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)

• ClinicalTrials.gov Identifier: NCT01419197
• Recruitment Status: Completed
• First Posted: August 18, 2011
• Results First Posted: May 5, 2014
• Last Update Posted: October 12, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• 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
• Enrollment: 602

Participant Flow

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description	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 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.
Period Title: Overall Study
Started	404	198
Switched to Trastuzumab Emtansine	0	94
Completed	0	0
Not Completed	404	198
Reason Not Completed
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

Arm/Group Title		Trastuzumab Emtansine	Treatment of Physician’s Choice	Total
Arm/Group Description		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 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 of all reporting groups
Overall Number of Baseline Participants		404	198	602
Baseline Analysis Population Description		Randomized population: All participants who were randomized to the study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	404 participants	198 participants	602 participants
		53.3 (10.4)	54.3 (10.8)	53.6 (10.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	404 participants	198 participants	602 participants
	Female	401 99.3%	197 99.5%	598 99.3%
	Male	3 0.7%	1 0.5%	4 0.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	404	198
Median (95% Confidence Interval); Unit of Measure: Months
	6.2; (5.59 to 6.87)	3.3; (2.89 to 4.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	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%.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.528
	Confidence Interval	(2-Sided) 95%; 0.422 to 0.661
	Estimation Comments	The hazard ratio was estimated by Cox regression.

2. Primary Outcome

Title	Overall Survival
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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	404	198
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (13.14 to NA)	14.9 [2]; (11.27 to NA)

[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

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0034
	Comments	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).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.552
	Confidence Interval	(2-Sided) 95%; 0.369 to 0.826
	Estimation Comments	The hazard ratio was estimated by Cox regression.

3. Secondary Outcome

Title	Percentage of Participants With an Objective Response
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	345	163
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	31.3; (26.5 to 36.5)	8.6; (5.1 to 13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Percentage
	Estimated Value	22.7
	Confidence Interval	(2-Sided) 95%; 16.2 to 29.2
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Duration of the Objective Response
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	108	14
Median (95% Confidence Interval); Unit of Measure: Months
	9.7; (6.60 to 10.51)	NA [1]; (2.40 to NA)

[1]

The median and the upper confidence interval value could not be estimated due to too few events.

5. Secondary Outcome

Title	6-month and 1-year Survival
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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	404	198
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
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

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	6-month survival
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
	Method	z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Survival Percentage
	Estimated Value	12.6
	Confidence Interval	(2-Sided) 95%; 5.03 to 20.09
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	1-year survival
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1805
	Comments	The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.
	Method	z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Survival Percentage
	Estimated Value	11.7
	Confidence Interval	(2-Sided) 95%; -5.41 to 28.75
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Time to Pain Symptom Progression
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	297	117
Median (95% Confidence Interval); Unit of Measure: Months
	2.9; (2.2 to 3.7)	3.6; (2.7 to 4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4952
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.115
	Confidence Interval	(2-Sided) 95%; 0.819 to 1.517
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	297	117
Mean (Standard Deviation); Unit of Measure: Units on a scale
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] (NA)
Cycle 19 (n=8,0)	1.4 (9.3)	NA [1] (NA)
Cycle 20 (n=4,0)	-5.6 (23.1)	NA [1] (NA)
Cycle 21 (n=3,0)	-3.7 (6.4)	NA [1] (NA)
Termination Visit (n=84,37)	-1.6 (21.8)	-9.0 (23.3)

[1]

There were no participants with available data.

8. Secondary Outcome

Title	Overall Survival (Final Analysis)
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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	404	198
Median (95% Confidence Interval); Unit of Measure: Months
	22.7; (19.35 to 27.47)	15.8; (13.50 to 18.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0007
	Comments	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).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.677
	Confidence Interval	(2-Sided) 95%; 0.539 to 0.850
	Estimation Comments	The hazard ratio was estimated by Cox regression.

9. Secondary Outcome

Title	6-month and 1-year Survival (Final Analysis)
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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice
Arm/Group Description:	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 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.
Overall Number of Participants Analyzed	404	198
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
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

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	6-month survival
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
	Method	z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Survival Percentage
	Estimated Value	12.4
	Confidence Interval	(2-Sided) 95%; 5.67 to 19.14
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine, Treatment of Physician’s Choice
	Comments	1-year survival
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0104
	Comments	The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.
	Method	z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Survival Percentage
	Estimated Value	11.0
	Confidence Interval	(2-Sided) 95%; 2.58 to 19.33
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events were collected from treatment initiation until 30 days following the last administration of study drug or study discontinuation on 31 August 2015 (up to approximately 4 years).
Adverse Event Reporting Description	Safety population: All participants who received any amount of planned study treatment, according to treatment actually received. Data for participants in the Treatment of Physicians Choice (TPC) arm who switched treatment to receive trastuzumab emtansine (TE) following disease progression on TPC are presented separately. Median treatment duration of trastuzumab emtansine: 5.2 months (range 0.03-40.7),TPC: 2.7 months (range 0.03-31.0) and TE - Post TPC Treatment Switch: 4.5 months (range 1-43).
Arm/Group Title	Trastuzumab Emtansine	Treatment of Physician’s Choice (TPC)	Trastuzumab Emtansine - Post TPC Treatment Switch
Arm/Group Description	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 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.	Participants, who switched treatment in the Treatment of Physician's Choice arm to trastuzumab emtansine, were administered trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
All-Cause Mortality
	Trastuzumab Emtansine	Treatment of Physician’s Choice (TPC)	Trastuzumab Emtansine - Post TPC Treatment Switch
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Trastuzumab Emtansine	Treatment of Physician’s Choice (TPC)	Trastuzumab Emtansine - Post TPC Treatment Switch
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	102/403 (25.31%)	41/184 (22.28%)	19/94 (20.21%)
Blood and lymphatic system disorders
Anaemia † 1	1/403 (0.25%)	2/184 (1.09%)	1/94 (1.06%)
Febrile neutropenia † 1	1/403 (0.25%)	7/184 (3.80%)	0/94 (0.00%)
Granulocytopenia † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Neutropenia † 1	1/403 (0.25%)	2/184 (1.09%)	0/94 (0.00%)
Thrombocytopenia † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Cardiac disorders
Cardiac failure † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Endocrine disorders
Hypercalcaemia of malignancy † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Eye disorders
Vision blurred † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Abdominal pain † 1	4/403 (0.99%)	3/184 (1.63%)	1/94 (1.06%)
Abdominal pain upper † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Abdominal wall haematoma † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Colitis † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Diarrhoea † 1	2/403 (0.50%)	1/184 (0.54%)	0/94 (0.00%)
Gastric haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Ileus † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Nausea † 1	0/403 (0.00%)	2/184 (1.09%)	0/94 (0.00%)
Obstruction gastric † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Pancreatitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Proctitis Haemorrhagic † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Small intestinal obstruction † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Upper gastrointestinal haemorrhage † 1	0/403 (0.00%)	1/184 (0.54%)	1/94 (1.06%)
Vomiting † 1	2/403 (0.50%)	2/184 (1.09%)	0/94 (0.00%)
General disorders
Adverse drug reaction † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Asthenia † 1	3/403 (0.74%)	0/184 (0.00%)	0/94 (0.00%)
Death † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Device occlusion † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Fatigue † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
General physical health deterioration † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Malaise † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Non-cardiac chest pain † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Oedema peripheral † 1	2/403 (0.50%)	2/184 (1.09%)	0/94 (0.00%)
Pain † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Pyrexia † 1	7/403 (1.74%)	2/184 (1.09%)	1/94 (1.06%)
Vessel puncture site haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hepatobiliary disorders
Bile duct obstruction † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Cholangitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Cholecystitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Nodular regenerative hyperplasia † 1	3/403 (0.74%)	0/184 (0.00%)	0/94 (0.00%)
Hepatotoxicity † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Immune system disorders
Drug hypersensitivity † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Hypersensitivity † 1	1/403 (0.25%)	0/184 (0.00%)	1/94 (1.06%)
Infections and infestations
Appendicitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Bronchopneumonia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Cellulitis † 1	2/403 (0.50%)	4/184 (2.17%)	1/94 (1.06%)
Clostridium bacteraemia † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Device related infection † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Device related sepsis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Gastroenteritis † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Infected fistula † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Infection † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Infectious colitis † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Lung infection † 1	1/403 (0.25%)	0/184 (0.00%)	1/94 (1.06%)
Lymphangitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Mastitis † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Neutropenic sepsis † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Pharyngotonsillitis † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Pneumonia † 1	5/403 (1.24%)	0/184 (0.00%)	1/94 (1.06%)
Postoperative wound infection † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Sepsis † 1	3/403 (0.74%)	0/184 (0.00%)	0/94 (0.00%)
Sinusitis † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Tracheitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Upper respiratory tract infection † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Urinary tract infection † 1	4/403 (0.99%)	0/184 (0.00%)	0/94 (0.00%)
Urosepsis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Viral upper respiratory tract infection † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Wound infection † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Abdominal infection † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Abscess † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Biliary tract infection † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Injury, poisoning and procedural complications
Fall † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Femoral neck fracture † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Femur fracture † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Infusion related reaction † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Sternal fracture † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Subdural haematoma † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Subdural haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Thoracic vertebral fracture † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Traumatic intracranial haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Wound decomposition † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Wound haemorrhage † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Toxicity to various agents † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Upper limb fracture † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Investigations
Transaminases increased † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
White blood cell count decreased † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/403 (0.25%)	0/184 (0.00%)	1/94 (1.06%)
Dehydration † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hypercalcaemia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hyperglycaemia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hypokalaemia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hyponatraemia † 1	4/403 (0.99%)	0/184 (0.00%)	0/94 (0.00%)
Hypophagia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Malnutrition † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Back pain † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Bone pain † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Muscle haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Musculoskeletal chest pain † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Myalgia † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Spinal pain † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Muscular weakness † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal adenocarcinoma † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Tumour haemorrhage † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Tumor pain † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Tumour necrosis † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Nervous system disorders
Ataxia † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Brain oedema † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Cerebral haematoma † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Cerebral haemorrhage † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Cognitive disorder † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Depressed level of consciousness † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Dizziness † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Haemorrhage intracranial † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hepatic encephalopathy † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Loss of consciousness † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Paraesthesia † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Paraparesis † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Seizure † 1	5/403 (1.24%)	0/184 (0.00%)	1/94 (1.06%)
Somnolence † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Subarachnoid haemorrhage † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Transient ischaemic attack † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Visual field defect † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Epilepsy † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Hemiplegia † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Psychiatric disorders
Confusional state † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Renal and urinary disorders
Haematuria † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Reproductive system and breast disorders
Vaginal haemorrhage † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	6/403 (1.49%)	5/184 (2.72%)	2/94 (2.13%)
Epistaxis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Haemoptysis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Non-cardiogenic pulmonary oedema † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Obliterative bronchiolitis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Pleural effusion † 1	3/403 (0.74%)	2/184 (1.09%)	0/94 (0.00%)
Pleuritic pain † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Pneumonia aspiration † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Pneumonitis † 1	2/403 (0.50%)	1/184 (0.54%)	0/94 (0.00%)
Pneumothorax † 1	1/403 (0.25%)	1/184 (0.54%)	0/94 (0.00%)
Pulmonary embolism † 1	1/403 (0.25%)	2/184 (1.09%)	1/94 (1.06%)
Respiratory failure † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Pulmonary Fibrosis † 1	0/403 (0.00%)	0/184 (0.00%)	1/94 (1.06%)
Vascular disorders
Deep vein thrombosis † 1	2/403 (0.50%)	0/184 (0.00%)	0/94 (0.00%)
Embolism † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Embolism venous † 1	0/403 (0.00%)	1/184 (0.54%)	0/94 (0.00%)
Hypertensive crisis † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Hypotension † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
Lymphoedema † 1	0/403 (0.00%)	1/184 (0.54%)	1/94 (1.06%)
Superior vena cava syndrome † 1	1/403 (0.25%)	0/184 (0.00%)	0/94 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (16.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Trastuzumab Emtansine	Treatment of Physician’s Choice (TPC)	Trastuzumab Emtansine - Post TPC Treatment Switch
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	371/403 (92.06%)	148/184 (80.43%)	74/94 (78.72%)
Blood and lymphatic system disorders
Anaemia † 1	45/403 (11.17%)	19/184 (10.33%)	7/94 (7.45%)
Leukopenia † 1	9/403 (2.23%)	11/184 (5.98%)	0/94 (0.00%)
Neutropenia † 1	30/403 (7.44%)	39/184 (21.20%)	5/94 (5.32%)
Thrombocytopenia † 1	81/403 (20.10%)	6/184 (3.26%)	17/94 (18.09%)
Eye disorders
Lacrimation increased † 1	0/403 (0.00%)	0/184 (0.00%)	5/94 (5.32%)
Gastrointestinal disorders
Abdominal pain † 1	27/403 (6.70%)	20/184 (10.87%)	9/94 (9.57%)
Constipation † 1	90/403 (22.33%)	32/184 (17.39%)	7/94 (7.45%)
Diarrhoea † 1	52/403 (12.90%)	40/184 (21.74%)	10/94 (10.64%)
Dry mouth † 1	51/403 (12.66%)	2/184 (1.09%)	9/94 (9.57%)
Dyspepsia † 1	21/403 (5.21%)	12/184 (6.52%)	0/94 (0.00%)
Gingival bleeding † 1	21/403 (5.21%)	0/184 (0.00%)	0/94 (0.00%)
Nausea † 1	144/403 (35.73%)	40/184 (21.74%)	16/94 (17.02%)
Stomatitis † 1	13/403 (3.23%)	11/184 (5.98%)	0/94 (0.00%)
Vomiting † 1	77/403 (19.11%)	16/184 (8.70%)	10/94 (10.64%)
Abdominal pain upper † 1	0/403 (0.00%)	0/184 (0.00%)	7/94 (7.45%)
General disorders
Asthenia † 1	76/403 (18.86%)	33/184 (17.93%)	15/94 (15.96%)
Chills † 1	21/403 (5.21%)	4/184 (2.17%)	0/94 (0.00%)
Fatigue † 1	123/403 (30.52%)	48/184 (26.09%)	10/94 (10.64%)
Influenza like illness † 1	21/403 (5.21%)	2/184 (1.09%)	0/94 (0.00%)
Mucosal inflammation † 1	17/403 (4.22%)	10/184 (5.43%)	7/94 (7.45%)
Oedema peripheral † 1	26/403 (6.45%)	11/184 (5.98%)	0/94 (0.00%)
Pyrexia † 1	77/403 (19.11%)	22/184 (11.96%)	14/94 (14.89%)
Pain † 1	0/403 (0.00%)	0/184 (0.00%)	5/94 (5.32%)
Infections and infestations
Nasopharyngitis † 1	35/403 (8.68%)	12/184 (6.52%)	6/94 (6.38%)
Upper respiratory tract infection † 1	35/403 (8.68%)	8/184 (4.35%)	8/94 (8.51%)
Urinary tract infection † 1	26/403 (6.45%)	7/184 (3.80%)	9/94 (9.57%)
Sinusitis † 1	0/403 (0.00%)	0/184 (0.00%)	5/94 (5.32%)
Investigations
Alanine aminotransferase increased † 1	38/403 (9.43%)	10/184 (5.43%)	7/94 (7.45%)
Aspartate aminotransferase increased † 1	51/403 (12.66%)	13/184 (7.07%)	13/94 (13.83%)
Blood alkaline phosphatase increased † 1	21/403 (5.21%)	5/184 (2.72%)	7/94 (7.45%)
Blood bilirubin increased † 1	38/403 (9.43%)	2/184 (1.09%)	5/94 (5.32%)
Ejection fraction decreased † 1	11/403 (2.73%)	12/184 (6.52%)	0/94 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	66/403 (16.38%)	25/184 (13.59%)	15/94 (15.96%)
Hypokalaemia † 1	30/403 (7.44%)	4/184 (2.17%)	6/94 (6.38%)
Hyperglycaemia † 1	0/403 (0.00%)	0/184 (0.00%)	5/94 (5.32%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	60/403 (14.89%)	8/184 (4.35%)	7/94 (7.45%)
Back pain † 1	35/403 (8.68%)	13/184 (7.07%)	6/94 (6.38%)
Bone pain † 1	22/403 (5.46%)	7/184 (3.80%)	0/94 (0.00%)
Muscle spasms † 1	26/403 (6.45%)	9/184 (4.89%)	0/94 (0.00%)
Musculoskeletal pain † 1	18/403 (4.47%)	10/184 (5.43%)	7/94 (7.45%)
Myalgia † 1	47/403 (11.66%)	14/184 (7.61%)	6/94 (6.38%)
Pain in extremity † 1	44/403 (10.92%)	9/184 (4.89%)	0/94 (0.00%)
Nervous system disorders
Dizziness † 1	31/403 (7.69%)	6/184 (3.26%)	6/94 (6.38%)
Headache † 1	100/403 (24.81%)	22/184 (11.96%)	16/94 (17.02%)
Neuropathy peripheral † 1	20/403 (4.96%)	10/184 (5.43%)	7/94 (7.45%)
Paraesthesia † 1	28/403 (6.95%)	11/184 (5.98%)	9/94 (9.57%)
Psychiatric disorders
Insomnia † 1	35/403 (8.68%)	6/184 (3.26%)	8/94 (8.51%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	76/403 (18.86%)	24/184 (13.04%)	12/94 (12.77%)
Dyspnoea † 1	42/403 (10.42%)	21/184 (11.41%)	6/94 (6.38%)
Epistaxis † 1	67/403 (16.63%)	7/184 (3.80%)	12/94 (12.77%)
Skin and subcutaneous tissue disorders
Alopecia † 1	9/403 (2.23%)	20/184 (10.87%)	0/94 (0.00%)
Pruritus † 1	23/403 (5.71%)	17/184 (9.24%)	0/94 (0.00%)
Rash † 1	27/403 (6.70%)	19/184 (10.33%)	0/94 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (16.0)

Limitations and Caveats

[Not Specified]

More Information

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 Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

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):

Chen SC, Quartino A, Polhamus D, Riggs M, French J, Wang X, Vadhavkar S, Smitt M, Hoersch S, Strasak A, Jin JY, Girish S, Li C. Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens. Br J Clin Pharmacol. 2017 Dec;83(12):2767-2777. doi: 10.1111/bcp.13381. Epub 2017 Sep 3.

Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017 Jun;18(6):743-754. doi: 10.1016/S1470-2045(17)30313-3. Epub 2017 May 16.

Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):689-99. doi: 10.1016/S1470-2045(14)70178-0. Epub 2014 May 2.

• 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