A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA)

• Independently assessed Progression Free Survival [ Time Frame: Estimated 10 months ]
• Overall Survival [ Time Frame: Estimated 28 months ]

• Investigator Assessed Progression Free Survival [ Time Frame: Estimated 10 months ]
• Objective Response Rate (ORR) [ Time Frame: Estimated 10 months ]
• Clinical Benefit Rate (CBR) [ Time Frame: 24 weeks ]
  CBR is defined as Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 24 weeks.
• Duration of Response (DOR) [ Time Frame: Estimated 10 months ]
• Time to intervention for symptomatic metastatic central nervous system disease [ Time Frame: Estimated 10 months ]
• Safety (Adverse Events [AEs] and Serious Adverse Events [SAEs]) [ Time Frame: From consent through 30 days following treatment completion (estimated 11 months) ]
• Health Outcomes Assessments [ Time Frame: Estimated 10 months ]
  Validated Quality of Life Questionnaires; EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L

This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC patients who have received two or more prior HER2 directed regimens in the metastatic setting. Patients will be randomized in a 1:1 ratio to one of the following treatment arms:

• Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m^2 daily, 750 mg/m^2 twice daily [BID])
• Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m^2 daily, 1000 mg/m^2 BID)

Patients will receive either neratinib plus capecitabine combination or lapatinib plus capecitabine combination until the occurrence of death, disease progression, unacceptable toxicity, or other specified withdrawal criterion.

• Drug: neratinib
  240 mg orally, once daily with food, continuously in 21 day cycles
• Drug: capecitabine
  1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal. Taken on days 1 to 14 of each 21 day cycle.
  Other Name: Xeloda
• Drug: lapatinib
  1250 mg orally, once daily, continuously in 21 day cycles
  Other Names:

  • Tykerb
  • Tyverb
• Drug: capecitabine
  2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal. Taken on days 1 to 14 of each 21 day cycle.
  Other Name: Xeloda

• Experimental: neratinib plus capecitabine
  Interventions:

  • Drug: neratinib
  • Drug: capecitabine
• Active Comparator: lapatinib plus capecitabine
  Interventions:

  • Drug: lapatinib
  • Drug: capecitabine

Inclusion Criteria:

• Aged ≥18 years at signing of informed consent.
• Histologically confirmed MBC, current stage IV.
• Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry [IHC] 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+).
• Prior treatment with at least two (2) HER2-directed regimens for metastatic breast cancer.

Exclusion Criteria:

• Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2 directed tyrosine kinase inhibitor.

Note: There are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.