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.