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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.