Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (EMILIA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00829166
First received: January 22, 2009
Last updated: September 10, 2016
Last verified: September 2016
Results First Received: February 22, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Trastuzumab emtansine
Drug: Lapatinib
Drug: Capecitabine

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants of "Lapatinib + Capecitabine" arm were allowed to cross over to receive trastuzumab emtansine based on statistically significant Overall Survival (OS) benefit in favor of trastuzumab emtansine demonstrated in second interim analysis (cut-off date 31 July 2012). The safety analysis of the arm was then reported.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Participant Flow:   Overall Study
    Trastuzumab Emtansine   Lapatinib + Capecitabine
STARTED   495   496 
Treated   490   488 
COMPLETED   0   0 
NOT COMPLETED   495   496 
Death                305                333 
Lost to Follow-up                5                4 
Physician's Decision                4                3 
Subject's Decision                41                55 
Sponsor’s Decision                137                98 
Reason Not Specified                3                3 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat (ITT) population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.
Total Total of all reporting groups

Baseline Measures
   Trastuzumab Emtansine   Lapatinib + Capecitabine   Total 
Overall Participants Analyzed 
[Units: Participants]
 495   496   991 
Age 
[Units: Years]
Mean (Standard Deviation)
 52.2  (11.0)   53.2  (10.8)   52.7  (10.9) 
Gender 
[Units: Participants]
     
Female   494   492   986 
Male   1   4   5 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Primary
Measure Title Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)
Measure Description PD was assessed by an IRC using modified Response Evaluation Criteria in Solid Tumors (RECIST). All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as target lesions (TLs) and recorded at baseline. TLs should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements either by imaging or clinically. A sum of the longest diameter for all TLs was calculated as baseline sum longest diameter (SLD). All other lesions (or sites of disease) should be identified as non-TLs and recorded at baseline. PD for TLs was defined as greater than or equal to (>/=) 20 percent (%) increase in SLD, taking as reference smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Percentage of Participants with PD by IRC or death from any cause was reported.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC) 
[Units: Percentage of participants]
 53.5   61.3 

No statistical analysis provided for Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)



2.  Primary:   Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)
Measure Description Tumor response was assessed by an IRC according to modified RECIST. All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs (on the basis of their size and their suitability for accurate repeated measurements either by imaging or clinically) and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. All other lesions were identified as non-TLs and recorded at baseline. PD for TLs: >/= 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs: appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. PFS: time from randomization to first documented PD by IRC or death from any cause (whichever occurred earlier). The median duration of PFS was estimated using Kaplan-Meier method. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint) 
[Units: Months]
Median (95% Confidence Interval)
 9.6 
 (8.25 to 10.64) 
 6.4 
 (5.68 to 7.06) 


Statistical Analysis 1 for Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.650
95% Confidence Interval 0.549 to 0.771
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or greater than [>] 1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.



3.  Primary:   Percentage of Participants Who Died: Second Interim Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

Measure Type Primary
Measure Title Percentage of Participants Who Died: Second Interim Analysis
Measure Description The percentage of participants who died from any cause was reported. The results are reported from second interim analysis, which deemed to be the confirmatory.
Time Frame From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants Who Died: Second Interim Analysis 
[Units: Percentage of participants]
 30.1   36.7 

No statistical analysis provided for Percentage of Participants Who Died: Second Interim Analysis



4.  Primary:   Overall Survival: Second Interim Analysis (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

Measure Type Primary
Measure Title Overall Survival: Second Interim Analysis (Co-primary Endpoint)
Measure Description OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results are reported from second interim analysis, which deemed to be the confirmatory.
Time Frame From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Overall Survival: Second Interim Analysis (Co-primary Endpoint) 
[Units: Months]
Median (95% Confidence Interval)
 30.9 
 (26.81 to 34.27) 
 25.1 
 (22.74 to 27.96) 


Statistical Analysis 1 for Overall Survival: Second Interim Analysis (Co-primary Endpoint)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0006
Hazard Ratio (HR) [4] 0.682
95% Confidence Interval 0.548 to 0.849
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.



5.  Primary:   Percentage of Participants Who Died: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

Measure Type Primary
Measure Title Percentage of Participants Who Died: Final Analysis
Measure Description The percentage of participants who died from any cause was reported. The results reported are from the final analysis. The final analysis is descriptive.
Time Frame From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants Who Died: Final Analysis 
[Units: Percentage of participants]
 61.2   67.1 

No statistical analysis provided for Percentage of Participants Who Died: Final Analysis



6.  Primary:   Overall Survival: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

Measure Type Primary
Measure Title Overall Survival: Final Analysis
Measure Description OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results reported are from the final analysis. The final analysis is descriptive.
Time Frame From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Overall Survival: Final Analysis 
[Units: Months]
Median (95% Confidence Interval)
 29.9 
 (26.32 to 34.10) 
 25.9 
 (22.74 to 28.32) 


Statistical Analysis 1 for Overall Survival: Final Analysis
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0003
Hazard Ratio (HR) [4] 0.749
95% Confidence Interval 0.639 to 0.877
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.



7.  Primary:   Percentage of Participants Who Were Alive at Year 1   [ Time Frame: Year 1 ]

Measure Type Primary
Measure Title Percentage of Participants Who Were Alive at Year 1
Measure Description 1 year survival was defined as the percentage of participants alive 1 year after starting treatment. The results reported are from the final analysis.
Time Frame Year 1  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants Who Were Alive at Year 1 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 85.3 
 (82.15 to 88.54) 
 78.9 
 (75.19 to 82.65) 

No statistical analysis provided for Percentage of Participants Who Were Alive at Year 1



8.  Primary:   Percentage of Participants Who Were Alive at Year 2   [ Time Frame: Year 2 ]

Measure Type Primary
Measure Title Percentage of Participants Who Were Alive at Year 2
Measure Description 2 year survival was defined as the percentage of participants alive 2 years after starting treatment. The results reported are from the final analysis.
Time Frame Year 2  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants Who Were Alive at Year 2 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 59.6 
 (55.10 to 64.06) 
 52.4 
 (47.81 to 57.08) 

No statistical analysis provided for Percentage of Participants Who Were Alive at Year 2



9.  Secondary:   Percentage of Participants With PD or Death as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With PD or Death as Assessed by the Investigator
Measure Description PD was assessed by the investigator using modified RECIST. All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. PD for TLs was defined as >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. The percentage of participants who died or experienced PD by Investigator was reported.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants With PD or Death as Assessed by the Investigator 
[Units: Percentage of participants]
 58.0   67.5 

No statistical analysis provided for Percentage of Participants With PD or Death as Assessed by the Investigator



10.  Secondary:   PFS as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title PFS as Assessed by the Investigator
Measure Description Tumor response was assessed by the investigator according to modified RECIST. All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. PD for TLs was defined as >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. PFS was defined as the time from randomization to first documented PD by Investigator or death from any cause (whichever occurred earlier). The median duration of PFS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
PFS as Assessed by the Investigator 
[Units: Months]
Median (95% Confidence Interval)
 9.4 
 (7.49 to 10.78) 
 5.8 
 (5.59 to 6.93) 


Statistical Analysis 1 for PFS as Assessed by the Investigator
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.658
95% Confidence Interval 0.560 to 0.774
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.



11.  Secondary:   Percentage of Participants With Objective Response (OR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With Objective Response (OR) as Assessed by an IRC
Measure Description Tumor response was assessed by an IRC according to modified RECIST. OR was defined as the percentage of participants with a complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. For TLs, a CR was defined as the disappearance of all TLs and a PR was defined as >/= 30% decrease in the SLD of TLs, taking as reference the baseline SLD. For non-TLs, a CR was defined as the disappearance of all non-TLs and a PR was defined as the persistence of 1 or more non-TLs. Confirmation of response at a consecutive tumor assessment at least 4 weeks apart was required. Participants without a post-baseline tumor assessment were considered non-responders. The percentage of participants with CR or PR by IRC was reported. The 95% CI was computed using Blyth-Still Casella exact CI method.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization. Only participants with measurable disease at baseline were included in the analysis.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 397   389 
Percentage of Participants With Objective Response (OR) as Assessed by an IRC 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 43.6 
 (38.6 to 48.6) 
 30.8 
 (26.3 to 35.7) 


Statistical Analysis 1 for Percentage of Participants With Objective Response (OR) as Assessed by an IRC
Groups [1] All groups
Method [2] Mantel-Haenszel chi-squared test
P Value [3] 0.0002
Difference in Objective Response Rates [4] 12.7
95% Confidence Interval 6.0 to 19.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  The 95% CI for the difference in objective response rate (Trastuzumab emtansine minus Lapatinib + Capecitabine) was computed by using the approximate normal method.



12.  Secondary:   Duration of Objective Response (DOR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Duration of Objective Response (DOR) as Assessed by an IRC
Measure Description Tumor response was assessed by an IRC according to modified RECIST. DOR was defined as the time from first documented OR to first documented PD or death from any cause, whichever occurred earlier. OR was defined as a CR or PR determined on 2 consecutive tumor assessments at least 4 weeks apart. For TLs, CR was defined as the disappearance of all TLs; PR was defined as >/=30% decrease in the SLD of TLs, taking as reference the baseline SLD; and PD was defined as >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. For non-TLs, CR was defined as the disappearance of all non-TLs; PR was defined as the persistence of 1 or more non-TLs; and PD was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization. Only participants with an objective response were included in the analysis.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 173   120 
Duration of Objective Response (DOR) as Assessed by an IRC 
[Units: Months]
Median (95% Confidence Interval)
 12.6 
 (8.38 to 20.76) 
 6.5 
 (5.45 to 7.16) 

No statistical analysis provided for Duration of Objective Response (DOR) as Assessed by an IRC



13.  Secondary:   Percentage of Participants With Clinical Benefit as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With Clinical Benefit as Assessed by an IRC
Measure Description Tumor response was assessed by an IRC according to modified RECIST. Participants were considered as experienced clinical benefit if they had an OR or maintained stable disease (SD) for at least 6 months from randomization. OR: CR or PR determined on 2 consecutive tumor assessments >/=4 weeks apart. For TLs, CR: disappearance of all TLs; PR: >/=30% decrease in the SLD of TLs, taking as reference the baseline SLD; PD: >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or appearance of 1 or more new lesions; and SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For non-TLs, CR: disappearance of all non-TLs; PR/SD: persistence of 1 or more non-TLs; and PD: appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Participants without a post-baseline tumor assessment were considered non-responders. The 95% CI was computed using Blyth-Still Casella exact CI method.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization. Only participants with measurable disease at Baseline were included in the analysis.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 397   389 
Percentage of Participants With Clinical Benefit as Assessed by an IRC 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 58.2 
 (53.3 to 63.1) 
 44.2 
 (39.2 to 49.2) 


Statistical Analysis 1 for Percentage of Participants With Clinical Benefit as Assessed by an IRC
Groups [1] All groups
Difference in Clinical Benefit Rate [2] 14
95% Confidence Interval 7.0 to 20.9
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The 95% CI for the difference in clinical benefit rate (Trastuzumab emtansine minus Lapatinib + Capecitabine) was computed by using the normal approximation method.



14.  Secondary:   Percentage of Participants With Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With Treatment Failure
Measure Description Treatment failure was defined as discontinuation of treatment for any reason, including PD (per investigator review), treatment toxicity, or death from any cause. For "Lapatinib + Capecitabine" arm, a participant was considered as treatment failure only if both drugs were discontinued. For TLs, PD was defined as >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. For non-TLs, PD was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Percentage of participants with treatment failure was reported.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Percentage of Participants With Treatment Failure 
[Units: Percentage of participants]
 63.2   74.8 

No statistical analysis provided for Percentage of Participants With Treatment Failure



15.  Secondary:   Time to Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Time to Treatment Failure
Measure Description Time to treatment failure was defined as the time from randomization to discontinuation of treatment for any reason, including PD (per investigator review), treatment toxicity, or death from any cause. For "Lapatinib + Capecitabine" arm, a participant was considered as treatment failure only if both drugs were discontinued with treatment failure date as the later of the 2 discontinuation dates. For TLs, PD was defined as >/=20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. For non-TLs, PD was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. The median time to treatment failure was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 495   496 
Time to Treatment Failure 
[Units: Months]
Median (95% Confidence Interval)
 7.9 
 (6.41 to 9.00) 
 5.8 
 (5.52 to 6.31) 


Statistical Analysis 1 for Time to Treatment Failure
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.703
95% Confidence Interval 0.602 to 0.820
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.



16.  Secondary:   Percentage of Participants With Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With Symptom Progression
Measure Description Symptom progression was defined as the documentation of a >/= 5-point decrease from baseline in the scoring of responses as measured by the Functional Assessment of Cancer Therapy-for participants with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contained 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer participants (breast cancer subscale [BCS]). All items in the questionnaire were rated by the participant on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96 with higher score indicating better perceived quality of life. The percentage of participants with symptom progression was reported.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization. Only female participants with a Baseline assessment and at least 1 follow-up assessment were included in the analysis.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 450   445 
Percentage of Participants With Symptom Progression 
[Units: Percentage of participants]
 54.7   57.8 

No statistical analysis provided for Percentage of Participants With Symptom Progression



17.  Secondary:   Time to Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

Measure Type Secondary
Measure Title Time to Symptom Progression
Measure Description Time to symptom progression was defined as the time from randomization to the first documentation of a >/= 5-point decrease from baseline in the scoring of responses as measured by the FACT-B questionnaire with the TOI-PFB subscale. The FACT-B TOI-PFB subscale contained 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer participants (BCS). All items in the questionnaire were rated by the participant on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96 with higher score indicating better perceived quality of life. The median time to symptom progression was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all randomized participants on the basis of the treatment assigned at randomization. Only female participants with a Baseline assessment and at least 1 follow-up assessment were included in the analysis.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Measured Values
   Trastuzumab Emtansine   Lapatinib + Capecitabine 
Participants Analyzed 
[Units: Participants]
 450   445 
Time to Symptom Progression 
[Units: Months]
Median (95% Confidence Interval)
 7.1 
 (5.59 to 8.44) 
 4.6 
 (4.14 to 5.78) 


Statistical Analysis 1 for Time to Symptom Progression
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0121
Hazard Ratio (HR) [4] 0.796
95% Confidence Interval 0.667 to 0.951
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified by region of enrollment, number of prior chemotherapeutic regimens (0-1 or >1), and visceral/ non-visceral disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HR (relative to Lapatinib + Capecitabine) was estimated by Cox regression.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


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