History of Changes for Study: NCT02131064

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

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Study Record Versions

Version	Submitted Date	Changes
1	May 2, 2014	None (earliest Version on record)
2	May 19, 2014	Contacts/Locations and Study Status
3	May 26, 2014	Contacts/Locations and Study Status
4	June 23, 2014	Recruitment Status, Study Status, Contacts/Locations and Study Description
5	June 30, 2014	Oversight and Study Status
6	July 7, 2014	Study Status and Contacts/Locations
7	July 14, 2014	Contacts/Locations and Study Status
8	July 21, 2014	Contacts/Locations and Study Status
9	July 28, 2014	Contacts/Locations and Study Status
10	August 4, 2014	Study Status and Contacts/Locations
11	August 19, 2014	Contacts/Locations and Study Status
12	August 26, 2014	Study Status
13	September 22, 2014	Study Status
14	October 6, 2014	Study Status
15	October 13, 2014	Contacts/Locations and Study Status
16	October 20, 2014	Contacts/Locations and Study Status
17	November 3, 2014	Contacts/Locations and Study Status
18	November 10, 2014	Contacts/Locations and Study Status
19	November 17, 2014	Contacts/Locations and Study Status
20	November 24, 2014	Contacts/Locations and Study Status
21	December 1, 2014	Study Status
22	December 8, 2014	Contacts/Locations and Study Status
23	December 15, 2014	Contacts/Locations and Study Status
24	December 23, 2014	Contacts/Locations and Study Status
25	December 29, 2014	Contacts/Locations and Study Status
26	January 6, 2015	Study Status and Contacts/Locations
27	January 19, 2015	Contacts/Locations and Study Status
28	February 5, 2015	Contacts/Locations, Study Status, Eligibility and Study Description
29	February 19, 2015	Contacts/Locations and Study Status
30	February 23, 2015	Contacts/Locations and Study Status
31	March 2, 2015	Study Status
32	March 9, 2015	Contacts/Locations and Study Status
33	March 23, 2015	Contacts/Locations and Study Status
34	April 2, 2015	Contacts/Locations and Study Status
35	May 5, 2015	Study Status
36	May 11, 2015	Contacts/Locations and Study Status
37	May 29, 2015	Contacts/Locations and Study Status
38	June 1, 2015	Study Status
39	July 1, 2015	Recruitment Status, Study Status, Contacts/Locations and Study Design
40	August 17, 2015	Study Status
41	September 1, 2015	Contacts/Locations and Study Status
42	September 9, 2015	Contacts/Locations and Study Status
43	October 1, 2015	Study Status and Contacts/Locations
44	November 2, 2015	Study Status and Contacts/Locations
45	December 1, 2015	Study Status
46	December 31, 2015	Study Status
47	February 1, 2016	Study Status and Contacts/Locations
48	March 1, 2016	Study Status
49	April 2, 2016	Study Status
50	May 4, 2016	Study Status
51	June 1, 2016	Contacts/Locations and Study Status
52	July 1, 2016	Study Status
53	August 1, 2016	Study Status
54	May 9, 2017	Study Status, Outcome Measures, Arms and Interventions, Study Identification, Results, Contacts/Locations, Eligibility, Conditions and Study Description
55	August 29, 2017	Study Status, Arms and Interventions and Contacts/Locations
56	November 21, 2017	Study Status and Contacts/Locations
57	April 25, 2018	Study Status and Contacts/Locations
58	July 31, 2018	Recruitment Status, Study Status and Contacts/Locations
59	September 20, 2018	Study Status
60	June 25, 2019	Outcome Measures, Adverse Events, Participant Flow, Study Status, Baseline Characteristics, Contacts/Locations, More Information and Oversight

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	BO28408
Brief Title:	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
Official Title:	A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer
Secondary IDs:	TRIO021 [Roche] 2012-004879-38 [EudraCT Number]

Study Status


Record Verification:	May 2017
Overall Status:	Active, not recruiting
Study Start:	June 2014
Primary Completion:	December 2015 [Actual]
Study Completion:	January 2018 [Anticipated]

First Submitted:	May 2, 2014
First Submitted that Met QC Criteria:	May 2, 2014
First Posted:	May 6, 2014 [Estimate]

Results First Submitted:	December 3, 2016
Results First Submitted that Met QC Criteria:	May 9, 2017
Results First Posted:	June 8, 2017 [Actual]

Last Update Submitted that Met QC Criteria:	May 9, 2017
Last Update Posted:	June 8, 2017 [Actual]

Sponsor/Collaborators


Sponsor:	Hoffmann-La Roche
Responsible Party:	Sponsor
Collaborators:

Oversight


U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring:

Study Description

Brief Summary:

This is a randomized, multicenter, open-label, two-arm study in treatment-naive participants with operable, locally advanced, or inflammatory, centrally-assessed HER2-positive early breast cancer (EBC) whose primary tumors were greater than or equal to (>/=) 2 centimeters (cm). The study was designed to evaluate the efficacy and safety of trastuzumab emtansine + pertuzumab (experimental arm; T-DM1 + P) versus chemotherapy, trastuzumab + pertuzumab (control arm; TCH + P). The study comprised a neoadjuvant treatment period, followed by surgery, and an adjuvant treatment period.

Treatment can be stopped due to disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination.

Detailed Description:

Conditions


Conditions:	Breast Neoplasms
Keywords:

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 3
Interventional Study Model:	Parallel Assignment
Number of Arms:	2
Masking:	None (Open Label)
Allocation:	Randomized
Enrollment:	444 [Actual]

Arms and Interventions

Arms

Assigned Interventions

Active Comparator: TCH + P

Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).

Drug: Carboplatin

Carboplatin IV infusion at a dose to achieve an AUC of 6 mg*min/mL q3w

Drug: Docetaxel

Docetaxel 75 mg/m^2 IV infusion q3w

Drug: Pertuzumab

Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w

Other Names:

Perjeta®, RO4368451

Drug: Trastuzumab

Trastuzumab 8 mg/kg (loading dose); and 6 mg/kg (maintenance dose) IV infusion q3w

Other Names:

Herceptin®

Experimental: T-DM1 + P

Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).

Drug: Pertuzumab

Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w

Other Names:

Perjeta®, RO4368451

Drug: Trastuzumab Emtansine

Trastuzumab Emtansine 3.6 mg/kg IV infusion q3w

Other Names:

Kadcyla®, RO5304020

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples [ Time Frame: Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months) ] 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.
Secondary Outcome Measures:
1.	Event-free Survival (EFS) Assessed by Investigator Based on Radiological, Clinical and Histological Assessment [ Time Frame: From randomization up to disease progression or recurrence or death (up to approximately 45 months) ] 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.
2.	Invasive Disease-free Survival (IDFS) [ Time Frame: From surgery to the first documented occurrence of IDFC event (up to approximately 45 months) ] IDFS is defined only for participants who undergo surgery. Participants who do not undergo surgery will be excluded from the analysis. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Distant recurrence (i.e., evidence of breast cancer, excluding ipsilateral invasive or local-regional breast cancer, in any anatomic site that has been either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); Contralateral invasive breast cancer; and death from any cause.
3.	Overall Survival [ Time Frame: From randomization until death (up to approximately 45 months) ] Overall survival is defined as the time from randomization to death from any cause.
4.	Percentage of Participants Who Received Breast-Conserving Surgery (BCS) [ Time Frame: 6 months ] BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer.
5.	Percentage of Participants With Selected Adverse Events (AEs) [ Time Frame: Neoadjuvant phase (Baseline up to Cycle 6, each cycle = 21 days) ] 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.
6.	Percentage of Participants by Response for Neuropathy Single Item [ Time Frame: Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months) ] 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.
7.	Percentage of Participants by Response for Skin Problem Single Items [ Time Frame: Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months) ] 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.
8.	Percentage of Participants by Response for Hair Loss Single Item [ Time Frame: Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months) ] 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.
9.	Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score [ Time Frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period ] 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.
10.	Time to Clinically Meaningful Deterioration in GHS/QoL Score [ Time Frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period ] 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.
11.	Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales [ Time Frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in 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.
12.	Time to Clinically Meaningful Deterioration in Function Subscale [ Time Frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period ] 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.
13.	Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales [ Time Frame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period ] 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.
14.	Maximum Observed Serum Concentration (Cmax) of Trastuzumab [ 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 period ] Only participants who received trastuzumab were to be analyzed for this outcome.
15.	Cmax of Trastuzumab Emtansine and Total Trastuzumab [ 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 period ] Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
16.	Minimum Observed Serum Concentration (Cmin) of Trastuzumab [ 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 period ] Only participants who received trastuzumab were to be analyzed for this outcome.
17.	Cmin of Trastuzumab Emtansine and Total Trastuzumab [ Time Frame: Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant period ] Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
18.	Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations [ Time Frame: Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 1 (cycle length = 21 days); 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant period ] DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
19.	Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1) [ Time Frame: Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 1 (cycle length = 21 days) in neoadjuvant period; 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period ]
20.	Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1 [ Time Frame: Baseline (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant period ] 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.
21.	Percentage of Participants With ATA to Trastuzumab [ 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 ]

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Histologically confirmed invasive breast cancer with a primary tumor size of greater than (>) 2 cm HER2-positive breast cancer Participants with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as HER2 positive Stage at presentation: cT2-cT4, cN0-cN3, cM0, according to American Joint Committee on Cancer (AJCC) staging system Known hormone receptor status of the primary tumor Participant agreement to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Baseline Left Ventricular Ejection Fraction (LVEF) >/= 55 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) Effective contraception as defined by protocol Exclusion Criteria: Stage IV (metastatic) breast cancer Participants who have received prior anti-cancer therapy for breast cancer except those participants with a history of breast lobular carcinoma in situ (LCIS) that was surgically managed or ductal carcinoma in situ (DCIS) treated exclusively with mastectomy. In case of prior history of LCIS/DCIS, >5 years must have passed from surgery until diagnosis of current breast cancer Participants with multicentric (multiple tumors involving more than 1 quadrant) or bilateral breast cancer Participants who have undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes Axillary lymph node dissection or positive sentinel lymph node prior to start of neoadjuvant therapy History of concurrent or previously non-breast malignancies except for appropriately treated (1) non-melanoma skin cancer and (2) in situ carcinomas, including cervix, colon, and skin. A participant with previous invasive non-breast cancer is eligible provided he/she has been disease-free >/= 5 years Treatment with any investigational drug within 28 days prior to randomization Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0 Any significant concurrent medical or surgical conditions or findings that would jeopardize the participant's safety or ability to complete the study Current pregnancy or breastfeeding

Contacts/Locations


Study Officials:	Clinical Trials Study Director Hoffmann-La Roche
Locations:	United States, California
	Fullerton, California, United States, 92835
	Los Angeles, California, United States, 90095-1772
	San Luis Obispo, California, United States, 93401
	San Luis Obispo, California, United States, 93454
	Santa Monica, California, United States, 90404
	United States, Florida
	Hollywood, Florida, United States, 33021
	Orlando, Florida, United States, 32806
	United States, Maine
	Scarborough, Maine, United States, 04074
	United States, Nevada
	Henderson, Nevada, United States, 89052
	United States, New York
	Lake Success, New York, United States, 11042
	The Bronx, New York, United States, 10467
	United States, North Carolina
	Asheville, North Carolina, United States, 28806
	Charlotte, North Carolina, United States, 28204
	United States, South Carolina
	Charleston, South Carolina, United States, 29414
	United States, Tennessee
	Nashville, Tennessee, United States, 37203
	United States, Texas
	Houston, Texas, United States, 77030
	Belgium
	Edegem, Belgium, 2650
	Leuven, Belgium, 3000
	Liège, Belgium, 4000
	Namur, Belgium, 5000
	Wilrijk, Belgium, 2610
	Canada
	Quebec, Canada, G1S 4L8
	Canada, Alberta
	Edmonton, Alberta, Canada, T6G 1Z2
	Canada, Ontario
	Toronto, Ontario, Canada, M4N 3M5
	Toronto, Ontario, Canada, M5B 1W8
	Canada, Quebec
	Montreal, Quebec, Canada, H2L 4M1
	Montreal, Quebec, Canada, H3T 1E2
	France
	Angers, France, 49000
	Besancon, France, 25030
	Brest, France, 29200
	La Roche Sur Yon, France, 85925
	Lille, France, 59020
	Marseille, France, 13273
	Nantes, France, 44202
	Saint Herblain, France, 44805
	Strasbourg, France, 67091
	Germany
	Böblingen, Germany, 71032
	Düsseldorf, Germany, 40235
	Erlangen, Germany, 91054
	Mainz, Germany, 55131
	München, Germany, 80336
	Korea, Republic of
	Gyeonggi-do, Korea, Republic of, 10408
	Gyeonggi-do, Korea, Republic of, 13620
	Seoul, Korea, Republic of, 03080
	Seoul, Korea, Republic of, 05505
	Seoul, Korea, Republic of, 06351
	Seoul, Korea, Republic of, 120-752
	Russian Federation
	Kislino, Kursk Region, Russian Federation, 305524
	Moscow, Russian Federation, 115478
	Orenburg, Russian Federation, 460021
	Saratov, Russian Federation, 410004
	St Petersburg, Russian Federation, 197022
	Russian Federation, Moskovskaja Oblast
	Moscovskaya Oblast, Moskovskaja Oblast, Russian Federation, 143423
	Spain
	Avila, Spain, 05071
	Barcelona, Spain, 08003
	Barcelona, Spain, 08006
	Jaen, Spain, 23007
	La Coruña, Spain, 15006
	Madrid, Spain, 28007
	Madrid, Spain, 28040
	Madrid, Spain, 28050
	Madrid, Spain, 28223
	Malaga, Spain, 29020
	Sevilla, Spain, 41013
	Valencia, Spain, 46010
	Zaragoza, Spain, 50009
	Spain, Barcelona
	Sabadell, Barcelona, Spain, 08208
	Spain, Guipuzcoa
	San Sebastian, Guipuzcoa, Spain, 20014
	Spain, Lerida
	Lleida, Lerida, Spain, 25198
	Taiwan
	Kaohsiung, Taiwan, 807
	Taipei, Taiwan, 00112
	Taipei, Taiwan, 100
	Taipei, Taiwan, 104
	Taipei, Taiwan, 112
	Taipei, Taiwan, 11490
	Ukraine
	Cherkassy, Ukraine, 18009
	Dnipropetrovsk, Ukraine, 43102
	Kharkiv, Ukraine, 61070
	Lvov, Ukraine, 79031

IPDSharing


Plan to Share IPD:

References


Links:
Available IPD/Information:

Participant Flow

Recruitment Details

Pre-assignment Details

A total of 574 participants were screened at 68 sites in 10 countries, of which 444 participants were randomized in two arms: Trastuzumab (TCH) + Pertuzumab (P) (Arm A) and Trastuzumab Emtansine (TDM1) + P (Arm B)

Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).

Period Title: Overall Study
Started	221	223
Completed	0	0
Not Completed	221	223
Reason Not Completed
Death	0	1
Lost to Follow-up	0	1
Withdrawal by Subject	6	14
Ongoing	214	207
Other	1	0

Baseline Characteristics


Arm/Group Title		TCH + P	T-DM1 + P	Total
Arm/Group Description		Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).	Total of all reporting groups
Overall Number of Baseline Participants		221	223	444
Baseline Analysis Population Description
Age, Continuous Mean (Standard Deviation) Unit of measure: years	Number Analyzed	221 Participants	223 Participants	444 Participants
		49.3(11.2)	50.5(10.6)	49.9(10.9)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	221 Participants	223 Participants	444 Participants
	Female	221 100%	222 99.55%	443 99.77%
	Male	0 0%	1 0.45%	1 0.23%

Outcome Measures

1. Primary Outcome:

Title

Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples

Description

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)

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	221	223
Number (95% Confidence Interval) Unit of Measure: percentage of participants	55.7(48.84 to 62.32)	44.4(37.76 to 51.18)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	95% CI for the difference in tPCR rates between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.0155
	Comments	Threshold for significance at 5%
	Method	Cochran-Mantel-Haenszel Chi-Square
	Comments	The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation.


Method of Estimation	Estimation Parameter	Difference in tpCR rate
	Estimated Value	-11.26
	Confidence Interval	(2-sided) 95% -20.50 to -2.02
	Estimation Comments	[Not specified]

2. Secondary Outcome:


Title	Event-free Survival (EFS) Assessed by Investigator Based on Radiological, Clinical and Histological Assessment
Description	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.
Time Frame	From randomization up to disease progression or recurrence or death (up to approximately 45 months)
Anticipated Reporting Date	January 2019
Outcome Measure Data Not Reported

3. Secondary Outcome:


Title	Invasive Disease-free Survival (IDFS)
Description	IDFS is defined only for participants who undergo surgery. Participants who do not undergo surgery will be excluded from the analysis. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Distant recurrence (i.e., evidence of breast cancer, excluding ipsilateral invasive or local-regional breast cancer, in any anatomic site that has been either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); Contralateral invasive breast cancer; and death from any cause.
Time Frame	From surgery to the first documented occurrence of IDFC event (up to approximately 45 months)
Anticipated Reporting Date	January 2019
Outcome Measure Data Not Reported

4. Secondary Outcome:


Title	Overall Survival
Description	Overall survival is defined as the time from randomization to death from any cause.
Time Frame	From randomization until death (up to approximately 45 months)
Anticipated Reporting Date	January 2019
Outcome Measure Data Not Reported

5. Secondary Outcome:

Title

Percentage of Participants Who Received Breast-Conserving Surgery (BCS)

Description

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

6 months

Outcome Measure Data

Analysis Population Description

A subset of ITT population including participants who had non-inflammatory breast cancer at baseline. Participants were analyzed according to their randomized treatment.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	213	218
Number (95% Confidence Interval) Unit of Measure: percentage of participants	52.6(45.65 to 59.45)	41.7(35.12 to 48.33)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	95% CI for the difference in BCS rate between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in BCS rate
	Estimated Value	-10.84
	Confidence Interval	(2-sided) 95% -20.21 to -1.47
	Estimation Comments	[Not specified]

6. Secondary Outcome:

Title

Percentage of Participants With Selected Adverse Events (AEs)

Description

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

Neoadjuvant phase (Baseline up to Cycle 6, each cycle = 21 days)

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	219	223
Measure Type: Number Unit of Measure: percentage of participants
Hepatotoxicity	11.9	24.2
Pulmonary Toxicity	0	0.9
Cardiac Dysfunction	0.9	0.4
Neutropenia	45.2	0.9
Thrombocytopenia	21.9	7.6
Peripheral Neuropathy	30.1	9.9
Hemorrhage	14.6	20.2
IRR/Hypersensitivity	11.9	17.9
IRR/Hypersensitivity symptoms	5.9	13.9
Rash	34.7	21.5
Diarrhea	73.5	33.2
Mucositis	40.2	15.2

7. Secondary Outcome:

Title

Percentage of Participants by Response for Neuropathy Single Item

Description

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 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = participants evaluable for this outcome measure. Number Analyzed = participants evaluable for the specified category. Percentage values are based on ITT N.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	194	205
Measure Type: Number Unit of Measure: percentage of participants
Not at all: Baseline	76.9	80.7
A little bit: Baseline	9.5	10.3
Somewhat: Baseline	0	0
Quite a bit: Baseline	0.9	0.9
Very much: Baseline	0.5	0
Not at all: Cycle 3	55.2	61.9
A little bit: Cycle 3	20.8	20.2
Somewhat: Cycle 3	0	0
Quite a bit: Cycle 3	3.6	2.7
Very much: Cycle 3	2.3	0.4
Not at all: Cycle 5	37.1	55.2
A little bit: Cycle 5	29.9	22.0
Somewhat: Cycle 5	0	0
Quite a bit: Cycle 5	8.1	2.7
Very much: Cycle 5	6.8	1.8
Not at all: Pre-Surgery	24.0	53.4
A little bit: Pre-Surgery	28.1	18.8
Somewhat: Pre-Surgery	0	0
Quite a bit: Pre-Surgery	15.8	5.4
Very much: Pre-Surgery	10.0	1.3

8. Secondary Outcome:

Title

Percentage of Participants by Response for Skin Problem Single Items

Description

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 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)

Outcome Measure Data

Analysis Population Description


Arm/Group Title		TCH + P	T-DM1 + P
Arm/Group Description		Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed		194	205
Measure Type: Number Unit of Measure: percentage of participants
Question 1: Not at all: Baseline	Number Analyzed	Participants	Participants
Question 1: Not at all: Baseline		70.6	72.6
Question 1: A little bit: Baseline	Number Analyzed	Participants	Participants
Question 1: A little bit: Baseline		14.5	16.6
Question 1: Somewhat: Baseline	Number Analyzed	Participants	Participants
Question 1: Somewhat: Baseline		0	0
Question 1: Quite a bit: Baseline	Number Analyzed	Participants	Participants
Question 1: Quite a bit: Baseline		2.3	2.2
Question 1: Very much: Baseline	Number Analyzed	Participants	Participants
Question 1: Very much: Baseline		0	0.4
Question 1: Not at all: Cycle 3	Number Analyzed	Participants	Participants
Question 1: Not at all: Cycle 3		35.3	50.7
Question 1: A little bit: Cycle 3	Number Analyzed	Participants	Participants
Question 1: A little bit: Cycle 3		32.1	28.3
Question 1: Somewhat: Cycle 3	Number Analyzed	Participants	Participants
Question 1: Somewhat: Cycle 3		0	0
Question 1: Quite a bit: Cycle 3	Number Analyzed	Participants	Participants
Question 1: Quite a bit: Cycle 3		11.8	4.5
Question 1: Very much: Cycle 3	Number Analyzed	Participants	Participants
Question 1: Very much: Cycle 3		2.3	1.8
Question 1: Not at all: Cycle 5	Number Analyzed	Participants	Participants
Question 1: Not at all: Cycle 5		48.9	48.0
Question 1: A little bit: Cycle 5	Number Analyzed	Participants	Participants
Question 1: A little bit: Cycle 5		22.6	25.6
Question 1: Somewhat: Cycle 5	Number Analyzed	Participants	Participants
Question 1: Somewhat: Cycle 5		0	0
Question 1: Quite a bit: Cycle 5	Number Analyzed	Participants	Participants
Question 1: Quite a bit: Cycle 5		7.7	6.7
Question 1: Very much: Cycle 5	Number Analyzed	Participants	Participants
Question 1: Very much: Cycle 5		2.3	1.3
Question 1: Not at all: Pre-Surgery	Number Analyzed	Participants	Participants
Question 1: Not at all: Pre-Surgery		40.7	49.3
Question 1: A little bit: Pre-Surgery	Number Analyzed	Participants	Participants
Question 1: A little bit: Pre-Surgery		27.1	22.4
Question 1: Somewhat: Pre-Surgery	Number Analyzed	Participants	Participants
Question 1: Somewhat: Pre-Surgery		0	0
Question 1: Quite a bit: Pre-Surgery	Number Analyzed	Participants	Participants
Question 1: Quite a bit: Pre-Surgery		7.7	5.8
Question 1: Very much: Pre-Surgery	Number Analyzed	Participants	Participants
Question 1: Very much: Pre-Surgery		2.3	1.3
Question 2: Not at all: Baseline	Number Analyzed	Participants	Participants
Question 2: Not at all: Baseline		64.3	66.8
Question 2: A little bit: Baseline	Number Analyzed	Participants	Participants
Question 2: A little bit: Baseline		19.9	18.4
Question 2: Somewhat: Baseline	Number Analyzed	Participants	Participants
Question 2: Somewhat: Baseline		0	0
Question 2: Quite a bit: Baseline	Number Analyzed	Participants	Participants
Question 2: Quite a bit: Baseline		3.2	6.3
Question 2: Very much: Baseline	Number Analyzed	Participants	Participants
Question 2: Very much: Baseline		0.5	0.4
Question 2: Not at all: Cycle 3	Number Analyzed	Participants	Participants
Question 2: Not at all: Cycle 3		13.6	25.1
Question 2: A little bit: Cycle 3	Number Analyzed	Participants	Participants
Question 2: A little bit: Cycle 3		40.7	40.4
Question 2: Somewhat: Cycle 3	Number Analyzed	Participants	Participants
Question 2: Somewhat: Cycle 3		0	0
Question 2: Quite a bit: Cycle 3	Number Analyzed	Participants	Participants
Question 2: Quite a bit: Cycle 3		20.4	15.2
Question 2: Very much: Cycle 3	Number Analyzed	Participants	Participants
Question 2: Very much: Cycle 3		7.2	4.5
Question 2: Not at all: Cycle 5	Number Analyzed	Participants	Participants
Question 2: Not at all: Cycle 5		21.3	26.9
Question 2: A little bit: Cycle 5	Number Analyzed	Participants	Participants
Question 2: A little bit: Cycle 5		35.7	37.2
Question 2: Somewhat: Cycle 5	Number Analyzed	Participants	Participants
Question 2: Somewhat: Cycle 5		0	0
Question 2: Quite a bit: Cycle 5	Number Analyzed	Participants	Participants
Question 2: Quite a bit: Cycle 5		19.9	13.5
Question 2: Very much: Cycle 5	Number Analyzed	Participants	Participants
Question 2: Very much: Cycle 5		5.0	4.0
Question 2: Not at all: Pre-Surgery	Number Analyzed	Participants	Participants
Question 2: Not at all: Pre-Surgery		20.8	28.7
Question 2: A little bit: Pre-Surgery	Number Analyzed	Participants	Participants
Question 2: A little bit: Pre-Surgery		33.9	37.2
Question 2: Somewhat: Pre-Surgery	Number Analyzed	Participants	Participants
Question 2: Somewhat: Pre-Surgery		0	0
Question 2: Quite a bit: Pre-Surgery	Number Analyzed	Participants	Participants
Question 2: Quite a bit: Pre-Surgery		16.7	9.0
Question 2: Very much: Pre-Surgery	Number Analyzed	Participants	Participants
Question 2: Very much: Pre-Surgery		6.3	4.0

9. Secondary Outcome:

Title

Percentage of Participants by Response for Hair Loss Single Item

Description

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 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	194	205
Measure Type: Number Unit of Measure: percentage of participants
Not at all: Baseline	79.6	87.4
A little bit: Baseline	7.7	4.5
Somewhat: Baseline	0	0
Quite a bit: Baseline	0.5	0
Very much: Baseline	0	0
Not at all: Cycle 3	8.6	67.3
A little bit: Cycle 3	11.8	17.5
Somewhat: Cycle 3	0	0
Quite a bit: Cycle 3	20.8	0.4
Very much: Cycle 3	40.7	0
Not at all: Cycle 5	20.4	59.2
A little bit: Cycle 5	19.9	20.2
Somewhat: Cycle 5	0	0
Quite a bit: Cycle 5	15.4	1.8
Very much: Cycle 5	26.2	0.4
Not at all: Pre-Surgery	31.7	51.6
A little bit: Pre-Surgery	12.7	25.1
Somewhat: Pre-Surgery	0	0
Quite a bit: Pre-Surgery	11.3	2.2
Very much: Pre-Surgery	22.2	0

10. Secondary Outcome:

Title

Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score

Description

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

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = Number of participants evaluable for this outcome measure.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	193	205
Measure Type: Number Unit of Measure: percentage of participants	69.9	45.4

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	95% CI for the difference in clinically meaningful deterioration in GHS/QoL score between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in Deterioration
	Estimated Value	-24.58
	Confidence Interval	(2-sided) 95% -33.98 to -15.19
	Estimation Comments	[Not specified]

11. Secondary Outcome:

Title

Time to Clinically Meaningful Deterioration in GHS/QoL Score

Description

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

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = Number of participants evaluable for this outcome measure.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	191	200
Median (95% Confidence Interval) Unit of Measure: months	3.02(2.83 to 3.38)	4.63(4.11 to 7.98)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	Stratified cox proportional hazards regression model was used to estimate Hazard Ratio and CI. Stratification by hormonal receptor status and clinical stage at presentation (stratification factors).
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-sided) 95% 0.46 to 0.78
	Estimation Comments	[Not specified]

12. Secondary Outcome:

Title

Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales

Description

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

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = Number of participants evaluable for this outcome measure.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	193	205
Measure Type: Number Unit of Measure: percentage of participants
Cognitive Functioning	59.1	42.4
Physical Functioning	72.5	40.0
Role Functioning	76.7	47.8

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	This is the statistical analysis for cognitive functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in Deterioration
	Estimated Value	-16.63
	Confidence Interval	(2-sided) 95% -26.32 to -6.94
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	This is the statistical analysis for physical functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in Deterioration
	Estimated Value	-32.54
	Confidence Interval	(2-sided) 95% -41.74 to -23.34
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	TCH + P, T-DM1 + P
	Comments	This is the statistical analysis for role functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in Deterioration
	Estimated Value	-28.88
	Confidence Interval	(2-sided) 95% -37.95 to -19.80
	Estimation Comments	[Not specified]

13. Secondary Outcome:

Title

Time to Clinically Meaningful Deterioration in Function Subscale

Description

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

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = Number of participants evaluable for this outcome measure.


Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	191	200
Median (95% Confidence Interval) Unit of Measure: months
Physical Function	2.79(2.79 to 2.96)	4.86(4.40 to 7.98)
Role Function	2.79(2.17 to 2.89)	4.44(4.04 to 4.53)
Cognitive Function	3.42(3.02 to 4.24)	4.44(4.21 to NA)^[1]

[1]	NA Explanation: Here, NA represents data not estimable.

14. Secondary Outcome:

Title

Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales

Description

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

Outcome Measure Data

Analysis Population Description

ITT population. Participants were analyzed according to their randomized treatment. Overall number of participants analyzed = Number of participants evaluable for this outcome measure. Number Analyzed = participants evaluable for the specified category.


Arm/Group Title		TCH + P	T-DM1 + P
Arm/Group Description		Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed		194	205
Measure Type: Number Unit of Measure: percentage of participants
Appetite Loss	Number Analyzed	Participants	Participants
Appetite Loss		61.1	47.8
Any Hair Loss	Number Analyzed	Participants	Participants
Any Hair Loss		91.2	40.5
Systemic Therapy Side-Effects	Number Analyzed	Participants	Participants
Systemic Therapy Side-Effects		89.7	75.1
Constipation	Number Analyzed	Participants	Participants
Constipation		33.2	32.7
Diarrhea	Number Analyzed	Participants	Participants
Diarrhea		79.3	50.7
Dyspnea	Number Analyzed	Participants	Participants
Dyspnea		56.0	31.2
Fatigue	Number Analyzed	Participants	Participants
Fatigue		87.6	68.8
Nausea/Vomiting	Number Analyzed	Participants	Participants
Nausea/Vomiting		66.3	43.9
Pain	Number Analyzed	Participants	Participants
Pain		56.0	36.6
Insomnia	Number Analyzed	Participants	Participants
Insomnia		42.5	30.2

15. Secondary Outcome:

Title

Maximum Observed Serum Concentration (Cmax) of Trastuzumab

Description

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 period

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population:all participants who received at least one dose of T-DM1 (in T-DM1 + P arm) or TCH (in TCH + P arm), and had at least one post-treatment serum sample. Overall number of participants analyzed=Participants in PK Population evaluable for this outcome. Number Analyzed=participants evaluable for specified category.


Arm/Group Title	TCH + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
Overall Number of Participants Analyzed	162
Mean (Standard Deviation) Unit of Measure: micrograms per milliliter (mcg/mL)
Cycle 1	167(47.1)
Cycle 6	148(44.7)

16. Secondary Outcome:

Title

Cmax of Trastuzumab Emtansine and Total Trastuzumab

Description

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 period

Outcome Measure Data

Analysis Population Description

PK population. Overall number of participants analyzed = Participants in PK Population evaluable for this outcome measure. Number Analyzed = participants evaluable for specified category.


Arm/Group Title		T-DM1 + P
Arm/Group Description		Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed		207
Mean (Standard Deviation) Unit of Measure: mcg/mL
Trastuzumab emtansine: Cycle 1	Number Analyzed	Participants
Trastuzumab emtansine: Cycle 1		80.3(26.6)
Trastuzumab emtansine: Cycle 6	Number Analyzed	Participants
Trastuzumab emtansine: Cycle 6		72.3(30.0)
Total Trastuzumab: Cycle 1	Number Analyzed	Participants
Total Trastuzumab: Cycle 1		79.0(25.7)
Total Trastuzumab: Cycle 6	Number Analyzed	Participants
Total Trastuzumab: Cycle 6		79.5(30.9)

17. Secondary Outcome:

Title

Minimum Observed Serum Concentration (Cmin) of Trastuzumab

Description

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 period

Outcome Measure Data

Analysis Population Description

PK population. Overall number of participants analyzed = Number of participants in PK Population with evaluable samples at a given timepoint.


Arm/Group Title	TCH + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
Overall Number of Participants Analyzed	165
Mean (Standard Deviation) Unit of Measure: mcg/mL	45.8(17.8)

18. Secondary Outcome:

Title

Cmin of Trastuzumab Emtansine and Total Trastuzumab

Description

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 period

Outcome Measure Data

Analysis Population Description

PK population. Overall number of participants analyzed = Participants in PK Population evaluable for this outcome measure. Number Analyzed = participants evaluable for specified category.


Arm/Group Title		T-DM1 + P
Arm/Group Description		Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed		191
Mean (Standard Deviation) Unit of Measure: mcg/mL
Trastuzumab emtansine	Number Analyzed	Participants
Trastuzumab emtansine		3.06(7.68)
Total Trastuzumab	Number Analyzed	Participants
Total Trastuzumab		12.5(8.90)

19. Secondary Outcome:

Title

Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations

Description

DM1 is the metabolite of trastuzumab emtansine. 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 1 (cycle length = 21 days); 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant period

Outcome Measure Data

Analysis Population Description

PK population. Overall number of participants analyzed = Participants in PK Population evaluable for this outcome measure. Number Analyzed = participants evaluable for specified category.


Arm/Group Title	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	211
Mean (Standard Deviation) Unit of Measure: nanograms per milliliter (ng/mL)
Cycle 1: Pre-dose	0.0841(0.881)
Cycle 1: 15-30 min post-dose	4.98(2.82)
Cycle 6: 15-30 min post-dose	4.85(2.74)

20. Secondary Outcome:


Title	Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)
Description
Time Frame	Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 1 (cycle length = 21 days) in neoadjuvant period; 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
Anticipated Reporting Date	January 2019
Outcome Measure Data Not Reported

21. Secondary Outcome:

Title

Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1

Description

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 (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant period

Outcome Measure Data

Analysis Population Description

ITT population, including participants from T-DM1 + P arm only. Overall number of participants analyzed = participants evaluable for this outcome measure. Number Analyzed = participants evaluable for the specified category.


Arm/Group Title	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
Overall Number of Participants Analyzed	216
Measure Type: Number Unit of Measure: percentage of participants
Neoadjuvant Phase: At Baseline	5.6
Neoadjuvant Phase: At Post-Baseline	8.0

22. Secondary Outcome:


Title	Percentage of Participants With ATA to Trastuzumab
Description
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
Anticipated Reporting Date	January 2019
Outcome Measure Data Not Reported

Adverse Events


Time Frame	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Adverse Event Reporting Description	Safety population was analyzed.

Arm/Group Title	TCH + P	T-DM1 + P
Arm/Group Description	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).	Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
All-Cause Mortality
	TCH + P	T-DM1 + P
	Affected / At Risk (%)	Affected / At Risk (%)
Total	/	/
Serious Adverse Events
	TCH + P	T-DM1 + P
	Affected / At Risk (%)	Affected / At Risk (%)
Total	63 / 219 (28.77%)	11 / 223 (4.93%)
Blood and lymphatic system disorders
Anaemia ^{∗ A}	0 / 219 (0%)	3 / 223 (1.35%)
Febrile neutropenia ^{∗ A}	26 / 219 (11.87%)	3 / 223 (1.35%)
Neutropenia ^{∗ A}	7 / 219 (3.2%)	0 / 223 (0%)
Thrombocytopenia ^{∗ A}	1 / 219 (0.46%)	1 / 223 (0.45%)
Cardiac disorders
Cardiac failure ^{∗ A}	2 / 219 (0.91%)	1 / 223 (0.45%)
Sinus tachycardia ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Gastrointestinal disorders
Abdominal pain ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Abdominal pain upper ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Colitis ^{∗ A}	3 / 219 (1.37%)	0 / 223 (0%)
Diarrhoea ^{∗ A}	9 / 219 (4.11%)	0 / 223 (0%)
Gastritis ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Gastrointestinal haemorrhage ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Haemorrhoids ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Ileus ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Nausea ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Small intestinal obstruction ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Stomatitis ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Vomiting ^{∗ A}	4 / 219 (1.83%)	1 / 223 (0.45%)
General disorders
Asthenia ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Pyrexia ^{∗ A}	2 / 219 (0.91%)	0 / 223 (0%)
Immune system disorders
Anaphylactic reaction ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Hypersensitivity ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Infections and infestations
Bacteraemia ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Breast cellulitis ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Cellulitis ^{∗ A}	2 / 219 (0.91%)	0 / 223 (0%)
Clostridium difficile colitis ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Clostridium difficile infection ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Device related infection ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Diarrhoea infectious ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Enterocolitis infectious ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Gastroenteritis ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Gastroenteritis norovirus ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Kidney infection ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Pneumonia ^{∗ A}	2 / 219 (0.91%)	2 / 223 (0.9%)
Postoperative wound infection ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Sepsis ^{∗ A}	2 / 219 (0.91%)	0 / 223 (0%)
Skin infection ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Subcutaneous abscess ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Upper respiratory tract infection ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Wound infection ^{∗ A}	0 / 219 (0%)	2 / 223 (0.9%)
Injury, poisoning and procedural complications
Procedural intestinal perforation ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Subcutaneous haematoma ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Investigations
Ejection fraction decreased ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Lipase increased ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Neutrophil count decreased ^{∗ A}	3 / 219 (1.37%)	0 / 223 (0%)
Metabolism and nutrition disorders
Decreased appetite ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Dehydration ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Hypermagnesaemia ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Hypomagnesaemia ^{∗ A}	2 / 219 (0.91%)	0 / 223 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Nervous system disorders
Headache ^{∗ A}	1 / 219 (0.46%)	1 / 223 (0.45%)
Neuropathy peripheral ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Seizure ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Transient ischaemic attack ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Psychiatric disorders
Anxiety ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Renal and urinary disorders
Acute kidney injury ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Renal failure ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Reproductive system and breast disorders
Adenomyosis ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Breast haematoma ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Respiratory, thoracic and mediastinal disorders
Epistaxis ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Pleural effusion ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Pneumonitis ^{∗ A}	0 / 219 (0%)	2 / 223 (0.9%)
Pulmonary embolism ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Respiratory failure ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Vascular disorders
Deep vein thrombosis ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Hypertensive crisis ^{∗ A}	0 / 219 (0%)	1 / 223 (0.45%)
Shock haemorrhagic ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
Thrombophlebitis superficial ^{∗ A}	1 / 219 (0.46%)	0 / 223 (0%)
∗Indicates events were collected by non-systematic methods. ATerm from vocabulary, MedDRA 18.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	TCH + P	T-DM1 + P
	Affected / At Risk (%)	Affected / At Risk (%)
Total	215 / 219 (98.17%)	198 / 223 (88.79%)
Blood and lymphatic system disorders
Anaemia ^{∗ A}	78 / 219 (35.62%)	30 / 223 (13.45%)
Neutropenia ^{∗ A}	58 / 219 (26.48%)	9 / 223 (4.04%)
Thrombocytopenia ^{∗ A}	21 / 219 (9.59%)	16 / 223 (7.17%)
Eye disorders
Dry eye ^{∗ A}	11 / 219 (5.02%)	14 / 223 (6.28%)
Lacrimation increased ^{∗ A}	17 / 219 (7.76%)	4 / 223 (1.79%)
Gastrointestinal disorders
Abdominal pain ^{∗ A}	29 / 219 (13.24%)	18 / 223 (8.07%)
Abdominal pain upper ^{∗ A}	18 / 219 (8.22%)	4 / 223 (1.79%)
Constipation ^{∗ A}	39 / 219 (17.81%)	25 / 223 (11.21%)
Diarrhoea ^{∗ A}	159 / 219 (72.6%)	83 / 223 (37.22%)
Dry mouth ^{∗ A}	2 / 219 (0.91%)	23 / 223 (10.31%)
Dyspepsia ^{∗ A}	15 / 219 (6.85%)	22 / 223 (9.87%)
Gastrooesophageal reflux disease ^{∗ A}	15 / 219 (6.85%)	7 / 223 (3.14%)
Haemorrhoids ^{∗ A}	14 / 219 (6.39%)	4 / 223 (1.79%)
Nausea ^{∗ A}	132 / 219 (60.27%)	95 / 223 (42.6%)
Stomatitis ^{∗ A}	47 / 219 (21.46%)	21 / 223 (9.42%)
Vomiting ^{∗ A}	68 / 219 (31.05%)	29 / 223 (13%)
General disorders
Asthenia ^{∗ A}	57 / 219 (26.03%)	39 / 223 (17.49%)
Chills ^{∗ A}	9 / 219 (4.11%)	23 / 223 (10.31%)
Fatigue ^{∗ A}	93 / 219 (42.47%)	74 / 223 (33.18%)
Influenza like illness ^{∗ A}	6 / 219 (2.74%)	13 / 223 (5.83%)
Mucosal inflammation ^{∗ A}	30 / 219 (13.7%)	18 / 223 (8.07%)
Oedema peripheral ^{∗ A}	27 / 219 (12.33%)	5 / 223 (2.24%)
Pyrexia ^{∗ A}	29 / 219 (13.24%)	30 / 223 (13.45%)
Infections and infestations
Nasopharyngitis ^{∗ A}	15 / 219 (6.85%)	22 / 223 (9.87%)
Upper respiratory tract infection ^{∗ A}	9 / 219 (4.11%)	16 / 223 (7.17%)
Urinary tract infection ^{∗ A}	14 / 219 (6.39%)	9 / 223 (4.04%)
Injury, poisoning and procedural complications
Radiation skin injury ^{∗ A}	20 / 219 (9.13%)	9 / 223 (4.04%)
Investigations
Alanine aminotransferase increased ^{∗ A}	23 / 219 (10.5%)	52 / 223 (23.32%)
Aspartate aminotransferase increased ^{∗ A}	18 / 219 (8.22%)	39 / 223 (17.49%)
Neutrophil count decreased ^{∗ A}	22 / 219 (10.05%)	4 / 223 (1.79%)
Platelet count decreased ^{∗ A}	27 / 219 (12.33%)	13 / 223 (5.83%)
Weight decreased ^{∗ A}	22 / 219 (10.05%)	13 / 223 (5.83%)
White blood cell count decreased ^{∗ A}	15 / 219 (6.85%)	4 / 223 (1.79%)
Metabolism and nutrition disorders
Decreased appetite ^{∗ A}	39 / 219 (17.81%)	26 / 223 (11.66%)
Hypokalaemia ^{∗ A}	20 / 219 (9.13%)	10 / 223 (4.48%)
Hypomagnesaemia ^{∗ A}	11 / 219 (5.02%)	0 / 223 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{∗ A}	30 / 219 (13.7%)	19 / 223 (8.52%)
Back pain ^{∗ A}	17 / 219 (7.76%)	8 / 223 (3.59%)
Bone pain ^{∗ A}	14 / 219 (6.39%)	4 / 223 (1.79%)
Muscle spasms ^{∗ A}	7 / 219 (3.2%)	12 / 223 (5.38%)
Musculoskeletal pain ^{∗ A}	12 / 219 (5.48%)	7 / 223 (3.14%)
Myalgia ^{∗ A}	29 / 219 (13.24%)	26 / 223 (11.66%)
Nervous system disorders
Dizziness ^{∗ A}	25 / 219 (11.42%)	18 / 223 (8.07%)
Dysgeusia ^{∗ A}	43 / 219 (19.63%)	30 / 223 (13.45%)
Headache ^{∗ A}	35 / 219 (15.98%)	62 / 223 (27.8%)
Hypoaesthesia ^{∗ A}	14 / 219 (6.39%)	5 / 223 (2.24%)
Neuropathy peripheral ^{∗ A}	27 / 219 (12.33%)	15 / 223 (6.73%)
Paraesthesia ^{∗ A}	19 / 219 (8.68%)	4 / 223 (1.79%)
Peripheral sensory neuropathy ^{∗ A}	22 / 219 (10.05%)	16 / 223 (7.17%)
Psychiatric disorders
Depression ^{∗ A}	14 / 219 (6.39%)	8 / 223 (3.59%)
Insomnia ^{∗ A}	29 / 219 (13.24%)	32 / 223 (14.35%)
Reproductive system and breast disorders
Breast pain ^{∗ A}	9 / 219 (4.11%)	15 / 223 (6.73%)
Respiratory, thoracic and mediastinal disorders
Cough ^{∗ A}	15 / 219 (6.85%)	26 / 223 (11.66%)
Dyspnoea ^{∗ A}	14 / 219 (6.39%)	13 / 223 (5.83%)
Epistaxis ^{∗ A}	24 / 219 (10.96%)	35 / 223 (15.7%)
Oropharyngeal pain ^{∗ A}	11 / 219 (5.02%)	7 / 223 (3.14%)
Skin and subcutaneous tissue disorders
Alopecia ^{∗ A}	142 / 219 (64.84%)	31 / 223 (13.9%)
Dermatitis acneiform ^{∗ A}	13 / 219 (5.94%)	7 / 223 (3.14%)
Dry skin ^{∗ A}	23 / 219 (10.5%)	27 / 223 (12.11%)
Nail discolouration ^{∗ A}	14 / 219 (6.39%)	0 / 223 (0%)
Nail disorder ^{∗ A}	14 / 219 (6.39%)	6 / 223 (2.69%)
Pruritus ^{∗ A}	16 / 219 (7.31%)	13 / 223 (5.83%)
Rash ^{∗ A}	54 / 219 (24.66%)	42 / 223 (18.83%)
Vascular disorders
Hot flush ^{∗ A}	30 / 219 (13.7%)	17 / 223 (7.62%)
Hypertension ^{∗ A}	14 / 219 (6.39%)	10 / 223 (4.48%)
∗Indicates events were collected by non-systematic methods. ATerm from vocabulary, MedDRA 18.1

Limitations and Caveats


The reported results are interim only.

More Information


Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There IS an agreement between the Principal Investigator 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/Official Title:	Medical Communications
Organization:	Hoffmann-La Roche
Phone:	800-821-8590
Email:	genentech@druginfo.com