
Methods
Patients
Inclusion criteria for the study were female sex,
an age of 18 years or older, and a diagnosis of
metastatic breast cancer with measurable disease
that was histologically documented as ER-nega-
tive, PR-negative, and not having overexpression
of HER2. Other inclusion criteria were Eastern
Cooperative Oncology Group performance status
score (which ranges from 0 to 5) of 0 or 1, with
0 representing a patient who is fully active and
able to carry out predisease performance without
restrictions, and 1 representing a patient who is
restricted with respect to physically strenuous
activity but is ambulatory and able to carry out
work of a light or sedentary nature, (e.g., light
housework or office work)
26
; and adequate bone
marrow, hepatic, and renal function. Central
nervous system metastases were permitted if the
patient did not require glucocorticoids or brain
radiotherapy and if brain metastases were clini-
cally stable. Up to two prior chemotherapy regi-
mens for metastatic disease were permitted, as
was prior adjuvant or neoadjuvant chemo therapy,
with the exception of treatment with gemcita-
bine, carboplatin, cisplatin, or a PARP inhibitor.
All patients provided written informed con-
sent before enrollment. All tests (immunohisto-
chemistry for ER, PR, and HER2 and fluores-
cence in situ hybridization for HER2) were done
according to each institution’s standards and
were performed with the use of archived-tissue
specimens, the majority of which were derived
from primary breast cancers.
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Iniparib plus Chemotherapy in Triple-Negative Breast Cancer
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Study Design
The study was approved by the central institution-
al review board of US Oncology (www.usoncology
.com) and complied with the provisions of the
Good Clinical Practice guidelines. The study was
sponsored by BiPar Sciences (now a wholly owned
subsidiary of Sanofi-Aventis). The study was de-
signed by the principal academic investigator and
lead academic author in collaboration with other
academic authors and authors from BiPar Sciences.
Data collection and analysis were performed by
ICON Clinical Research in collaboration with the
sponsor. The academic authors vouch for the com-
pleteness and accuracy of the data, the data analy-
ses, and the fidelity of this report to the study
protocol (available with the full text of this arti-
cle at NEJM.org). The article was written by one
academic and one industry author, with editorial
assistance provided by the sponsor, and was re-
viewed by all coauthors and the sponsor.
This multicenter, open-label, randomized,
phase 2 study was conducted at 20 centers within
the US Oncology network. Patients were recruited
from September 2007 through March 2009. All
eligible patients were randomly assigned, in a 1:1
ratio, to receive gemcitabine plus carboplatin, ei-
ther alone (the chemotherapy-alone group) or in
combination with iniparib (the iniparib group).
Assignment to treatment groups was conducted
by means of an integrated web randomization
system. Randomization was not stratified accord-
ing to study center.
Primary end points were the rate of clinical
benefit (defined as the percentage of patients who
had a complete response, a partial response, or
stable disease for at least 6 months), as well as
safety and tolerability of iniparib. Secondary end
points were the overall rate of response and pro-
gression-free survival, defined as the time from
randomization to confirmation of disease pro-
gression or death. Overall survival (defined as the
time from randomization until the date of death)
was not prespecified as an end point but was
analyzed to explore the potential effect of inipa-
rib on survival.
Treatment
Patients received chemotherapy as follows: during
each 21-day period, on days 1 and 8, intravenous
gemcitabine (1000 mg per square meter of body-
surface area) over a 30-minute period and carbo-
platin (at a dose equivalent to an area under the
concentration–time curve of 2) over a 60-minute
period. This regimen was administered either
alone or together with intravenous iniparib (4.0 mg
per kilogram) over a 60-minute period, on days
1, 4, 8, and 11.
The protocol was amended in January 2008 to
increase the iniparib dose to 5.6 mg per kilogram
on the basis of emerging phase 1 safety data.
Twenty patients received the lower iniparib dose
before the amendment and thereafter had the
dose increased to 5.6 mg per kilogram. Patients
randomly assigned to the chemotherapy-alone
group were allowed to cross over to receive inipa-
rib plus gemcitabine and carboplatin if disease
progression occurred.
Assessment
Tumor response was based on investigator assess-
ment of target and nontarget lesions and was as-
sessed by means of computed tomography or mag-
netic resonance imaging at baseline and every
6 weeks thereafter, in the absence of clinically
evident disease progression. Tumor measurements
according to the modified Response Evaluation
Criteria in Solid Tumors, version 1.0, were used
to evaluate tumor response and to establish dis-
ease progression (for details, see the Supplemen-
tary Appendix, available at NEJM.org).
27
Safety was assessed with the use of standard
clinical and laboratory tests (hematologic tests,
blood chemical tests, and urinalysis) throughout
the study period until 30 days after the last dose
of a study drug was administered. Adverse event
grades were defined on the basis of the National
Cancer Institute Common Terminology Criteria
for Adverse Events, version 3.0 (http://ctep.cancer
.gov/protocolDevelopment/electronic_applications/
docs/ctcaev3.pdf). Serious adverse events were
monitored and reported to MedWatch and the
ICON safety group by the primary investigator at
each site.
Statistical Analysis
The primary objective of the trial was to estimate
the rate of clinical benefit in the iniparib group.
We calculated that with a sample size of 60 pa-
tients per group, assuming that the observed rate
of clinical benefit in the iniparib group was ap-
proximately 0.60 (or 60%), the half-width of the
exact 90% binomial confidence interval would be
approximately equal to 0.11. In particular, for an
observed rate of clinical benefit of 0.60, the exact
90% binomial confidence interval was 0.49 to
0.71. In contrast, the anticipated rate of clinical
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benefit in the chemotherapy-alone group was as-
sumed to be approximately 0.45. If the rate of
clinical benefit in the iniparib group was 0.674 or
greater, then — on the basis of a one-sided test
of equality of proportions at the 5% level of sig-
nificance the trial would have a power of at
least 80% to detect an increase from the rate of
clinical benefit of 0.45 in the chemotherapy-
alone group.
In each of the two groups, the primary effi-
cacy end point (i.e., the rate of clinical benefit)
and the overall rate of response were estimated,
and the exact two-sided 95% confidence interval
was calculated. The rates of clinical benefit and
the overall rates of response in the two groups
were compared with the use of the Pearson chi-
square test. Efficacy end points of progression-
free and overall survival were estimated, and 95%
confidence intervals were calculated by means of
the Kaplan–Meier method. The distributions of
progression-free and overall survival in the two
groups were compared with the use of the log-
rank test. P values were not adjusted for multiple
interim analyses. All P values and confidence in-
tervals reported are two-sided, and all analyses
are of data for the intention-to-treat population
unless otherwise noted. Adverse events and seri-
ous adverse events were tabulated according to
trial group and the Medical Dictionary for Regulatory
Activities (MedDRA) System Organ Class catego-
rization and preferred terms. For patients in the
chemotherapy-alone group who crossed over to
the iniparib group, safety data reported after the
crossover were analyzed separately.
Results
Patients
Between October 16, 2007, and March 9, 2009,
123 patients were randomly assigned to a treat-
ment group: 62 to the chemotherapy-only group
and 61 to the iniparib group. A total of 116 pa-
tients (94%) received at least one dose of a study
drug (Fig. 1): 57 patients in the iniparib group
123 Patients underwent randomization
(intention-to-treat population)
61 Were assigned to receive gemcitabine
and carboplatin plus iniparib
62 Were assigned to receive gemcitabine
and carboplatin
4 Did not receive the study drugs
2 Withdrew consent
2 Had unknown reason
3 Did not receive the study drugs
2 Withdrew consent
1 Had a protocol violation
57 Received gemcitabine and carboplatin
plus iniparib (safety population)
59 Received gemcitabine and carboplatin
(safety population)
51 Discontinued the study treat-
ment
8 Had an adverse event
37 Had disease progression
3 Were withdrawn by
physician
3 Had other reason
55 Discontinued the study treat-
ment
13 Had an adverse event
37 Had disease pro-
gression (includes
patients who crossed
over to receive iniparib)
1 Did not comply
1 Was withdrawn by
physician
3 Had other reason
6 Were included in the ongoing study 4 Were included in the ongoing study
Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.
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Iniparib plus Chemotherapy in Triple-Negative Breast Cancer
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and 59 patients in the chemotherapy-alone group.
These 116 patients were included in the safety
analysis. As of the date of data cutoff, November
16, 2009, a total of 6 of the 57 patients (11%) in
the iniparib group and 4 of the 59 patients (7%)
in the chemotherapy-alone group were still re-
ceiving treatment. Thirty of 59 patients (51%) in
the chemotherapy-alone group crossed over to
receive iniparib in combination with gemcitabine
and carboplatin.
Table 1. Baseline Characteristics of the Study Patients, According to Treatment Group.
Characteristic
Gemcitabine–Carboplatin
and Iniparib (N = 61)
Gemcitabine–Carboplatin
Alone (N = 62)
Female sex — no. (%) 61 (100) 62 (100)
Age — yr
Median 56 53
Range 34–76 26–80
Race — no. (%)*
White 48 (79) 48 (77)
Black or African ancestry 9 (15) 12 (19)
Asian 1 (2) 0
Unknown 3 (5) 2 (3)
ECOG performance status — no. (%)†
0 42 (69) 42 (68)
1 18 (30) 20 (32)
Missing data or unknown 1 (2) 0
No. of metastatic organ sites — no. (%)
1 7 (11) 7 (11)
2 19 (31) 12 (19)
≥3 35 (57) 43 (69)
Metastatic site — no. (%)
Bone 20 (33) 23 (37)
Brain 2 (3) 6 (10)
Chest wall or skin 18 (30) 12 (19)
Liver 24 (39) 28 (45)
Lung 38 (62) 32 (52)
Lymph nodes 40 (66) 39 (63)
Prior neoadjuvant or adjuvant chemotherapy — no. (%) 47 (77) 43 (69)
No. of prior courses of chemotherapy for metastases —
no. (%)
0 35 (57) 37 (60)
1 21 (34) 13 (21)
2 4 (7) 6 (10)
3 0 1 (2)
Missing data 1 (2) 5 (8)
Bevacizumab-containing regimen — no. (%) 9 (15) 8 (13)
Taxane-containing regimen — no. (%) 51 (84) 44 (71)
Anthracycline-containing regimen — no. (%) 45 (74) 40 (65)
* Race was self-reported.
The Eastern Cooperative Oncology Group (ECOG) performance status reflects the daily-living abilities of the patient, on
a scale of 0 (fully active without symptoms) to 5 (dead).
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Overall, the two treatment groups were well-
balanced with regard to the baseline character-
istics of the patients (
Table 1
). A total of 60%
and 57% of patients in the chemotherapy-alone
and iniparib groups, respectively, received study
treatment as first-line therapy for metastatic dis-
ease. In all, 65% and 74% of patients, respective-
ly, had received prior anthracycline-containing
therapy, and 71% and 84% of patients, respec-
tively, had received prior taxane-containing
therapy.
Efficacy
In the intention-to-treat population, the rate of
clinical benefit was 56% (34 of 61 patients) in the
iniparib group and 34% (21 of 62 patients) in the
chemotherapy-alone group (P = 0.01). The overall
rate of response was 52% (32 of 61 patients) in
the iniparib group and 32% (20 of 62 patients) in
the chemotherapy-alone group (P = 0.02) (Table 2).
For patients who received at least one cycle of
therapy and underwent both baseline and post-
treatment assessments of tumor size, the rate of
clinical benefit was 62% (34 of 55 patients) in
the iniparib group and 39% (21 of 54 patients)
in the chemotherapy-alone group (P = 0.02). The
overall rate of response among these patients
was 58% (32 of 55 patients) in the iniparib group
and 37% (20 of 54 patients) in the chemotherapy-
alone group (P = 0.03).
The median progression-free survival in the
intention-to-treat population was 5.9 months in
the iniparib group and 3.6 months in the che-
motherapy-alone group (hazard ratio for disease
progression with iniparib, 0.59; 95% confidence
interval [CI], 0.39 to 0.90; P = 0.01) (Fig. 2A and
Table 2
).
The median overall survival in the intention-
to-treat population was 12.3 months in the inipa-
rib group and 7.7 months in the chemotherapy-
alone group (hazard ratio for death with iniparib,
0.57; 95% CI, 0.36 to 0.90; P = 0.01) (
Fig. 2B
and
Table 2
).
A total of 30 of 59 patients (51%) in the chemo-
therapy-alone group crossed over to receive
iniparib in combination with gemcitabine and
carboplatin, after disease progression occurred.
Patients who crossed over received a median of
1.5 cycles of iniparib; 25 of the 30 patients (83%)
discontinued treatment after one or two cycles.
Table 2. Summary of Efficacy Measures in the Intention-to-Treat Population.*
Outcome
Gemcitabine–Carboplatin
and Iniparib (N = 61)
Gemcitabine–Carboplatin
Alone (N = 62) P Value†
Overall survival
Months — median (95% CI) 12.3 (9.8–21.5) 7.7 (6.5–13.3) 0.01
Hazard ratio (95% CI) 0.57 (0.36–0.90)
Progression-free survival
Months — median (95% CI) 5.9 (4.5–7.2) 3.6 (2.6–5.2) 0.01
Hazard ratio (95% CI) 0.59 (0.39–0.90)
Overall rate of response — no. (%) 32 (52) 20 (32) 0.02
Best overall response — no. (%)
Complete response 2 (3) 1 (2)
Partial response 30 (49) 19 (31)
Stable disease 11 (18) 13 (21)
Stable disease for ≥6 mo 2 (3) 1 (2)
Progressive disease 10 (16) 18 (29)
Not able to be evaluated‡ 8 (13) 11 (18)
Clinical benefit — no. (%)§ 34 (56) 21 (34) 0.01
* CI denotes confidence interval.
P values were not adjusted for multiple interim analyses.
Patients for whom best overall response could be evaluated had completed at least one cycle of treatment and had
undergone both baseline and post-treatment assessment of tumor size.
§ The rate of clinical benefit was defined as the percentage of patients who had a complete response, a partial response,
or stable disease for at least 6 months.
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In 1 of the 30 patients (3%), there was an uncon-
firmed partial response, and 4 of the 30 patients
(13%) had stable disease.
Safety
Table 3 lists the most common adverse events in
the safety population. The most frequent adverse
events included grade 1 nausea, fatigue or asthe-
nia, and constipation; grade 3 anemia; and grade
3 or 4 neutropenia. The incidence of grade 3 or
4 adverse events was 86% in the iniparib group
and 81% in the chemotherapy-alone group; these
events included neutropenia, thrombocytopenia,
anemia, and leukopenia. The rates of both grade
3 or 4 anemia and thrombocytopenia were more
than 5% higher in the iniparib group than in the
chemotherapy-alone group, but no significant
differences were observed in the frequency of any
adverse event between the two treatment groups
(P>0.05 for any grade of adverse events and for
grade 3 or 4 adverse events).
The rate of serious adverse events was similar
in the two groups (29% in the chemotherapy-
alone group and 28% in the iniparib group). In
A Progression-free Survival
B Overall Survival
Overall Survival (%)
100
80
90
70
60
40
30
10
50
20
0
0 4 8 12 16 20
24
2 6 10 14 18
22
Months
Hazard ratio for death with iniparib,
0.57 (95% CI, 0.360.90)
P=0.01
No. at Risk
Gemcitabine–carboplatin plus iniparib
Gemcitabine–carboplatin alone
61
62
60
59
54
47
50
38
46
29
35
22
24
16
17
12
12
9
11
4
6
1
0
0
3
0
Gemcitabine–carboplatin
plus iniparib
Gemcitabine–carboplatin
alone
Progression-free Survival (%)
100
80
90
70
60
40
30
10
50
20
0
0 4 8 12 16 202 6 10 14 18
22
Months
Hazard ratio for progression with iniparib,
0.59 (95% CI, 0.390.90)
P=0.01
No. at Risk
Gemcitabine–carboplatin plus iniparib
Gemcitabine–carboplatin alone
61
62
51
38
38
25
25
12
16
6
9
4
7
4
5
2
3
1
2
0
1
0
0
0
Gemcitabine–carboplatin
plus iniparib
Gemcitabine–
carboplatin
alone
Figure 2. KaplanMeier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group.
Dots represent patients whose data were censored.
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Table 3. Common Adverse Events in the Safety Population.*
Event
Gemcitabine–Carboplatin and Iniparib
(N = 57)
Gemcitabine–Carboplatin Alone
(N = 59)
Any Grade 3 Grade 4 Any Grade 3 Grade 4
number of patients (percent)
Any event 57 (100) 30 (53) 19 (33) 59 (100) 26 (44) 22 (37)
Neutropenia 46 (81) 25 (44) 13 (23) 48 (81) 21 (36) 16 (27)
Anemia 38 (67) 13 (23) 0 40 (68) 9 (15) 0
Thrombocytopenia 36 (63) 10 (18) 11 (19) 30 (51) 6 (10) 10 (17)
Leukopenia 16 (28) 7 (12) 0 13 (22) 6 (10) 0
Fatigue or asthenia 40 (70) 4 (7) 0 43 (73) 10 (17) 1 (2)
Nausea 38 (67) 0 0 39 (66) 1 (2) 0
Constipation 24 (42) 1 (2) 0 32 (54) 1 (2) 0
Vomiting 16 (28) 1 (2) 0 21 (36) 1 (2) 0
Dyspnea 16 (28) 2 (4) 0 19 (32) 2 (3) 0
Headache 14 (25) 0 0 18 (31) 0 0
Pyrexia 14 (25) 0 0 10 (17) 0 0
Diarrhea 11 (19) 1 (2) 0 18 (31) 1 (2) 0
Stomatitis 11 (19) 0 0 9 (15) 0 0
Peripheral edema 11 (19) 0 0 9 (15) 1 (2) 0
Cough 10 (18) 1 (2) 0 10 (17) 0 0
Increased ALT 10 (18) 3 (5) 0 9 (15) 1 (2) 0
Arthralgia 9 (16) 1 (2) 0 10 (17) 0 0
Peripheral neuropathy 9 (16) 0 0 7 (12) 0 0
Alopecia 9 (16) 0 0 7 (12) 0 0
Anorexia 8 (14) 0 0 10 (17) 1 (2) 0
Dizziness 8 (14) 0 0 7 (12) 0 0
Bone pain 8 (14) 1 (2) 0 5 (8) 1 (2) 0
Anxiety 8 (14) 0 0 11 (19) 0 0
Increased AST 7 (12) 1 (2) 0 9 (15) 2 (3) 0
Dyspepsia 6 (11) 0 0 7 (12) 0 0
Insomnia 6 (11) 1 (2) 0 7 (12) 0 0
Dehydration 6 (11) 1 (2) 0 4 (7) 0 0
Depression 6 (11) 0 0 7 (12) 1 (2) 0
Rash 5 (9) 0 0 10 (17) 0 0
Hyperglycemia 5 (9) 1 (2) 0 6 (10) 0 0
Abdominal pain 3 (5) 0 0 8 (14) 2 (3) 0
Decreased weight 1 (2) 0 0 6 (10) 0 0
* Patients could have more than one adverse event. The safety population included all patients who received at least one
dose of a study drug. Other adverse events reported for at least 10% of patients included urinary tract infection, de-
creased appetite, dysgeusia, exertional dyspnea, oropharyngeal pain, erythema, back pain, musculoskeletal chest pain,
musculoskeletal pain, neck pain, and pain in an extremity. No significant differences were observed in the frequency of
any adverse event between the two treatment groups (P>0.05 for any grade of adverse events and for grade 3 or 4 ad-
verse events.) ALT denotes alanine aminotransferase, and AST aspartate aminotransferase.
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Iniparib plus Chemotherapy in Triple-Negative Breast Cancer
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the safety population, 8 of 57 patients (14%) in
the iniparib group and 13 of 59 patients (22%)
in the chemotherapy-alone group discontinued
treatment because of adverse events. The dose of
gemcitabine was reduced in 63% of patients (37
of 59) receiving chemotherapy alone and in 65%
of patients (37 of 57) receiving iniparib. The
dose of carboplatin was reduced in 78% of pa-
tients (46 of 59) receiving chemotherapy alone
and in 84% of patients (48 of 57) receiving ini-
parib. The dose of iniparib was reduced in 26%
of patients (15 of 57). The median number of
treatment cycles administered was seven in the
iniparib group and four in the chemotherapy-
alone group. Fatal adverse events occurred in 2 of
the 59 patients (3%) in the chemotherapy-alone
group and 3 of 57 patients (5%) in the iniparib
group, all attributable to disease progression
within 30 days after receipt of study treatment.
Discussion
This open-label phase 2 trial showed that the ad-
dition of iniparib to gemcitabine and carboplatin
significantly improved all measures of efficacy,
including the rate of clinical benefit, overall sur-
vival, progression-free survival, and the rate of ob-
jective (complete or partial) response, in patients
with metastatic triple-negative breast cancer.
The rate of clinical benefit, which encom-
passes both objective responses and stable dis-
ease for at least 6 months, was selected as the
primary end point for this study, rather than the
more commonly used phase 2 efficacy end point
of overall rate of response. The rate of clinical
benefit was selected on the basis of the hypothe-
sis that iniparib may exert cytostatic effects rather
than, or in addition to, cytotoxic effects when
used in combination with chemotherapy, result-
ing in disease stabilization in addition to tumor
regression. For this reason, stable disease last-
ing at least 6 months was regarded as clinically
meaningful in assessing the antitumor activity
of iniparib.
The gemcitabine–carboplatin combination has
been evaluated in several studies of metastatic
breast cancer and has demonstrated activity at
various doses and schedules. In our study, both
chemotherapy agents were given on days 1 and 8,
in close proximity to the doses of iniparib, to take
advantage of possible synergy among the agents.
The overall rate of response in the chemotherapy-
alone group (32%) was similar to the rate de-
scribed in previous studies of gemcitabine–plati-
num therapy for metastatic breast cancer (range,
26 to 34).
21-23
The addition of iniparib to chemo-
therapy significantly increased the overall rate of
response to 52% (P = 0.02), suggesting that ini-
parib may overcome the intrinsic drug resistance
of some triple-negative breast cancers. The fact
that nearly all patients eventually had disease pro-
gression while receiving iniparib plus chemother-
apy suggests an acquired resistance to iniparib.
Minimal antitumor activity of iniparib was
observed in crossover patients whose disease had
progressed on chemotherapy alone. These data
are analogous to the decreased benefit of olapa-
rib in patients with BRCA1/2-associated meta-
static breast cancer whose disease was platinum-
resistant.
28
Iniparibgemcitabinecarboplatin therapy
showed no significant increase in toxicity as com-
pared with gemcitabine–carboplatin. The similar
safety profiles in the two groups may be attrib-
utable to specificity in the targeting of tumor
cells deficient in homologous-recombination–
dependent DNA repair, which spares normal,
homologous-recombination–proficient cells.
29,30
Differences in the risk of adverse events between
the two groups were minimal, despite the greater
exposure to gemcitabine and carboplatin of pa-
tients in the iniparib group than patients in the
chemotherapy-alone group (seven vs. four cycles
of treatment).
Limitations of this open-label, phase 2 study
include the small sample size, which limits our
assessment of overall survival; potential investi-
gator bias in assessing the rate of clinical benefit
and progression-free survival; and the slight im-
balance in prognostic factors, favoring the inipa-
rib group over the chemotherapy-alone group
including the number of patients with three
or more metastatic sites and the particular sites
of metastases (
Table 1
). Finally, multiple interim
analyses were conducted to assess the need for
and design of a subsequent phase 3 trial.
In conclusion, despite its limitations, this
phase 2 study provides proof of concept that the
combination of iniparib with gemcitabine–carbo-
platin provides significant clinical benefit with a
favorable safety profile in patients with meta-
static triple-negative breast cancer. On the basis
of these results, a phase 3 trial of iniparib plus
chemotherapy in patients with metastatic triple-
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Th e
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negative breast cancer, adequately powered to
study overall survival and progression-free sur-
vival, is being conducted (ClinicalTrials.gov num-
ber, NCT00938652).
Supported by BiPar Sciences (now owned by Sanofi-Aventis).
Presented in part at the annual meeting of the American Society
of Clinical Oncology, Orlando, FL, May 31, 2009; the San Anto-
nio Breast Cancer Symposium, San Antonio, TX, December 12,
2008, and December 11, 2009; and the annual meeting of the
European Society for Medical Oncology, Milan, October 10, 2010.
Dr. O’Shaughnessy reports receiving speaking fees and con-
sulting fees from Sanofi-Aventis; Dr. Osborne, receiving travel
support from Sanofi-Aventis; Dr. Yoffe, owning stock in Sanofi-
Aventis; and Ms. Rocha and Drs. Koo, Sherman, and Bradley,
being employees of and owning stock or stock options in BiPar
Sciences. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Karla Burgos Polk and Joanne Brown for US Oncol-
ogy project management, Stephan Herrera for critical review of
a draft of the manuscript, and Alison Lovibond of Articulate-
Science (paid by Sanofi-Aventis) for editorial assistance on a
draft of the manuscript.
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