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PHASE III OPEN-LABEL RANDOMIZED STUDY OF ERIBULIN MESYLATE VERSUS
CAPECITABINE IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC BREAST
CANCER PREVIOUSLY TREATED WITH AN ANTHRACYCLINE AND A TAXANE
Meriam Khalil PharmD Candidate, Class of 2016July 27, 2015
Albany College of Pharmacy & Health Sciences
Module B: Ambulatory Care
Outline Intro/Background:
Metastatic Breast Cancer Eribulin (Halaven) Capecitabine (Xeloda)
Patients & methods Study Design Study Objectives Study Assessment QoL Analyses & Statistical Analyses Results Discussion & conclusion Study Analysis
Objectives
Discuss Metastatic Breast Cancer
Introduce study and summarize key points
Recommend appropriate treatment strategies
Metastatic Breast Cancer Overall Survival (OS) has improved. Long-term survival remains poor. First line
Anthracycline- or Taxane based regimens Neo (adjuvant)
No single standard of care after failure of Anthracycline- or Taxane therapy
Capecitabine (Xeloda): 1st, 2nd, or 3rd line Eribulin (Halaven): EMBRACE trial
Eribulin Mesylate (Halaven)
Classification: Antimicrotubial agent, non taxane
Mechanism of Action: Inhibits mitotic spindles
Administration: Infusion over 2-5 mins
Indication : Metastatic Breast Cancer who received 2 prior chemo regimens
Dosage: 1.4 mg/m2 IV on days 1 & 8 every 21 days
Adverse Events: Neutropenia, alopecia, constipation, Nausea
Interactions : Antiarrythmic agents
Manufacture : Eisai Inc., Woodcliff Lake, NJ
Capecitabine (Xeloda)
Classification: AntimetaboiteMechanism of Action: Prodrug of 5’ DFUR 5FUAdministration: PO
Indication : First line: Mestastic colon cancer
Dosage: 2000- 2500 mg/m2/day after a meal. Dose is given for 2 weeks followed by a 1 week rest period and repeated for 3 cycles.
Adverse Events: Diarrhea, edema, dermatitis, hand-foot syndrome, neutropenia, nausea (53%), headache, anemia
Interactions : Antacids. CYP2C9 inhibitors, leucovorin, phenytoin, anticoagulants
Manufacture : Genentech, Inc., South San Francisco, CA
Patients & Methods
Inclusion Criteria1. Female2. Age ≥ 18 years3. Histological or cytologically confirmed breast
cancer4. Up to THREE prior chemotherapy regimens and up
to TWO prior chemotherapy regimens for advanced and/or metastatic disease
5. Prior therapy with an anthracycline and a taxane6. Resolution of all chemotherapy- or radiation-related
toxicities to ≤ grade 1 (except for stable sensory neuropathy ≤ grade 2 and alopecia)
7. Eastern Cooperative Oncology Group performance status of 0 to 2
8. Adequate renal, bone marrow, and liver function.
Exclusion Prior capecitabine treatment and
radiation therapy encompassing more than 30% of marrow.
**Patients with HER2–positive disease could have received HER2-targeted therapy before or after study treatment but NOT while on study treatment.
Study Design
Phase III, randomized, open-label, parallel, two-arm, multicenter trial
Stratified patients by geographic region & HER2 status of their cancer.
Study Objectives Compare eribulin & capecitabine in patients with
locally advanced or metastatic breast Cancer previously treated with an Anthracycline and a Taxane
Primary Endpoints: Overall Survival (OS) Progression- Free Survival (PFS)
Secondary Endpoints: objectives response rate (ORR); duration of response;
1-, 2-, and 3-year survival; safety; QoL; and population pharmacokinetic/pharmacodynamic relationships.
Study Assessments 1. Overall survival (OS):
2. Progression-Free survival rate (PFS):
3. Tumor response:
4. Duration of response:
5. Adverse Events:
QoL Analyses & Statistical Analyses
QoL Analyses Two Quality of Life Questionnaires At baseline, 6 weeks, and at 3, 6, 18 & 24 months or
until disease progression or initiation of other antitumor treatments.
0 (worst) to 100 (best) scale
Statistical Analyses OS & PFS
Type error 1 was spit; 0.04 for OS and 0.01 for PFS. 2-sided log rank test Interim planned OS analysis
Tumor response: independent & investigator analysis ORRs: Fisher's exact test
Interpreting the data Positive Study
Either OS with eribulin was statistically significantly better (P ≤ .0372) versus capecitabine
or PFS with eribulin was statistically significantly better (P ≤ .01) versus capecitabin
& the HR for OS (eribulin/capecitabine) was < 1.
Results: Patients
Results: Efficacy
Results: Efficacy
Results: Safety
QoL Analyses1. > 95% QoL data= available at baseline 2. Completion rates over time = decreased 3. GHS/QoL scores = low 4. Over time average GHS/QoL scores =
improved
BOTH ARMS
Linear mixed model and pattern-mixture model showed no significant difference between the groups: Linear mixed model P = .958 Pattern-mixture model P = .949
Discussion & Conclusion Discussion
Although eribulin is an active single in patients with MBC, it was not superior to capecitabine with regard to either OS or PFS.
Resulted contrasted with those of EMBRACE * (significant improvement with eribulin compared with TPC)
Effects of QoL & AE profiles (of both drug) were consistent with their known AE.
Conclusion Eribulin was NOT shown to be superior to capecitabine with regard to OS or PFS.
Study Analysis Study Design Inclusion/Exclusion Criteria Interventions Objectives/Outcomes Statistical Analysis Results Conclusions
Further Analysis Strengths:
Power Randomized Intention to treat
Weaknesses: Funded by Eisai Open – labeled
Recommendation
Currently, there is no standard therapy for patients who have MBC & fail
Anthracyclines or Taxanes
Chemotherapy regimes should be based on contraindications, drug-drug
interaction, tolerability (side effects) & compliance
Questions
References Phase III Open-Label Randomized Study of Eribulin Mesylate
Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a TaxanePeter A. Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, Edith A. Perez, Galina Velikova, Martin S. Olivo, Yi He, Corina E. Dutcus, and Javier CortesJCO Feb 20, 2015:594-601; published online on January 20, 2015.
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