A Phase 3 interventional study of docetaxel and paclitaxel in Breast Cancer, sponsored by Hoffmann-La Roche. Completed at 257 sites in 38 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-03-04.
Sponsored by Hoffmann-La Roche · Phase 3, Interventional, and Treatment
This randomized, 3-arm, multicenter, phase III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) with pertuzumab or trastuzumab emtansine (T-DM1) with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab (Herceptin) plus taxane (docetaxel or paclitaxel) in participants with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Participants will be randomized to 1 of 3 treatment arms (Arms A, B or C). Arm A will be open-label, whereas Arms B and C will be blinded.
14,825 studies on the registry are indexed under Breast Neoplasms; 3,319 are open to participants now.
This study's enrollment of 1,095 is above the median of 72 across 10,896 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →Hoffmann-La Roche is the lead sponsor of 2,101 studies on the registry; 87 are open to participants now.
Of its 330 completed or terminated interventional studies of FDA-regulated products, 248 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HER2 is a protein, made from the ERBB2 gene, that drives the growth of some cancers. A study may look for a level of the protein, extra copies of the gene, or a particular change in it.
In breast cancer, protein tests are read as HER2-positive, HER2-low or HER2-negative; other cancers use their own rules. Check which test result the study requires.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
The standard rules for measuring tumours on CT or MRI scans, to tell whether a cancer is shrinking, stable or growing during treatment.
“Measurable disease per RECIST 1.1” usually means at least one tumour 10 mm or more at its longest on a CT scan, or a lymph node 15 mm or more across its short axis.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
HER2
HER2 is a protein, made from the ERBB2 gene, that drives the growth of some cancers. A study may look for a level of the protein, extra copies of the gene, or a particular change in it.
In breast cancer, protein tests are read as HER2-positive, HER2-low or HER2-negative; other cancers use their own rules. Check which test result the study requires.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Measurable disease
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
RECIST
The standard rules for measuring tumours on CT or MRI scans, to tell whether a cancer is shrinking, stable or growing during treatment.
“Measurable disease per RECIST 1.1” usually means at least one tumour 10 mm or more at its longest on a CT scan, or a lymph node 15 mm or more across its short axis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Drug: docetaxel · Drug: paclitaxel · Drug: trastuzumab [Herceptin]
Drug: pertuzumab · Drug: trastuzumab emtansine
Drug: pertuzumab-placebo · Drug: trastuzumab emtansine
75 mg/m2 or 100 mg/m2 intravenously every 3 weeks for a minimum of 6 cycles.
80 mg/m2 intravenously weekly for a minimum of 18 weeks
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
trastuzumab \[Herceptin\] doses when administered with docetaxel: 8 mg/kg intravenously on cycle 1 followed by 6 mg/kg every 3 weeks in subsequent cycles or trastuzumab (Herceptin) doses when administered with paclitaxel: 4 mg/kg intravenously on day 1 of cycle 1 followed by 2 mg/kg weekly starting on day 8 of cycle 1.
3.6 mg/kg intravenously every 3 weeks
Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment
Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Progression-Free Survival (PFS) According to IRF Assessment
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants Who Died Prior to Clinical Cutoff
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Overall Survival (OS) at Clinical Cutoff
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Percentage of Participants With Death or Disease Progression According to Investigator Assessment
Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
PFS According to Investigator Assessment
Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants Experiencing Treatment Failure
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. The percentage of participants with treatment failure was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Time to Treatment Failure (TTF)
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. TTF was defined as the time from randomization to treatment failure. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
One-Year Survival Rate
The percentage of participants alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error.
Time frame: From randomization until 1 year
Percentage of Participants With Grade ≥3 Adverse Events
Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death.
Time frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
Percentage of Participants Who Died at 2 Years
Time frame: From randomization until 2 years
Overall Survival Truncated at 2 Years
Overall Survival truncated at 2 years was defined as the percentage of participants alive at 2 years.
Time frame: From randomization until 2 years
Percentage of Participants With Grade 5 Adverse Events
Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.
Time frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose)
Percentage of Participants With Grade 3-4 Laboratory Parameters
Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival.
Time frame: Day 1, 8, and 15 of Cycle 1-3 and on Day 1 of each subsequent cycle up to 50 months from randomization until clinical cutoff of 16-Sept-2014
Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance status is a scale used to quantify cancer participants' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, \< 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, \> 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.
Time frame: Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months)
Hospitalization Days
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per participants.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Percentage of Participants With Hospitalization
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Percentage of Participants With Objective Response According to IRF Assessment
Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the objective response rate \[ORR\]) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants With Objective Response According to Investigator Assessment
Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Duration of Response According to IRF Assessment
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR, PR, or SD was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score
The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of participants receiving taxane-containing chemotherapy. The FACT-TaxS consists of 16 items including 11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration. Items are rated from 0 (not at all) to 4 (very much) and a total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as a ≥5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. The percentage of participants with treatment-related symptoms was calculated using following formula: \[number of participants meeting the above threshold divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time frame: Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with nausea was calculated using following formula: \[number of participants with any level of either symptom divided by the number analyzed\] multiplied by 100.
Time frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with diarrhea was calculated using following formula: \[number of participants with any level of either symptom divided by the number analyzed\] multiplied by 100.
Time frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
Percentage of Participants With a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as Measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score
The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of participants with deterioration was calculated as \[number of participants meeting the above threshold divided by the number analyzed\] multiplied by 100.
Time frame: Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time frame: Baseline up to 39 months from randomization until clinical cutoff of 16-Sept-2014
Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score
The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as \[mean score at the assessment visit minus mean score at Baseline\]. The higher the score, the higher the level of impairment or burden.
Time frame: Baseline, Cycle 7 (Week 18)
Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect)
Time frame: Baseline, Cycle 7 (Week 18)
Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect).
Time frame: Baseline, Cycle 7 (Week 18)
Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
PFS According to IRF Assessment Among Those With High HER2 mRNA Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
Time frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
OS at Clinical Cutoff Among Those With High HER2 mRNA Levels
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values.
Time frame: Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
| Milestone | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Started | 365 | 367 | 363 |
| Treated | 355 | 365 | 360 |
| Completed | 0 | 0 | 0 |
| Not completed | 365 | 367 | 363 |
| Withdrew: Adverse event | 0 | 1 | 0 |
| Withdrew: Lost to follow-up | 13 | 13 | 11 |
| Withdrew: Physician decision | 9 | 1 | 3 |
| Withdrew: Reason not specified | 8 | 3 | 12 |
| Withdrew: Sponsor decision to terminate study | 133 | 144 | 143 |
| Withdrew: Subject/ guardian decision to withdraw | 32 | 29 | 25 |
| Withdrew: Death | 170 | 176 | 169 |
Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment | 63.3 | 64.3 | 59.8 |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Progression-Free Survival (PFS) According to IRF Assessment | 13.7 (12.4 to 14.9) | 14.1 (10.9 to 16.8) | 15.2 (12.5 to 18.8) |
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Who Died Prior to Clinical Cutoff | 46.3 | 47.7 | 46.3 |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Overall Survival (OS) at Clinical Cutoff | 50.86 (44.75 to 60.75) | 53.68 (48.36 to 64.36) | 51.78 (47.87 to NA) |
Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Death or Disease Progression According to Investigator Assessment | 72.1 | 70.3 | 67.5 |
Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| PFS According to Investigator Assessment | 12.5 (10.5 to 13.6) | 14.1 (12.2 to 16.7) | 14.8 (12.4 to 17.8) |
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. The percentage of participants with treatment failure was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Experiencing Treatment Failure | 85.8 | 82.6 | 80.2 |
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. TTF was defined as the time from randomization to treatment failure. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Time to Treatment Failure (TTF) | 10.2 (9.2 to 11.8) | 12.1 (9.9 to 13.9) | 11.8 (9.9 to 14.2) |
The percentage of participants alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error.
| percentage probability of being alive | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| One-Year Survival Rate | 91.4 (88.44 to 94.41) | 92.4 (89.62 to 95.15) | 91.9 (89.00 to 94.77) |
Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Grade ≥3 Adverse Events | 54.1 | 45.4 | 46.2 |
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Who Died at 2 Years | 20.3 | 20.2 | 19.6 |
Overall Survival truncated at 2 years was defined as the percentage of participants alive at 2 years.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Overall Survival Truncated at 2 Years | 79.7 (NA to NA) | 79.8 (NA to NA) | 80.4 (NA to NA) |
Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Grade 5 Adverse Events | 1.7 | 1.1 | 1.9 |
Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Hemoglobin-Low: Grade 3 | 4.3 | 5.8 | 6.9 |
| Neutrophils-Low: Grade 3 | 20.2 | 5.5 | 5.0 |
| Neutrophils-Low: Grade 4 | 43.8 | 1.9 | 0.8 |
| Platelets-Low: Grade 3 | 0.9 | 12.7 | 12.9 |
| Platelets-Low: Grade 4 | 0.3 | 2.8 | 2.5 |
| Alkaline Phosphate-High: Grade 3 | 1.1 | 3.9 | 3.0 |
| Alanine Transaminase-High: Grade 3 | 3.4 | 9.1 | 8.0 |
| Alanine Transaminase-High: Grade 4 | 0.0 | 0.3 | 0.6 |
| Aspartate Aminotransferase-High: Grade 3 | 1.1 | 11.9 | 6.9 |
| Aspartate Aminotransferase-High: Grade 4 | 0.0 | 0.3 | 0.3 |
| Creatinine-High: Grade 3 | 0.9 | 0.3 | 1.1 |
| Creatinine-High: Grade 4 | 0.0 | 0.0 | 0.3 |
| Potassium-Low: Grade 3 | 4.3 | 4.7 | 5.2 |
| Potassium-Low: Grade 4 | 0.6 | 1.7 | 0.6 |
| Total Bilirubin-High: Grade 3 | 0.3 | 0.3 | 0.3 |
The ECOG performance status is a scale used to quantify cancer participants' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, \< 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, \> 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status | 7.6 | 6.1 | 7.9 |
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per participants.
| days | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Hospitalization Days | 6 (1 to 50) | 5 (1 to 117) | 8 (1 to 381) |
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Hospitalization | 21.8 (17.62 to 26.36) | 20.2 (16.20 to 24.71) | 22.1 (18.03 to 26.70) |
Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the objective response rate \[ORR\]) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Objective Response According to IRF Assessment | 67.9 (62.26 to 73.31) | 59.7 (54.07 to 65.30) | 64.2 (58.62 to 69.65) |
Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Objective Response According to Investigator Assessment | 69.3 (63.74 to 74.52) | 64.6 (59.12 to 69.87) | 67.5 (62.17 to 72.68) |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Duration of Response According to IRF Assessment | 12.5 (10.5 to 16.6) | 20.7 (14.8 to 25.0) | 21.2 (15.8 to 29.3) |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR, PR, or SD was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
No measurements were reported for this outcome.
The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of participants receiving taxane-containing chemotherapy. The FACT-TaxS consists of 16 items including 11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration. Items are rated from 0 (not at all) to 4 (very much) and a total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as a ≥5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. The percentage of participants with treatment-related symptoms was calculated using following formula: \[number of participants meeting the above threshold divided by the number analyzed\] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score | 93.1 (88.48 to 96.06) | 60.8 (53.39 to 67.93) | 68.8 (61.32 to 75.92) |
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with nausea was calculated using following formula: \[number of participants with any level of either symptom divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Nausea, Baseline (n=166,166,150) | 22.3 | 14.5 | 21.3 |
| Nausea, Cycle 1 Day 8 (n=121,114,95) | 38.0 | 36.0 | 52.6 |
| Nausea, Cycle 2 Day 1 (n=147,151,138) | 27.2 | 20.5 | 36.2 |
| Nausea, Cycle 2 Day 8 (n=122,121,105) | 35.2 | 28.1 | 45.7 |
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with diarrhea was calculated using following formula: \[number of participants with any level of either symptom divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Diarrhea, Baseline (n=173,170,153) | 15.0 | 7.6 | 11.8 |
| Diarrhea, Cycle 1 Day 8 (n=124,117,98) | 34.7 | 17.9 | 34.7 |
| Diarrhea, Cycle 2 Day 1 (n=161,160,144) | 24.2 | 11.3 | 39.6 |
| Diarrhea, Cycle 2 Day 8 (n=125,123,107) | 34.4 | 8.1 | 41.1 |
The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of participants with deterioration was calculated as \[number of participants meeting the above threshold divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as Measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score | 61.8 | 50.9 | 50.6 |
The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score | 3.6 (3.0 to 4.4) | 7.7 (6.2 to 11.9) | 9.0 (5.1 to 14.5) |
The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as \[mean score at the assessment visit minus mean score at Baseline\]. The higher the score, the higher the level of impairment or burden.
| units on a scale | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Baseline (n=344,355,344) | 85.0 (82.9 to 87.2) | 85.5 (83.3 to 87.8) | 85.7 (83.5 to 87.8) |
| Change From Baseline at Cycle 7 (n=261,252,261) | -1.6 (-4.2 to 1.0) | 2.3 (0.4 to 4.2) | -0.2 (-2.1 to 1.6) |
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect)
| percent of work | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| % Work Time Missed at Baseline (n=66,63,67) | 15.3 (9.2 to 21.4) | 9.5 (4.2 to 14.8) | 13.6 (7.7 to 19.6) |
| Change in % Work Time Missed (n=35,33,36) | 0.4 (-7.3 to 8.2) | -0.0 (-4.5 to 4.5) | -4.3 (-13.0 to 4.6) |
| % Impairment While Working at Baseline(n=67,64,67) | 20.0 (14.1 to 25.9) | 15.3 (9.5 to 21.1) | 19.9 (13.6 to 26.1) |
| Change in % Impairment While Working (n=34,32,35) | 8.8 (2.0 to 15.6) | -0.3 (-11.0 to 10.5) | -2.7 (-11.0 to 5.2) |
| % Overall Work Impairment at Baseline (n=65,62,66) | 28.5 (20.7 to 36.2) | 21.2 (13.8 to 28.7) | 28.1 (20.3 to 35.9) |
| Change in % Overall Work Impairment (n=34,31,35) | 9.1 (-0.4 to 18.6) | -1.1 (-13.0 to 11.0) | -4.6 (-14.0 to 5.0) |
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect).
| units on a scale | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| % Activity Impairment at Baseline (n=312,334,321) | 32.9 (29.6 to 36.3) | 33.6 (30.2 to 37.0) | 32.7 (29.5 to 36.0) |
| Change in % Activity Impairment (n=227,222,234) | 4.5 (0.2 to 8.7) | -5.3 (-9.5 to -1.1) | -3.7 (-7.2 to -0.1) |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels | 75.0 | 66.9 | 63.9 |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to \<10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels | 61.9 | 51.7 | 66.1 |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels | 59.4 | 57.6 | 56.1 |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| PFS According to IRF Assessment Among Those With High HER2 mRNA Levels | 15.9 (0.1 to 46.4) | 18.6 (0.1 to 46.0) | 18.7 (0.1 to 48.1) |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels | 66.5 | 70.1 | 62.4 |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels | 12.4 (0.1 to 47.3) | 10.2 (0.1 to 43.6) | 14.5 (0.1 to 40.7) |
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels | 38.8 | 41.2 | 45.1 |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| OS at Clinical Cutoff Among Those With High HER2 mRNA Levels | NA (50.86 to NA) | 65.97 (54.54 to 67.98) | 55.39 (48.23 to NA) |
The percentage of participants who died prior to clinical cutoff was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
| percentage of participants | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels | 51.8 | 52.9 | 45.2 |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values.
| months | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels | 43.96 (37.19 to 54.87) | 47.84 (42.09 to 53.85) | 53.29 (46.75 to NA) |
Collected over Up to 70 months from randomization until clinical cutoff of 16 September 2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Trastuzumab + Taxane | — | 81/353 (22.9%) | 342/353 (96.9%) |
| Trastuzumab Emtansine + Placebo | — | 86/361 (23.8%) | 352/361 (97.5%) |
| Trastuzumab Emtansine + Pertuzumab | — | 93/366 (25.4%) | 352/366 (96.2%) |
| Event | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 13/353 | 0/361 | 0/366 |
| Infusion related reactionInjury, poisoning and procedural complications | 1/353 | 7/361 | 13/366 |
| AnaemiaBlood and lymphatic system disorders | 1/353 | 5/361 | 6/366 |
| NeutropeniaBlood and lymphatic system disorders | 5/353 | 0/361 | 0/366 |
| PyrexiaGeneral disorders | 2/353 | 4/361 | 5/366 |
| PneumoniaInfections and infestations | 4/353 | 3/361 | 5/366 |
| DiarrhoeaGastrointestinal disorders | 4/353 | 0/361 | 0/366 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 4/353 | 2/361 | 1/366 |
| VomitingGastrointestinal disorders | 1/353 | 0/361 | 4/366 |
| SepsisInfections and infestations | 1/353 | 0/361 | 4/366 |
| Event | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab |
|---|---|---|---|
| AlopeciaSkin and subcutaneous tissue disorders | 212/353 | 26/361 | 33/366 |
| NauseaGastrointestinal disorders | 131/353 | 174/361 | 192/366 |
| DiarrhoeaGastrointestinal disorders | 173/353 | 92/361 | 178/366 |
| FatigueGeneral disorders | 128/353 | 120/361 | 130/366 |
| EpistaxisRespiratory, thoracic and mediastinal disorders | 53/353 | 113/361 | 127/366 |
| HeadacheNervous system disorders | 80/353 | 116/361 | 120/366 |
| PyrexiaGeneral disorders | 59/353 | 96/361 | 118/366 |
| VomitingGastrointestinal disorders | 69/353 | 80/361 | 111/366 |
| Neuropathy peripheralNervous system disorders | 99/353 | 52/361 | 69/366 |
| Oedema peripheralGeneral disorders | 98/353 | 37/361 | 35/366 |
Intent-to-Treat (ITT) Population: All participants randomized in the study.
| Age, Continuous(years) | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab | Total |
|---|---|---|---|---|
| Mean | 54.2 ± 11.3 | 52.6 ± 11.4 | 52.2 ± 12.0 | 53.0 ± 11.6 |
| Sex: Female, Male(Participants) | Trastuzumab + Taxane | Trastuzumab Emtansine + Placebo | Trastuzumab Emtansine + Pertuzumab | Total |
|---|---|---|---|---|
| Female | 362 | 365 | 361 | 1088 |
| Male | 3 | 2 | 2 | 7 |
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Studies of the drugs tested here: Pertuzumab · Ado-Trastuzumab Emtansine