Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer

Joyce OShaughnessy, Cynthia Osborne, John E. Pippen, Mark Yoffe, Debra Patt, Christine Rocha, Ingrid Chou Koo, Barry M. Sherman, and Charles Bradley

N Engl J Med 2011;JAN,364:205-14.

BREAST CANCER

INCIDENCE

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding 75 80 years

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding Less than 11 years more 20% risk of developing than 14 years

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding < 20years > 35 years / nulliparous

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding 13% positive family history

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding African American population

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding Hormonal Replacement Therapy Estrogen 1.2- 1.7 fold Progesterone further increases

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding Hodgkin's Lymphoma

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding Heavy alcohol consumption

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding < 40 years - risk

Post menopausal women - risk

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding

RISK FACTORS
Age Age at menarche Age of first live birth First degree relatives Ethnicity Estrogen exposure Radiation exposure Diet Obesity Exercise Breastfeeding

Carcinogenesis
Cancer stem cell hypothesis

Classification of breast cancer

Carcinoma In Situ o Ductal CIS o Lobular CIS Invasive Carcinoma o No Special Type Basal like cancers Triple negative breast cancer

Classification of breast cancer

Carcinoma In Situ o Ductal CIS o Lobular CIS Invasive Carcinoma o No Special Type o Lobular Ca o Tubular Ca o Mucinous Ca o Medullary Ca o Papillary Ca o Metaplastic Ca

Treatment of breast cancer

Combined approach Surgery Chemotherapy Radiotherapy

Combination Chemotherapy Regimens

CEF CMF CAF CMFP CMFVP AC AC/DOCETAXEL AC/PACLITAXEL

Endocrine therapy
Antiestrogens
o o o o o Tamoxifen Pure Antiestrogens Surgical adrenalectomy Aromatase inhibitors High dose progesterone

Todays drugs

Gemcitabine
Mechanism of action

Gemcitabine
Mechanism of action Pharmacokinetics IV Volume of distribution o 1.4 L/kg Half life- 40mins Plasma protein binding o Negligible Clearance 37.8mL/min/kg aged Urinary excretion -<10%

Gemcitabine
Mechanism of action Pharmacokinetics Therapeutic uses Metastatic pancreatic cancer Non squamous lung cancer Non small cell lung cancer Ovarian cancer Bladder cancer breast cancer

Gemcitabine
Mechanism of action Pharmacokinetics Therapeutic uses Clinical toxicities Myelosuppression Hepatotoxicity Interstitial pneumonia Flu like syndrome

Carboplatin
Mechanism of action

Carboplatin
Mechanism of action Pharmacokinetics IV Volume of distribution o 0.24 L/kg Half life- 2 hours Plasma protein binding o Negligible Clearance 1.5mL/min/kg renal dysfunction Urinary excretion -77%

Carboplatin
Mechanism of action Pharmacokinetics Therapeutic uses Advanced ovarian cancer Cancer of unknown origin Head and neck cancer Cancer cervix Hodgkins disease leukemia

Carboplatin
Mechanism of action Pharmacokinetics Therapeutic uses Clinical toxicities Nephrotoxicity Myelosuppression Alopecia Metabolic imbalance GI disturbances

Iniparib
Mechanism of action

Iniparib
Mechanism of action

Iniparib
Mechanism of action Pharmacokinetics IV

Iniparib
Mechanism of action Pharmacokinetics Therapeutic uses Phase III trials for triple negative breast cancer Nonoperable brain metastases clinical trial Uterine cancer clinical trial Ovarian cancer clinical trial Malignant glioma clinical trial

Iniparib
Mechanism of action Pharmacokinetics Therapeutic uses Clinical toxicities GI disturbances Asthenia, Fatigue Acute renal failure Pulm. Embolism Headache peripheral neuropathy

Background
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

Introduction
Metastatic triple-negative breast cancer Patients with triple-negative breast cancer treated with preoperative chemotherapy have higher rates of pathological complete response than patients with hormone receptor positive breast cancer. metastatic disease - very poor prognosis - median survival of approximately 1 year. No standard-of-care therapy exists for patients with metastatic triple-negative breast cancer

Methodology
Inclusion criteria
o Female sex o an age of 18 years or older o a diagnosis of metastatic breast cancer with measurable disease that was histologically documented as ER-negative, PR-negative, and not having overexpression of HER2.

Methodology contd..
Other inclusion criteria o Eastern Cooperative Oncology Group performance status score (which ranges from 0 to 5) of 0 or 1 o Central nervous system metastases were permitted if the patient did not require glucocorticoids or brain radiotherapy and if brain metastases were clinically stable. Up to two prior chemotherapy regimens for metastatic disease were permitted, as was prior adjuvant or neoadjuvant chemotherapy, with the exception of treatment with gemcitabine, carboplatin, cisplatin, or a PARP inhibitor.

Methodology contd..
Exclusion criteria
o Patients with CNS metastases requiring : Glucocorticoids Brain radiotherapy o Prior treatment with Gemcitabine Carboplatin Cisplatin PARP Inhibitor

Methodology contd..
All patients provided written informed consent before enrollment. All tests (immunohistochemistry for ER, PR, and HER2 and fluorescence in situ hybridization for HER2) were done according to each institutions standards

Methodology contd..
Study design o Study approval : Central IRB of US oncology o Complied with the provisions of the GCP guidelines. o Sponsored by : bipar sciences o Study designed by: the principal academic investigator and lead academic author in collaboration with other academic authors and authors from bipar sciences. o Data collection and analysis : by icon clinical research in collaboration with the sponsor.

Methodology contd..
Study design o Study type open-label, randomized, phase 2 study Multicenter: 20 centers within the US Oncology network Patient recruitment: September 2007 to march 2009

Methodology contd..
Study design
o Randomization: All eligible patients were randomly assigned, in a 1:1 ratio, to receive gemcitabine plus carboplatin, either alone (the chemotherapy-alone group) or in combination with iniparib (the iniparib group). o Assignment to treatment groups was conducted by means of an integrated web randomization system. o Randomization was not stratified according to study center.

Methodology contd..
Study design Primary end points: 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 progression free survival, defined as the time from randomization to confirmation of disease progression or death. Overall survival -defined as the time from randomization until the date of death

Methodology contd..
Treatment protocol
o 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 carboplatin (at a dose equivalent to an area under the concentrationtime curve of 2) over a 60-minuteperiod. 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.

Methodology contd..
Protocol amendment
o in January 2008 to increase the iniparib dose to 5.6 mg per kilogram on the basis of emerging phase 1 safety data. o Twenty patients received the lower iniparib dose before the amendment and thereafter had the dose increased to 5.6 mg per kilogram.

Methodology contd..
Treatment protocol Crossing over o Patients randomly assigned to the chemotherapy-alone group were allowed to cross over to receive iniparib plus gemcitabine and carboplatin if disease progression occurred.

Methodology contd..
Assessment Tumor response was based on investigator assessment of target and nontarget lesions and was assessed by means of CT or MRI 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 disease progression

Methodology contd..
Assessment contd 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.

Methodology contd..
Assessment contd..
o Adverse event grades were defined on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 o Serious adverse events were monitored and reported to MedWatch and the ICON safety group by the primary investigator at each site.

Methodology contd..
Statistical Analysis
o SAMPLE SIZE- 60 per group o Sample size calculation was done by confidence interval approach o Power of the study- 80%

Methodology contd..
Statistical Analysis contd..
o o o o Primary end points evaluation Two sided confidence intervals 95%(2 S.D) Pearson chi square test Sample size is >20 to evaluate by this test

Methodology contd..
Statistical Analysis contd..
o Efficacy end points of progression free survival and overall survival o Kapler Meier method is applied for survival analysis of individual group o Confidence interval 95%(2SD) o Log rank test is applied to compare between chemotherapy alone group and iniparib group

Results

Enrollment, Randomization, and Follow-up of the Study Patients

Results contd..

Baseline Characteristics of the Study Patients, According to Treatment Group

Results contd..

Summary of Efficacy Measures in the Intention-toTreat Population

Results contd..

KaplanMeier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group

Results contd..

KaplanMeier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group

Results contd..

Common Adverse Events in the Safety Population

Discussion
The addition of iniparib significantly improved all measures of efficacy The rate of clinical benefit was selected on the basis of the hypothesis that iniparib may exert cytostatic effects rather than, or in addition to, cytotoxic effects when used in combination with chemotherapy, resulting in disease stabilization in addition to tumor regression.

Discussion contd
The gemcitabinecarboplatin 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.

Discussion contd
The overall rate of response in the chemotherapy alone group (32%) was similar to the rate described in previous studies of gemcitabineplatinum therapy for metastatic breast cancer (range, 26 to 34). The addition of iniparib to chemotherapy significantly increased the overall rate of response to 52% (P = 0.02), suggesting that iniparib may overcome the intrinsic drug resistance of some triple-negative breast cancers.

Discussion contd
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 olaparib in patients with BRCA1/2associated metastatic breast cancer whose disease was platinum resistant

Discussion contd
Iniparibgemcitabinecarboplatin therapy showed no significant increase in toxicity as compared with gemcitabinecarboplatin.

Conclusion
Combination of iniparib with gemcitabine carboplatin provides significant clinical benefit with a favorable safety profile in patients with metastatic triple-negative breast cancer.

Critical evaluation: Positive

Study : Authors have taken up this study to address the treatment deficiencies in metastatic triple negative breast cancer Abstract Introduction

Critical evaluation: Positive contd..

Methods
Inclusion criteria Informed consent Ethical approval Compliant with GCP Guidelines Study type Randomization not stratified according to study center o Primary end points o Secondary end points o o o o o o

Critical evaluation: Positive contd..

Methods contd.. o Treatment protocol o Treatment protocol amendment o Cross over o Assessments Tumor response Safety o Serious adverse effects- MedWatch o Statistical analysis

Critical evaluation: Positive contd..

Results Discussion o Limitations

Critical evaluation: Negative

Title Abstract o Objectives o Conclusion o Clinical trial registration number Methodology o Exclusion criteria o Study design Open label Screening process

Critical evaluation: Negative contd..

Methodology contd o Study design contd.. Sample size Data collection and analysis o Treatment protocol Dose of carboplatin Results o Baseline intergroup comparison o Intergroup comparisons of adverse events Discussion Conclusion

Thank you