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A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy (TH3RESA)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01419197
First Posted: August 18, 2011
Last Update Posted: October 12, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Hoffmann-La Roche
Results First Submitted: February 7, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Trastuzumab emtansine
Drug: Treatment of physician's choice

  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
A total of 602 patients were randomized to the study (404 to receive Trastuzumab Emtansine and 198 to receive Treatment of Physician’s Choice).

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and human epidermal growth factor receptor 2 (HER2)-directed therapy.

Participant Flow:   Overall Study
    Trastuzumab Emtansine   Treatment of Physician’s Choice
STARTED   404   198 
Switched to Trastuzumab Emtansine   0   94 
COMPLETED   0   0 
NOT COMPLETED   404   198 
Death                247                122 
Physician Decision                4                4 
Non-compliance                3                1 
Withdrawal by Subject                33                32 
Study Completed by Sponsor                103                34 
Reason Not Specified                0                1 
Lost to Follow-up                14                4 



  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.
Randomized population: All participants who were randomized to the study.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.
Total Total of all reporting groups

Baseline Measures
   Trastuzumab Emtansine   Treatment of Physician’s Choice   Total 
Overall Participants Analyzed 
[Units: Participants]
 404   198   602 
Age 
[Units: Years]
Mean (Standard Deviation)
 53.3  (10.4)   54.3  (10.8)   53.6  (10.5) 
Gender 
[Units: Participants]
     
Female   401   197   598 
Male   3   1   4 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Progression-free Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Primary
Measure Title Progression-free Survival
Measure Description Progression-free survival was defined as the time from randomization to the first documented disease progression by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. Progression-free survival was a co-primary endpoint.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 404   198 
Progression-free Survival 
[Units: Months]
Median (95% Confidence Interval)
 6.2 
 (5.59 to 6.87) 
 3.3 
 (2.89 to 4.14) 


Statistical Analysis 1 for Progression-free Survival
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.0001
Hazard Ratio (HR) [5] 0.528
95% Confidence Interval 0.422 to 0.661
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The two-sided stratified log-rank test was used to compare progression-free survival between the two treatment arms at the overall two-sided significance level of 0.5%.
[5] Other relevant estimation information:
  The hazard ratio was estimated by Cox regression.



2.  Primary:   Overall Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Primary
Measure Title Overall Survival
Measure Description Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was a co-primary endpoint.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 404   198 
Overall Survival 
[Units: Months]
Median (95% Confidence Interval)
 NA [1] 
 (13.14 to N/A) 
 14.9 [2] 
 (11.27 to N/A) 
[1] The median and the upper limit of the confidence interval could not be estimated due to too few events.
[2] The upper limit of the confidence interval could not be estimated due to too few events.


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.0034
Hazard Ratio (HR) [5] 0.552
95% Confidence Interval 0.369 to 0.826
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The 2-sided stratified log-rank test was used at the overall two-sided significance level of 4.5%. The pre-specified O’Brien-Fleming stopping boundary for this first OS interim analysis was HR<0.363 (p-value < 0.0000013).
[5] Other relevant estimation information:
  The hazard ratio was estimated by Cox regression.



3.  Secondary:   Percentage of Participants With an Objective Response   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Percentage of Participants With an Objective Response
Measure Description An objective response was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Only participants with measurable disease at Baseline were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 345   163 
Percentage of Participants With an Objective Response 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 31.3 
 (26.5 to 36.5) 
 8.6 
 (5.1 to 13.8) 


Statistical Analysis 1 for Percentage of Participants With an Objective Response
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mantel Haenszel
P Value [4] <0.0001
Difference in Response Percentage [5] 22.7
95% Confidence Interval 16.2 to 29.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] 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.
[5] Other relevant estimation information:
  No text entered.



4.  Secondary:   Duration of the Objective Response   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Duration of the Objective Response
Measure Description Duration of the objective response was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Only participants with an objective response were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 108   14 
Duration of the Objective Response 
[Units: Months]
Median (95% Confidence Interval)
 9.7 
 (6.60 to 10.51) 
 NA [1] 
 (2.40 to N/A) 
[1] The median and the upper confidence interval value could not be estimated due to too few events.

No statistical analysis provided for Duration of the Objective Response



5.  Secondary:   6-month and 1-year Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title 6-month and 1-year Survival
Measure Description 6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 404   198 
6-month and 1-year Survival 
[Units: Percentage of participants]
Number (95% Confidence Interval)
   
6-Month Survival   90.9 
 (87.79 to 94.01) 
 78.3 
 (71.49 to 85.19) 
1-Year Survival   68.6 
 (59.91 to 77.28) 
 56.9 
 (42.22 to 71.63) 


Statistical Analysis 1 for 6-month and 1-year Survival
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] z-test
P Value [4] 0.0011
Difference in Survival Percentage [5] 12.6
95% Confidence Interval 5.03 to 20.09
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  6-month survival
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for 6-month and 1-year Survival
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] z-test
P Value [4] 0.1805
Difference in Survival Percentage [5] 11.7
95% Confidence Interval -5.41 to 28.75
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  1-year survival
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.
[5] Other relevant estimation information:
  No text entered.



6.  Secondary:   Time to Pain Symptom Progression   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Time to Pain Symptom Progression
Measure Description Time to pain symptom progression was defined as the time from randomization to the first documentation of an increase in narcotic use and/or a 10 point increase from Baseline in the pain score as measured by the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22). The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Only participants with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 297   117 
Time to Pain Symptom Progression 
[Units: Months]
Median (95% Confidence Interval)
 2.9 
 (2.2 to 3.7) 
 3.6 
 (2.7 to 4.5) 


Statistical Analysis 1 for Time to Pain Symptom Progression
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.4952
Hazard Ratio (HR) [5] 1.115
95% Confidence Interval 0.819 to 1.517
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] 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.
[5] Other relevant estimation information:
  No text entered.



7.  Secondary:   Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle
Measure Description The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. A negative change score indicates improvement.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  

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.
Randomized population: All participants who were randomized to the study. Only participants with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 297   117 
Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle 
[Units: Units on a scale]
Mean (Standard Deviation)
   
Cycle 2 (n=282,98)   -3.4  (21.1)   -9.4  (22.1) 
Cycle 3 (n=257,86)   -4.6  (21.1)   -6.1  (21.4) 
Cycle 4 (n=236,74)   -4.8  (19.6)   -3.8  (24.1) 
Cycle 5 (n=224,54)   -6.6  (22.8)   -2.7  (18.9) 
Cycle 6 (n=195,42)   -4.8  (23.5)   2.4  (17.1) 
Cycle 7 (n=163,30)   -4.2  (23.8)   -1.5  (15.6) 
Cycle 8 (n=130,20)   -7.0  (21.0)   2.2  (18.6) 
Cycle 9 (n=97,15)   -5.8  (22.2)   6.7  (20.1) 
Cycle 10 (n=80,7)   -8.9  (21.2)   1.6  (11.9) 
Cycle 11 (n=56,8)   -10.5  (23.1)   0.0  (8.4) 
Cycle 12 (n=48,7)   -11.3  (25.8)   1.6  (7.7) 
Cycle 13 (n=40,5)   -10.0  (23.3)   2.2  (12.2) 
Cycle 14 (n=33,5)   -10.1  (21.8)   0.0  (7.9) 
Cycle 15 (n=27,3)   -13.2  (22.0)   0.0  (0.0) 
Cycle 16 (n=19,3)   -12.3  (19.6)   -3.7  (6.4) 
Cycle 17 (n=15,2)   -7.4  (22.9)   -5.6  (7.9) 
Cycle 18 (n=11,0)   -9.1  (12.0)   NA [1] 
Cycle 19 (n=8,0)   1.4  (9.3)   NA [1] 
Cycle 20 (n=4,0)   -5.6  (23.1)   NA [1] 
Cycle 21 (n=3,0)   -3.7  (6.4)   NA [1] 
Termination Visit (n=84,37)   -1.6  (21.8)   -9.0  (23.3) 
[1] There were no participants with available data.

No statistical analysis provided for Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle



8.  Secondary:   Overall Survival (Final Analysis)   [ Time Frame: Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years) ]

Measure Type Secondary
Measure Title Overall Survival (Final Analysis)
Measure Description Overall survival was defined as the time from randomization to death from any cause.
Time Frame Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years)  

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.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 404   198 
Overall Survival (Final Analysis) 
[Units: Months]
Median (95% Confidence Interval)
 22.7 
 (19.35 to 27.47) 
 15.8 
 (13.50 to 18.66) 


Statistical Analysis 1 for Overall Survival (Final Analysis)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.0007
Hazard Ratio (HR) [5] 0.677
95% Confidence Interval 0.539 to 0.850
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease versus no visceral disease).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The two-sided stratified log-rank test was used at the overall two-sided significance level of 4.5%. The pre-specified O’Brien-Fleming stopping boundary for this second and final interim analysis was HR<0.748 (p value < 0.012).
[5] Other relevant estimation information:
  The hazard ratio was estimated by Cox regression.



9.  Secondary:   6-month and 1-year Survival (Final Analysis)   [ Time Frame: Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years) ]

Measure Type Secondary
Measure Title 6-month and 1-year Survival (Final Analysis)
Measure Description 6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method.
Time Frame Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years)  

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.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
   Trastuzumab Emtansine   Treatment of Physician’s Choice 
Participants Analyzed 
[Units: Participants]
 404   198 
6-month and 1-year Survival (Final Analysis) 
[Units: Percentage of participants]
Number (95% Confidence Interval)
   
6-Month Survival   91.3 
 (88.52 to 94.11) 
 78.9 
 (72.78 to 85.04) 
1-Year Survival   76.5 
 (72.23 to 80.79) 
 65.6 
 (58.36 to 72.76) 


Statistical Analysis 1 for 6-month and 1-year Survival (Final Analysis)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] z-test
P Value [4] 0.0003
Difference in Survival Percentage [5] 12.4
95% Confidence Interval 5.67 to 19.14
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  6-month survival
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for 6-month and 1-year Survival (Final Analysis)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] z-test
P Value [4] 0.0104
Difference in Survival Percentage [5] 11.0
95% Confidence Interval 2.58 to 19.33
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  1-year survival
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.
[5] Other relevant estimation information:
  No text entered.




  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.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
phone: 800 821-8590


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01419197     History of Changes
Other Study ID Numbers: TDM4997g
BO25734 ( Other Identifier: Hoffmann-La Roche )
2011-000509-29 ( EudraCT Number )
First Submitted: August 16, 2011
First Posted: August 18, 2011
Results First Submitted: February 7, 2014
Results First Posted: May 5, 2014
Last Update Posted: October 12, 2016