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Iniparib plus Chemotherapy
in Metastatic Triple-Negative Breast
Cancer
The New England Journal of Medicine
January 20,2011 Vol.364 No.3
Prof. Beak Sun Kyung / R2 Hwang Jin Kyung
Kyung Hee University Medical Center
INTRODUCTION
Triple-Negative Breast Cancer ?
Negative
Negative
Negative
Human
epidermal
growth factor
receptor type 2
(HER2)
Estrogenreceptor
(ER)
Progesteronereceptor (PR)
INTRODUCTION
 Metastatic triple-negative breast cancer
– 15 to 20% of all cases of breast cancer.
– Aggressive subtype of breast cancer.
• Higher rates of visceral and central nervous system metastases.
• Median survival of approximately 1 year.
• No standard-of-care therapy exists.
– Related with dysregulation of BRCA1.
• Critical roles in the homologous recombination–dependent DNA-repair
pathway.
• Methylation and over-expression of the negative regulators ID4 and
HMG.
• Aberrations of MRE11–RAD50–NBS1, ATM, p53, and PALB2
have also been implicated in the tumorigenesis.
 Providing a strong rationale for developing new agents that
exploit DNA-repair defects in these cancers.
INTRODUCTION
 Poly Adenosine diphosphate–Ribose polymerase 1 (PARP1)
– An important regulator of the DNA base-excision–repair pathway.
– Iniparib (also known as BSI-201) is anticancer agent with PARP
inhibitory activity.
Preclinical study
Iniparib
Clinical study
Phase 1-1b
study
Iniparib alone,
Iniparib + CTx
In vitro models
Enhances effects
of carboplatin and
gemcitabine.
Advanced solid
tumors
Mild toxicity, with
no maximal dose.
In this study
Phase 2 study
Iniparib alone
Iniparib + CTx
Iniparib alone
Iniparib + CTx
acceptable toxicity
levels
acceptable toxicity
levels
Metastatic breast
cancer
Metastatic triple
negative breast
cancer
Rates of response
26 ~ 34%.
?
METHODS
 Patients
– Female, age ≥ 18 years.
– Metastatic triple negative breast cancer, histologically confirmed.
– Eastern Cooperative Oncology Group performance status score `:
0~1.
• 0 : fully active and able to carry out predisease performance.
• 1 : restricted physically strenuous activity but ambulatory and light ~
sedentary nature able to carry out, adequate bone marrow, hepatic,
and renal function.
– Clinically stable CNS metastases without glucocorticoids or brain
RTx.
– Prior CTx regimens ≤ 2 for metastatic disease as adjuvant or
neoadjuvant CTx.
• Except gemcitabine, carboplatin, cisplatin, or a PARP inhibitor.
– Immunohistochemistry for ER, PR, and HER2 and FISH for HER2,
according to each institution’s standards with the archived-tissue
specimens.
CTx : chemotherapy, RTx : radiotherapy, ER : estrogen receptor, PR: progesterone receptor,
HER2 : Human epidermal growth factor receptor type 2, FISH : fluorescence in situ hybridization
METHODS
 Study design
– Multicenter, open-label, randomized, phase 2 study.
Conducted at 20 centers within the US Oncology network.
– Recruited September 2007~March 2009, randomly assigned, in a
1:1 ratio.
• Gemcitabine + Carboplatin vs. Gemcitabine + Carboplatin + Iniparib.
– Integrated web randomization system.
– Primary end points
• Rate of clinical benefit : percentage of CR, a PR, or SD for at least 6
months, as well as safety and tolerability of iniparib.
– Secondary end points
• Overall rate of response and progression-free survival, defined as the
time from randomization to confirmation of disease progression or
death.
– Overall survival
• Time of randomization ~ death was not prespecified as an end point.
• Analyzed to explore the potential effect of iniparib on survival.
METHODS
 Treatment
– Patients received chemotherapy during 21-day.
D1
D8
IV Gemcitabine 1000 mg/m2 over a 30 min
D1
D8
IV Carboplatin AUC of conc.-time over a 60
min
D8
D11
IV Iniparib 4.0 mg/kg over a 60 min (before Jan.
IV Iniparib 5.6 mg/kg over a 60 min (after
Jan.
2008)
2008)
D1
D4
– 20 patients of iniparib group
: 4.0 mg/kg (before Jan. 2008)  5.6 mg/kg (after Jan. 2008)
– Chemotherapy-alone group
: cross over to receive iniparib + gemcitabine/carboplatin if
disease progression occurred.
METHODS
 Assessment
– Tumor response
• Based on target and non-target lesions.
• By CT or MRI imaging at baseline and every 6 weeks, in the absence
of clinically evident disease progression.
• Modified Response Evaluation Criteria in Solid Tumors, version 1.0.
– Safety
• Standard clinical and laboratory tests (hematologic tests, blood
chemical tests, and urinalysis) throughout the study period until 30
days after the last dose.
– Adverse event
• Defined on the basis of the National Cancer Institute Common
Terminology Criteria for Adverse Events, version 3.0.
– Serious adverse events
• Monitored and reported to MedWatch and the ICON safety group by
the primary investigator at each site.
METHODS
 Statistical Analysis
– Pearson chisquare test
• Compare the rates of clinical benefit and the overall rates of response.
– Kaplan–Meier method
• 95% confidence intervals were calculated.
– Logrank test
• Compare the distributions of progression-free and overall survival.
– Adverse events and serious adverse events
• Tabulated according to trial group and the Medical Dictionary for
Regulatory Activities (MedDRA) System Organ Class categorization
and preferred terms.
– Safety data reported after the crossover (chemothrapy-alone 
iniparib group) were analyzed separately.
Enrollment, Randomization, and Follow-up of Study Patients.
51
%
Baseline Characteristics of the Study Patients, According to Treatment
Group.
Summary of Efficacy Measures in the Intention-to-Treat
Population.
Kaplan-Meier Estimates of Progression-free and Overall Survival
Rates,
According to Treatment Group.
Common Adverse Events in the Safety Population
Conclusion
Iniparib + chemotherapy
in metastatic triple-negative breast
cancer.
 Improved the clinical benefit and
survival.
 No significantly increased toxic effects.