A Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( that is \[i.e.\], ypT0/is, ypN0 in the American Joint Committee on Cancer \[AJCC\] staging system, 7th edition). Percentage of participants with tpCR was reported.

Time frame: Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)

Population: The Intent-to-treat (ITT) Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment.

Only participants who received trastuzumab emtansine were to be analyzed for this outcome.

Time frame: 15-30 min post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period.

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Only participants who received trastuzumab emtansine were to be analyzed for this outcome.

Time frame: Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Event-free survival (EFS) is defined as the time from randomization to disease progression or disease recurrence (local, regional, distant, or contralateral, invasive or non-invasive), or death from any cause. 3 years EFS rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.

Time frame: From randomization up to disease progression or recurrence or death (up to approximately 47 months)

Population: The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment.

IDFS is defined only for participants who undergo surgery. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence; Ipsilateral local-regional invasive breast cancer recurrence; Distant recurrence; Contralateral invasive breast cancer; and death from any cause. 3 years of IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.

Time frame: From surgery to the first documented occurrence of IDFC event (up to approximately 47 months)

Population: The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment.

Only participants who received trastuzumab were to be analyzed for this outcome.

Time frame: 15-30 minutes (min) post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Only participants who received trastuzumab were to be analyzed for this outcome.

Time frame: Pre-study treatment infusion (0 hours [hr]) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. 3 years OS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.

Time frame: From randomization until death (up to approximately 47 months)

Population: The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment.

Participants answered the Question Have you lost any hair?, from the mQLQ-BR23, on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.

Time frame: Baseline,Cycle(C) 3, C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4(approx 47 months)

Population: ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis.

Participants answered the question Did you have tingling hands/feet?, from the Modified Quality of Life Questionnaire Breast Cancer 23 (mQLQ-BR23), on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.

Time frame: Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)

Population: ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis.

Participants answered the Question 1 Did itching skin bother you? and Question 2 Have you had skin problems?, from the mQLQ-BR23, on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.

Time frame: Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)

Population: ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis.

BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer.

Time frame: Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)

Participants rated their function on EORTC QLQ C-30, with total score and single-item (physical, cognitive and role functioning) scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Clinically meaningful deterioration was defined as a decrease in score of 10 points in physical function; decrease of 7 points in cognitive function and decrease of 14 points in role function.

Time frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period

Population: The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only.

Participants rated their quality of life (global health status) on European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ- C30), with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Clinically meaningful deterioration in GHS/QoL was defined as a decrease in score of 10 points in GHS/QoL.

Time frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period

Population: The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only.

Participants rated their symptoms on EORTC QLQ C-30 and mQLQ-BR23, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates greater degree of symptoms. Clinically meaningful increase in symptoms was defined as an increase in score (deterioration) of 11 points in nausea and vomiting, pain, dyspnea; increase of 9 points in insomnia; increase of 14 points in appetite loss; increase of 15 points in diarrhea, constipation; increase of 10 points in fatigue, systemic therapy side effects, hair loss.

Time frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period

Population: The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only.

Participants were considered post-baseline ATA positive if they had ATAs post-baseline that were either treatment-induced or treatment-enhanced. Participants had treatment-induced ATAs if they had a negative or missing ATA result at baseline, and at least one positive ATA result post-baseline. Participants had treatment-enhanced ATAs if they had a positive ATA result at baseline, and at least one positive ATA result post-baseline that was greater than or equal to (\>/=) 0.60 titer units higher than the result at baseline.

Time frame: Baseline (b) (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (pb) (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period

Population: The participants included in this analysis were the participants who received at least one dose of trastuzumab emtansine and had at least one reported serum or plasma results.

Time frame: Baseline (Pre-trastuzumab [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-trastuzumab infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period

Population: The participants included in this analysis were the participants who received at least one dose of trastuzumab and had at least one reported serum or plasma results.

Selected AEs included hepatotoxicity, pulmonary toxicity, cardiac dysfunction, neutropenia, thrombocytopenia, peripheral neuropathy, hemorrhage, infusion related reaction (IRR)/hypersensitivity, IRR/Hypersensitivity symptoms, rash, diarrhea and mucositis. An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.

Time frame: Baseline to end of study (approximately 47 months)

Population: The Safety Population comprised all patients who received at least one full or partial dose of any study treatment. Patients were analyzed according to the treatment they actually received.

DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.

Time frame: 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Time frame: 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period

Population: The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample.

Participants rated their function on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by physical function; to first 14-point (or greater) decrease as measured by role function, to first 7-point (or greater) decrease as measured by cognitive function. Median time to deterioration was estimated with Kaplan-Meier method. The 95% CI for the median was computed using the method of Brookmeyer and Crowley.

Time frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period

Population: Patients of the ITT population with a baseline assessment and at least one post-treatment assessment was included in this analysis.

Participants rated their quality of life (global health status) on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by GHS/QoL. All valid GHS/QoL questionnaires of the neoadjuvant phase including surgery were used. Participants without deterioration were censored at the time of completing the last GHS/QoL plus 1 day. Median time to deterioration was estimated with Kaplan-Meier method. The 95% confidence interval (CI) for the median was computed using the method of Brookmeyer and Crowley.

Time frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period

Population: The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only.