A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01772472
• Collaborator: NSABP Foundation Inc (Other), German Breast Group (Other)
• Enrollment: 1,486
• Locations: 276
• Arms: 2
• Anticipated Duration (Months): 144
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: trastuzumab; Drug: trastuzumab emtansine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1486 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Open-Label Phase III Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy for Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically in the Breast or Axillary Lymph Nodes Following Preoperative Therapy
• Actual Study Start Date: Apr 3, 2013
• Actual Primary Completion Date: Jul 25, 2018
• Anticipated Study Completion Date: Apr 3, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Trastuzumab	Drug: trastuzumab; 6 mg/kg intravenously every 3 weeks, 14 cycles
Experimental: Trastuzumab emtansine	Drug: trastuzumab emtansine; 3.6 mg/kg intravenously every 3 weeks, 14 cycles

Outcome Measures

Primary Outcome Measures

1. Invasive Disease-free Survival (IDFS) [From randomization to data cut-off date of 25 July 2018 (approximately up to 64 months)]

   IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma 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 in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. 3-year 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 randomization.

Secondary Outcome Measures

1. Invasive Disease-free Survival Including Second Primary Non-breast Cancer [From baseline up to 12 years]

   IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site). 3-year IDFS including second primary non-breast cancer event-free rates per treatment arm 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 randomization.

2. Disease-free Survival [From baseline up to 12 years]

   Disease-free survival was defined as the time between randomization and the date of the first occurrence of an invasive disease-free survival event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. 3-year DFS event-free rates 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 randomization.

3. Overall Survival (OS) [Baseline up to 12 years]

   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. 5 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 5 years after treatment.

4. Distant Recurrence-Free Interval (DRFI) [Baseline up to 12 years]

   DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3 years DRFI 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.

5. Percentage of Participants With Adverse Events [From Day 1 to 30 days after last dose of study drug, up to the clinical cutoff date (approximately 64 months)]

   An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).

6. Percentage of Participants With Cardiac Dysfunction [From baseline up to 12 years]

   Cardiac events were reported based on the NCI-CTCAE, v4.0.

7. Change From Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) [Baseline, Cycle 5, 11, Follow-up (FU) Month 6, Follow-up Month 12]

   The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1).

8. Change From Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23) [Baseline, Cycle 5, 11, Follow-up Month 6, Follow-up Month 12]

   EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL.

9. Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (Including Total Trastuzumab and DM1) [Cycle (C) 1, Day (D) 1 and C4D1 of pre-infusion, C1D1 and C4D1 post-infusion, C2D1 and C5D1 pre-infusion and study treatment termination]

   Blood and serum samples for measurement of trastuzumab emtansine, total trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab emtansine arm.

10. Serum Concentrations (AUC) of Trastuzumab [C1D1 and C4D1 of post-infusion and study treatment termination]

    Serum blood samples were collected for trastuzumab measurement prior to dosing and 15-30 minutes post infusion for Cycle 1 and Cycle 4. Additional serum samples were collected at study treatment termination.

11. Plasma Concentrations of DM1 [Day 1 on Cycles 1 and 4. Each cycle is 21 days.]

12. Trastuzumab Emtansine Exposure [Day 1 on Cycles 1, 2, 4 and 5, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.]

13. Anti-trastuzumab Emtansine Antibody (ATA) [Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.]

14. Anti-trastuzumab Antibody (ATA) [Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patient, >/= 18 years of age

• HER2-positive breast cancer

• Histologically confirmed invasive breast carcinoma

• Clinical stage T1-4/N0-3/M0 at presentation (patients with T1a/bN0 tumors will not be eligible)

• Completion of preoperative systemic chemotherapy and HER2-directed treatment consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy

• Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as specified in protocol

• Pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy

• An interval of no more than 12 weeks between the date of surgery and the date of randomization

• Known hormone-receptor status

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Adequate hematologic, renal and liver function

• Screening Left ventricular ejection fraction (LVEF) >/= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >/= 55% after completion of neoadjuvant chemotherapy.

• For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study drug

• Documentation of hepatitis B virus and hepatitis C virus serology is required

Exclusion Criteria:

• Stage IV (metastatic) breast cancer

• History of any prior (ipsi- or contralateral breast cancer except lobular carcinoma in situ

• Evidence of clinically evident gross residual or recurrent disease following preoperative therapy and surgery

• Progressive disease during preoperative systemic therapy

• Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment

• History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with a similar outcome to those mentioned above

• Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons

• Current NCI CTCAE (Version 4.0) Grade >/= 2 peripheral neuropathy

• History of exposure to the following cumulative doses of anthracyclines: Doxorubicin > 240 mg/m2; Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) > 480 mg/m2; For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m2

• Cardiopulmonary dysfunction as defined by protocol

• Prior treatment with trastuzumab emtansine

• Current severe, uncontrolled systemic disease

• Pregnant or lactating women

• Any known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis

• Concurrent serious uncontrolled infections requiring treatment or known infection with HIV

• History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
2	Todd Cancer Institute at Long Beach Memorial Medical Center	Long Beach	California	United States	90806
3	Chao Family Comprehensive Cancer Center; UC Irvine Medical Center	Orange	California	United States	92868
4	Stanford University Medical Center	Palo Alto	California	United States	94304
5	Kaiser Permanente - San Diego	San Diego	California	United States	92120
6	Breastlink Medical Group Inc	Santa Ana	California	United States	92705
7	Kaiser Permanente - Vallejo	Vallejo	California	United States	94589
8	Kaiser Permanente - Franklin	Denver	Colorado	United States	80205
9	Colorado Cancer Research Program/Admin	Denver	Colorado	United States	80222
10	Rocky Mountain Cancer Centers - Colorado Springs (Circle)	Lone Tree	Colorado	United States	80124
11	Hartford Hospital	Hartford	Connecticut	United States	06102
12	Yale Cancer Center	New Haven	Connecticut	United States	06520
13	Washington Cancer Institute; Washington Hospital Center	Washington	District of Columbia	United States	20010
14	University of Florida; Davis Cancer Pavilion and Shands Medical Plaza	Gainesville	Florida	United States	32610
15	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
16	UF Health Orlando	Orlando	Florida	United States	32806
17	Moffitt Cancer Center	Tampa	Florida	United States	33612
18	Rush University Medical Center	Chicago	Illinois	United States	60612
19	Edward Cancer Center Naperville	Naperville	Illinois	United States	60540
20	Edward Cancer Center Plainfield	Plainfield	Illinois	United States	60585
21	University of Iowa	Iowa City	Iowa	United States	52242
22	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
23	Norton Healthcare Inc.	Louisville	Kentucky	United States	40202
24	Cancer Care of Maine	Brewer	Maine	United States	04412
25	New England Cancer Specialists	Scarborough	Maine	United States	04074
26	Mercy Medical Center; Medical Oncology & Hematology	Baltimore	Maryland	United States	21202
27	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
28	Med Star Franklin Square Medical Center/Weinburg Cancer Institute	Baltimore	Maryland	United States	21237
29	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
30	Henry Ford Health System	Detroit	Michigan	United States	48202
31	Spectrum Health Hospitals	Grand Rapids	Michigan	United States	49503
32	Breslin Cancer Center	Lansing	Michigan	United States	48910
33	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
34	US oncology research at Minnesota Oncology	Saint Paul	Minnesota	United States	55102
35	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
36	Sparta Cancer Center	Sparta	New Jersey	United States	07871-1791
37	Columbia University Medical Center	New York	New York	United States	10032
38	Troy Cancer Treatment Program	Troy	New York	United States	12180
39	Carolinas Medical Center	Charlotte	North Carolina	United States	28204-2839
40	Batte Cancer Center - Carolinas Medical Center	Concord	North Carolina	United States	28025
41	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58102
42	Aultman Hospital; Aultman Hospital Cancer Center	Canton	Ohio	United States	44710
43	Fairview Hospital; Cleveland Clinic Cancer Center	Cleveland	Ohio	United States	44111
44	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
45	Ohio State University, Arthur James Cancer Hospital	Columbus	Ohio	United States	43210
46	Lake Health/University Hospitals - Mentor Campus	Mentor	Ohio	United States	44060
47	Columbia River Oncology Program	Portland	Oregon	United States	97213
48	Kimmel Cancer Center Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
49	Allegheny Cancer Center	Pittsburgh	Pennsylvania	United States	15212
50	Uni of Pittsburgh; Magee-Women'S Hospital	Pittsburgh	Pennsylvania	United States	15213
51	York Hospital	York	Pennsylvania	United States	17403
52	Medical University of South Carolina; Hollings Cancer Center	Charleston	South Carolina	United States	29425
53	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
54	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916-2305
55	Baylor College of Medicine	Houston	Texas	United States	77030
56	Houston Methodist Hospital Outpatient Center	Houston	Texas	United States	77030
57	Uni of Texas - Md Anderson Cancer Center; Dept of Breast Medical Oncology	Houston	Texas	United States	77030
58	Joe Arrington Cancer Research & Treatment Center	Lubbock	Texas	United States	79410
59	Hematology Oncology Associates of Fredericksburg, Inc.	Fredericksburg	Virginia	United States	22408
60	Lynchburg Hem Onc Clinic Inc	Lynchburg	Virginia	United States	24501
61	Virginia Commonwealth University - Massey Cancer Center	Richmond	Virginia	United States	23298
62	Swedish Cancer Institute - Issaquah	Issaquah	Washington	United States	98029
63	PeaceHealth St. John Medical Center - Lower Columbia Cancer Center	Longview	Washington	United States	98632
64	Cancer Care Northwest	Spokane	Washington	United States	99204
65	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
66	Fundación CENIT para la Investigación en Neurociencias	Buenos Aires		Argentina	C1125ABD
67	Centro Oncologico Riojano Integral (CORI)	La Rioja		Argentina	F5300COE
68	Instituto de Oncología de Rosario	Rosario		Argentina	S2000KZE
69	Tiroler Landeskrankenanstalten Ges.M.B.H.; Abt. Für Gynäkologie	Innsbruck		Austria	6020
70	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg		Austria	5020
71	Medizinische Universität Wien; Univ.Klinik für Frauenheilkunde - Klinik für Gynäkologie	Wien		Austria	1090
72	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie	Wien		Austria	1090
73	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
74	AZ Sint Lucas (Sint Lucas)	Gent		Belgium	9000
75	CHU Sart-Tilman	Liège		Belgium	4000
76	Sint Augustinus Wilrijk	Wilrijk		Belgium	2610
77	Iop Instituto de Oncologia Do Parana	Curitiba	PR	Brazil	80530-010
78	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ	Brazil	20560-120
79	Clinicas Oncologicas Integradas - COI	Rio De Janeiro	RJ	Brazil	22290-160
80	UPCO - Unidade de Pesquisas Clínicas em Oncologia	Pelotas	RS	Brazil	96015-280
81	Hospital Moinhos de Vento	Porto Alegre	RS	Brazil	90035-001
82	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS	Brazil	91350-200
83	Hospital de Cancer de Barretos	Barretos	SP	Brazil	14784-400
84	Instituto de Ensino e Pesquisa Sao Lucas - IEP	Sao Paulo	SP	Brazil	01236-030
85	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP	Brazil	01246-000
86	Hospital Perola Byington	Sao Paulo	SP	Brazil	01317-000
87	Hospital Sao Jose	Sao Paulo	SP	Brazil	01321-001
88	Tom Baker Cancer Centre; Dept of Medicine	Calgary	Alberta	Canada	T2N 4N2
89	Cross Cancer Institute ; Dept of Medical Oncology	Edmonton	Alberta	Canada	T6G 1Z2
90	BC Cancer - Surrey	Surrey	British Columbia	Canada	V3V 1Z2
91	British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
92	London Regional Cancer Centre	London	Ontario	Canada	N6A 4L6
93	The Ottawa Hospital; Division of Infectious Diseases	Ottawa	Ontario	Canada	K1H 8L6
94	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 1Z5
95	CSSS champlain - Charles-Le Moyne	Greenfield Park	Quebec	Canada	J4V 2H1
96	Centre Hospitalier de l'Université de Montréal (CHUM)	Montreal	Quebec	Canada	H2X 0C2
97	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
98	McGill University Health Centre - Glen Site	Montreal	Quebec	Canada	H4A 3J1
99	Hopital du Saint Sacrement	Quebec City	Quebec	Canada	G1S 4L8
100	the First Hospital of Jilin University	Changchun		China	130021
101	Sun Yet-sen University Cancer Center	Guangzhou		China	510060
102	Guangdong General Hospital	Guangzhou		China	510080
103	Harbin Medical University Cancer Hospital	Harbin		China	150081
104	Shandong Cancer Hospital	Jinan		China	250117
105	Fudan University Shanghai Cancer Center	Shanghai City		China	200120
106	Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)	Shanghai		China	200025
107	Clinica del Country	Bogota		Colombia	11001
108	Hospital Pablo Tobon Uribe	Medellin		Colombia	050034
109	Oncomedica S.A.	Monteria		Colombia	230002
110	Fakultni Nemocnice Hradec Kralove; Dept of Radiotherapy & Oncology	Hradec Kralove		Czechia	500 05
111	Fakultni nemocnice Olomouc; Onkologicka klinika	Olomouc		Czechia	779 00
112	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 08
113	Institut Sainte Catherine;Recherche Clinique	Avignon		France	84918
114	HOPITAL JEAN MINJOZ; Oncologie	Besancon		France	25030
115	Institut Bergonie; Oncologie	Bordeaux		France	33076
116	Centre Hospitalier Fleyriat; Oncologie/Hematologie	Bourg En Bresse		France	01012
117	Centre Francois Baclesse; Comite Sein	Caen		France	14076
118	Centre Jean Perrin; Oncologie	Clermont Ferrand		France	63011
119	Clinique Victor Hugo; Chimiotherapie	Le Mans		France	72015
120	Institut Paoli Calmettes; Oncologie Medicale	Marseille		France	13273
121	Centre Val Aurelle Paul Lamarque; Recherche Clinique	Montpellier		France	34298
122	Institut Curie; Oncologie Medicale	Paris		France	75231
123	Hopital Saint Louis; Oncologie Medicale	Paris		France	75475
124	HOPITAL TENON; Cancerologie Medicale	Paris		France	75970
125	Centre Henri Becquerel; Oncologie Medicale	Rouen		France	76038
126	Centre Rene Huguenin; CONSULT SPECIALISEES	St Cloud		France	92210
127	Centre Paul Strauss; Oncologie Medicale	Strasbourg		France	67065
128	Institut Gustave Roussy; Departement Oncologie Medicale	Villejuif		France	94805
129	Hämatologisch-onkologische Praxis Dr. med. - Heinrich, - Bangerter	Augsburg		Germany	86150
130	Praxisklinik Krebsheilkunde für Frauen / Brustzentrum (Dres. Kittel/Klare)	Berlin		Germany	10367
131	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin		Germany	10707
132	HELIOS Klinikum Berlin-Buch; Klinik für Gynäkologie und Geburtshilfe	Berlin		Germany	13125
133	Studienzentrum Berlin City	Berlin		Germany	14169
134	Onkologische Schwerpunktpraxis Bielefeld	Bielefeld		Germany	33604
135	Klinikum Sindelfingen-Böblingen; Frauenklinik	Böblingen		Germany	71032
136	St. Johannes-Hospital	Dortmund		Germany	44137
137	Luisenkrankenhaus GmbH & Co. KG., Brustzentrum	Düsseldorf		Germany	40235
138	Universitätsklinikum Erlangen; Frauenklinik	Erlangen		Germany	91054
139	Universitätsklinikum Essen; Zentrum Für Frauenheilkunde	Essen		Germany	45122
140	Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum	Essen		Germany	45136
141	Klinikum Esslingen; Klinik für Frauenheilkunde und Geburtshilfe	Esslingen		Germany	73730
142	Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus	Frankfurt am Main		Germany	60389
143	Klinik Johann Wolfgang von Goethe Uni; Klinik für Frauenheilkunde und Geburtshilfe	Frankfurt		Germany	60596
144	Universitätsklinikum Freiburg; Frauenklinik	Freiburg		Germany	79106
145	Evangelische Kliniken Gelsenkirchen GmbH; Brustzentrum	Gelsenkirchen		Germany	45879
146	Universitätsklinikum Greifswald; Klinik für Frauenheilkunde und Brustzentrum	Greifswald		Germany	17475
147	Krankenhaus St. Elisabeth und St. Barbara, Klinik für Frauenheilkunde und Geburtshilfe	Halle		Germany	06110
148	Universitätsklinikum Halle (Saale); Universitätsklinik Und Poliklinik Für Gynäkologie	Halle		Germany	06120
149	Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem	Hamburg		Germany	20357
150	St. Barbara-Klinik Hamm-Heessen GmbH; Frauenklinik	Hamm		Germany	59073
151	Gynaekologisch-Onkologische Schwerpunktpraxis Prof. Dr. med. Lueck, Dr. Schrader und Dr. Noeding	Hannover		Germany	30177
152	Diakovere Henriettenstift, Frauenklinik	Hannover		Germany	30559
153	Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und Geburtshilfe	Hannover		Germany	30625
154	Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg	Heidelberg		Germany	69120
155	Elisabeth-Krankenhaus Brustzentrum	Kassel		Germany	34117
156	Klinikum Kassel GmbH; Klinik für Frauenheilkunde und Geburtshilfe	Kassel		Germany	34125
157	UNI-Klinikum Campus Kiel Klinik für Gynäkologie und Geburtshilfe	Kiel		Germany	24105
158	St. Elisabeth Krankenhaus Köln GmbH; Gynäkologie und Geburtshilfe	Koeln		Germany	50935
159	Kliniken der Stadt Köln gGmbH Krankenhaus Holweide; Brustzentrum	Köln		Germany	51067
160	Gemeinschaftspraxis für Hämatologie und Onkologie PD Dr. Bauer, Dr. Kremers	Lebach		Germany	66822
161	Klinikum der Universität München; Frauenklinik - Onkologie II	München		Germany	80337
162	Gemeinschaftspraxis Prof. Dr.med. Christoph Salat und Dr.med. Oliver J. Stötzer	München		Germany	80638
163	MVZ Nordhausen gGmbH, Praxis Dr. Grafe	Nordhausen		Germany	99734
164	Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe	Offenbach		Germany	63069
165	St. Vincenz-Krankenhaus Paderborn; Haus 3 Frauenklinik	Paderborn		Germany	33098
166	Oncologianova GmbH - Gesellschaft für Innovationen in der Onkologie	Recklinghausen		Germany	45659
167	Klinikum am Steinenberg Frauenklinik	Reutlingen		Germany	72764
168	Universitätsfrauen- und Poliklinik am Klinikum Suedstadt	Rostock		Germany	18059
169	Gynäkologie Kompetenzzentrum; Praxis Dr. med. Carsten Hielscher	Stralsund		Germany	18439
170	Robert-Bosch-Krankenhaus; Brustzentrum	Stuttgart		Germany	70376
171	Gemeinschaftspraxis Dr. Kronawitter und Dr. Jung	Traunstein		Germany	83278
172	Universitätsklinik Tübingen; Frauenklinik	Tübingen		Germany	72076
173	Universitätsklinikum Ulm Am Michelsberg; Frauenklinik	Ulm		Germany	89075
174	HELIOS Dr. Horst Schmidt Kliniken Wiesbaden; Klinik für Gynäkologie und gynäkologische Onkologie	Wiesbaden		Germany	65199
175	Marien-Hospital Witten; Frauenklinik Brustzentrum	Witten		Germany	58452
176	Hämatologisch-Onkologische Schwerpunktpraxis Dres. Schlag & Schöttker	Würzburg		Germany	97080
177	Univ General Hosp Heraklion; Medical Oncology	Heraklion		Greece	711 10
178	Euromedical General Clinic of Thessaloniki; Oncology Department	Thessaloniki		Greece	546450
179	Grupo Angeles	Guatemala City		Guatemala	01015
180	Centro Oncológico Sixtino / Centro Oncológico SA	Guatemala		Guatemala	01010
181	Queen Mary Hospital; Surgery	Hong Kong		Hong Kong	852
182	Pamela Youde Nethersole Eastern Hospital; Clinical Oncology	Hong Kong		Hong Kong
183	Tuen Mun Hospital; Clinical Oncology	Hong Kong		Hong Kong
184	Cork Uni Hospital; Oncology Dept	Cork		Ireland
185	St Vincent'S Uni Hospital; Medical Oncology	Dublin		Ireland	4
186	Mater Misericordiae Uni Hospital; Oncology	Dublin		Ireland	7
187	Beaumont Hospital; Cancer Clinical Trials Unit	Dublin		Ireland	9
188	Galway Uni Hospital; Oncology Dept	Galway		Ireland
189	University Hospital Limerick - Oncology	Limerick		Ireland
190	Soroka Medical Center	Beer Sheva		Israel	8410101
191	Shaare Zedek Medical Center; Oncology Dept	Jerusalem		Israel	9103102
192	Hadassah University Hospital - Ein Kerem	Jerusalem		Israel	9112001
193	Rabin MC; Davidof Center - Oncology Institute	Petach Tikva		Israel	4941492
194	Sheba Medical Center; Tel Hashomer	Ramat Gan		Israel	5262100
195	Kaplan Medical Center; Oncology Inst.	Rehovot		Israel	7610001
196	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania	Italy	80131
197	Università degli Studi Federico II; Clinica di Oncologia Medica	Napoli	Campania	Italy	80131
198	Policlinico S.Orsola-Malpighi; Istituto Oncologia R. Addarii	Bologna	Emilia-Romagna	Italy	40138
199	Ausl Di Bologna-Ospedale Bellaria;U.O. Oncologia Medica	Bologna	Emilia-Romagna	Italy	40139
200	Policlinico Universitario Campus Biomedico; Uoc Oncologia Medica	Roma	Lazio	Italy	00128
201	Az. Osp. Sant'Andrea; Oncologia Medica	Roma	Lazio	Italy	00189
202	IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A	Genova	Liguria	Italy	16132
203	Asst Papa Giovanni XXIII; Oncologia Medica	Bergamo	Lombardia	Italy	24127
204	ASST DI CREMONA; Unità di Patologia Mammaria Senologia e Breast Unit	Cremona	Lombardia	Italy	26100
205	Irccs Ospedale San Raffaele;Oncologia Medica	Milano	Lombardia	Italy	20132
206	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia	Italy	20133
207	Istituto Europeo Di Oncologia	Milano	Lombardia	Italy	20141
208	ASST DI MONZA; Oncologia Medica	Monza	Lombardia	Italy	20900
209	Fondazione Del Piemonte Per L'oncologia IRCC Di Candiolo	Candiolo	Piemonte	Italy	10060
210	Ospedale Antonio Perrino; Oncologia Medica	Brindisi	Puglia	Italy	72100
211	Azlenda Ospendaliero-Universitaria Pisana; C.O. Oncologia 2	Pisa	Toscana	Italy	56100
212	Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia	Pontedera	Toscana	Italy	56025
213	IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II	Padova	Veneto	Italy	35128
214	A.O.U.I. VERONA-OSPEDALE BORGO TRENTO; ONCOLODIA MEDICA-d.O.	Verona	Veneto	Italy	37126
215	Hospital Angeles Metropolitano; Room 220	Mexico City	Mexico CITY (federal District)	Mexico	06760
216	Centenario Hospital Miguel Hidalgo	Aguascalientes		Mexico	20230
217	Instituto Nacional de Cancerologia; Oncology	Distrito Federal		Mexico	14080
218	Nstituto Nacional de Ciancias Medicas Y Nutricion, Salvador Zubir	Mexico City		Mexico	14080
219	Oaxaca Site Management Organization	Oaxaca		Mexico	68000
220	Centro Hemato Oncologico Panama	Panama		Panama	0832
221	Centro Oncologico America	Panama		Panama	0834-02723
222	Centro Medico Monte Carmelo	Arequipa		Peru	04001
223	Hospital Nacional Carlos Alberto Seguin Escobedo-Essalud; Oncology & Haemathology	Arequipa		Peru	04001
224	Hospital IV Alberto Sabogal Sologuren; Unidad de Investigacion	Bellavista		Peru	Callao 2
225	Hospital Nacional Guillermo Almenara Irigoyen; Oncology	Lima		Peru	13
226	Clinica San Borja	Lima		Peru	Lima 41
227	Institute for Oncology and Radiology of Serbia; Medical Oncology	Belgrade		Serbia	11000
228	Oncology Institute of Vojvodina	Sremska Kamenica		Serbia	21204
229	Cape Town Oncology Trials	Cape Town		South Africa	7570
230	Hopelands Cancer Centre	Hilton		South Africa	3245
231	Medical Oncology Centre of Rosebank; Oncology	Johannesburg		South Africa	2196
232	Wits Donald Gordon Clinical Trial Centre; Medical Oncology	Parktown, Johannesburg		South Africa	2193
233	Cancercare	Port Elizabeth		South Africa	6045
234	Private Oncology Centre	Pretoria		South Africa	0081
235	Hospital de Donostia; Servicio de Oncologia Medica	San Sebastian	Guipuzcoa	Spain	20080
236	Hospital Severo Ochoa; Servicio de Oncologia	Leganes	Madrid	Spain	28911
237	Complexo Hospitalario de Vigo. Hospital Álvaro Cunqueiro; Servicio de Oncología	Vigo	Pontevedra	Spain	36312
238	Hospital Universitari Sant Joan de Reus; Servicio de Oncologia	Reus	Tarragona	Spain	43204
239	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona		Spain	08036
240	Hospital Universitario La Paz; Servicio de Oncologia	Madrid		Spain	28046
241	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia	Madrid		Spain	28050
242	Hospital Regional Universitario Carlos Haya; Servicio de Oncologia	Malaga		Spain	29011
243	Hospital de Navarra; Servicio de Oncologia	Navarra		Spain	31008
244	Hospital Clinico Universitario de Salamanca; Servicio de Oncologia	Salamanca		Spain	37007
245	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla		Spain	41013
246	Instituto Valenciano Oncologia; Oncologia Medica	Valencia		Spain	46009
247	Hospital Universitario Dr. Peset; Servicio de Oncologia	Valencia		Spain	46017
248	Gävle Sjukhus; Onkologiska Kliniken	Gävle		Sweden	80187
249	Skånes University Hospital, Skånes Department of Onclology	Lund		Sweden	221 85
250	Karolinska Hospital; Oncology - Radiumhemmet	Stockholm		Sweden	171 76
251	Kantonsspital Aarau AG Medizin Onkologie; ZENTRUM FÜR ONKOLOGIE, HÄMATOLOGIE & TRANSFUSIONSMEDIZIN	Aarau		Switzerland	5001
252	Brust-Zentrum Zürich AG Seefeldstrasse 214 Zürich	Zürich		Switzerland	8008
253	Taichung Veterans General Hospital; Dept of Surgery	Taichung		Taiwan	407
254	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei City		Taiwan	11259
255	VETERANS GENERAL HOSPITAL; Department of General Surgery	Taipei		Taiwan	00112
256	National Taiwan Uni Hospital; General Surgery	Taipei		Taiwan	100
257	Chang Gung Medical Foundation - Linkou; Dept of Surgery	Taoyuan		Taiwan	333
258	Uludag Uni Hospital; Oncology	Bursa		Turkey	16059
259	Trakya University Medical Faculty Research And Practice Hospital Medical Oncology Department	Edirne		Turkey	22770
260	Kartal Dr Lutfi Kirdar Sehir Hastanesi; Medical Oncology Department	Istanbul		Turkey	34865
261	Ege Uni Medical Faculty Hospital; Oncology Dept	Izmir		Turkey	35100
262	Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department	Malatya		Turkey	44280
263	University Hospital Birmingham The Cancer Centre, Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
264	Bradford Royal Infirmary; Dept of Medical Oncology C/O Ward15	Bradford		United Kingdom	BD9 6RJ
265	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
266	Royal Cornwall Hospital; Dept of Clinical Oncology	Cornwall		United Kingdom	TR1 3LQ
267	Castle Hill Hospital; The Queens Centre for Oncology and Haematology	Cottingham		United Kingdom	HU16 5JG
268	North Devon District Hospital	Devon		United Kingdom	EX31 4JB
269	Ninewells Hospital; Cancer Medicine	Dundee		United Kingdom	DD1 9SY
270	Huddersfield Royal Infirmary	Huddersfield		United Kingdom	HD3 3EA
271	Leeds Teaching Hosp NHS Trust;St James's Institute of Onc	Leeds		United Kingdom	LS9 7TF
272	St Thomas Hospital; Medicine Div.	London		United Kingdom	SE1 7EH
273	Charing Cross Hospital; Medical Oncology.	London		United Kingdom	W6 8RF
274	Christie Hospital Nhs Trust; Medical Oncology	Manchester		United Kingdom	M2O 4BX
275	Nottingham City Hospital; Oncology	Nottingham		United Kingdom	NG5 1PB
276	Weston Park Hospital	Sheffield		United Kingdom	S10 2SJ

Sponsors and Collaborators

• Hoffmann-La Roche
• NSABP Foundation Inc
• German Breast Group

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Oct 13, 2015
• Statistical Analysis Plan - Nov 5, 2012

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01772472
• Other Study ID Numbers: BO27938; 2012-002018-37
• First Posted: Jan 21, 2013
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Additional relevant MeSH terms: Breast Neoplasms; Neoplasm, Residual; Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine

Study Results

Participant Flow

Pre-assignment Detail	1486 patients were randomized in 268 centers across 28 countries.

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
Period Title: Overall Study
STARTED	743	743
COMPLETED	0	0
NOT COMPLETED	743	743

Baseline Characteristics

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine	Total
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.	Total of all reporting groups
Overall Participants	743	743	1486
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	675 90.8%	685 92.2%	1360 91.5%
>=65 years	68 9.2%	58 7.8%	126 8.5%
Sex: Female, Male (Count of Participants)
Female	740 99.6%	741 99.7%	1481 99.7%
Male	3 0.4%	2 0.3%	5 0.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	50 6.7%	36 4.8%	86 5.8%
Asian	64 8.6%	65 8.7%	129 8.7%
Native Hawaiian or Other Pacific Islander	1 0.1%	0 0%	1 0.1%
Black or African American	19 2.6%	21 2.8%	40 2.7%
White	531 71.5%	551 74.2%	1082 72.8%
More than one race	1 0.1%	1 0.1%	2 0.1%
Unknown or Not Reported	77 10.4%	69 9.3%	146 9.8%

Outcome Measures

1. Primary Outcome

Title	Invasive Disease-free Survival (IDFS)
Description	IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma 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 in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. 3-year 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 randomization.
Time Frame	From randomization to data cut-off date of 25 July 2018 (approximately up to 64 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
Measure Participants	743	743
Number (95% Confidence Interval) [Percent Probability]	77.02	88.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab, Trastuzumab Emtansine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	() 95%; 0.39 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Invasive Disease-free Survival Including Second Primary Non-breast Cancer
Description	IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site). 3-year IDFS including second primary non-breast cancer event-free rates per treatment arm 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 randomization.
Time Frame	From baseline up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Disease-free Survival
Description	Disease-free survival was defined as the time between randomization and the date of the first occurrence of an invasive disease-free survival event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. 3-year DFS event-free rates 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 randomization.
Time Frame	From baseline up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Overall Survival (OS)
Description	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. 5 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 5 years after treatment.
Time Frame	Baseline up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Distant Recurrence-Free Interval (DRFI)
Description	DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3 years DRFI 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	Baseline up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).
Time Frame	From Day 1 to 30 days after last dose of study drug, up to the clinical cutoff date (approximately 64 months)

Outcome Measure Data

Analysis Population Description

The safety population was defined as all participants who have received at least one dose of study medication.

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
Measure Participants	720	740
Number [Percentage of Participants]	93.3 12.6%	98.8 13.3%

7. Secondary Outcome

Title	Percentage of Participants With Cardiac Dysfunction
Description	Cardiac events were reported based on the NCI-CTCAE, v4.0.
Time Frame	From baseline up to 12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Change From Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)
Description	The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1).
Time Frame	Baseline, Cycle 5, 11, Follow-up (FU) Month 6, Follow-up Month 12

Outcome Measure Data

Analysis Population Description

Randomized Patient Population of patients with both a baseline assessment and at least one post-baseline assessment are included in the analysis.

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
Measure Participants	743	743
Baseline: Appetite Loss	7.9 (17.4)	7.1 (16.4)
Change at Cycle 5: Appetite Loss	1.0 (18.7)	6.5 (23.7)
Change at Cycle 11: Appetite Loss	-0.5 (17.2)	2.9 (20.2)
Change at FU Month 6: Appetite Loss	-1.6 (18.3)	-1.7 (19.9)
Change at FU Month 12: Appetite Loss	0.5 (20.3)	-1.9 (20.1)
Baseline: Constipation	9.8 (20.2)	9.5 (19.0)
Change at Cycle 5: Constipation	1.0 (22.4)	4.6 (22.6)
Change at Cycle 11: Constipation	3.4 (23.6)	7.3 (23.1)
Change at FU Month 6: Constipation	4.1 (23.7)	3.7 (23.3)
Change at FU Month 12: Constipation	3.2 (23.2)	4.3 (24.6)
Baseline: Diarrhea	8.8 (17.6)	6.4 (14.9)
Change at Cycle 5: Diarrhea	-1.6 (19.3)	-1.5 (19.5)
Change at Cycle 11: Diarrhea	-0.4 (21.4)	-2.4 (17.5)
Change at FU Month 6: Diarrhea	-3.4 (18.5)	-1.9 (18.3)
Change at FU Month 12: Diarrhea	-2.8 (18.9)	-1.6 (18.4)
Baseline: Dyspnea	12.7 (20.7)	11.0 (18.8)
Change at Cycle 5: Dyspnea	2.3 (21.9)	4.1 (22.4)
Change at Cycle 11: Dyspnea	2.8 (21.2)	2.7 (20.4)
Change at FU Month 6: Dyspnea	3.3 (22.8)	3.8 (22.7)
Change at FU Month 12: Dyspnea	3.9 (24.9)	5.3 (22.4)
Baseline: Fatigue	29.2 (21.1)	28.0 (20.0)
Change at Cycle 5: Fatigue	1.1 (20.1)	5.5 (19.7)
Change at Cycle 11: Fatigue	1.1 (20.5)	3.8 (21.3)
Change at FU Month 6: Fatigue	-1.4 (21.9)	-0.1 (22.2)
Change at FU Month 12: Fatigue	-0.1 (23.3)	-0.1 (22.1)
Baseline: Financial Difficulties	28.6 (33.3)	27.6 (31.9)
Change at Cycle 5: Financial Difficulties	-3.1 (26.5)	-3.0 (28.0)
Change at Cycle 11: Financial Difficulties	-5.1 (27.6)	-1.7 (28.7)
Change at FU Month 6: Financial Difficulties	-8.4 (28.3)	-6.5 (30.6)
Change at FU Month 12: Financial Difficulties	-10.9 (30.5)	-7.3 (31.0)
Baseline: Insomnia	30.6 (30.8)	30.6 (29.2)
Change at Cycle 5: Insomnia	1.9 (28.4)	1.3 (29.7)
Change at Cycle 11: Insomnia	2.4 (29.9)	1.5 (30.3)
Change at FU Month 6: Insomnia	1.8 (31.3)	-0.9 (32.1)
Change at FU Month 12: Insomnia	0.3 (30.4)	0.7 (31.7)
Baseline: Nausea/Vomiting	3.3 (9.0)	2.8 (8.0)
Change at Cycle 5: Nausea/Vomiting	1.5 (11.2)	3.2 (12.5)
Change at Cycle 11: Nausea/Vomiting	1.3 (12.8)	3.0 (11.8)
Change at FU Month 6: Nausea/Vomiting	0.8 (10.4)	0.2 (11.1)
Change at FU Month 12: Nausea/Vomiting	0.4 (10.5)	1.2 (10.9)
Baseline: Pain	22.2 (22.2)	22.6 (22.8)
Change at Cycle 5: Pain	0.0 (23.2)	1.8 (23.9)
Change at Cycle 11: Pain	0.1 (23.1)	2.1 (24.4)
Change at FU Month 6: Pain	-0.3 (24.6)	-0.5 (24.3)
Change at FU Month 12: Pain	-1.2 (25.6)	-0.8 (25.4)
Baseline: Cognitive Functioning	83.3 (20.2)	84.4 (19.0)
Change at Cycle 5: Cognitive Functioning	-3.8 (18.4)	-4.5 (18.7)
Change at Cycle 11: Cognitive Functioning	-5.4 (21.3)	-5.3 (19.6)
Change at FU Month 6: Cognitive Functioning	-4.1 (22.0)	-6.1 (21.6)
Change at FU Month 12: Cognitive Functioning	-4.9 (22.2)	-6.9 (21.7)
Baseline: Emotional Functioning	75.0 (22.0)	75.2 (21.2)
Change at Cycle 5: Emotional Functioning	-0.4 (20.0)	-1.3 (21.3)
Change at Cycle 11: Emotional Functioning	-1.0 (21.3)	0.1 (22.0)
Change at FU Month 6: Emotional Functioning	-2.9 (22.0)	-0.8 (23.3)
Change at FU Month 12: Emotional Functioning	-2.0 (22.7)	-1.6 (23.5)
Baseline: Physical Functioning	84.5 (15.3)	85.8 (14.1)
Change at Cycle 5: Physical Functioning	0.3 (12.9)	-1.6 (12.7)
Change at Cycle 11: Physical Functioning	1.9 (14.2)	-0.6 (14.6)
Change at FU Month 6: Physical Functioning	2.8 (15.4)	0.7 (15.1)
Change at FU Month 12: Physical Functioning	2.7 (14.5)	0.8 (14.5)
Baseline: Role Functioning	77.5 (25.0)	78.6 (23.3)
Change at Cycle 5: Role Functioning	2.0 (24.3)	-0.2 (24.1)
Change at Cycle 11: Role Functioning	4.0 (24.3)	0.6 (24.5)
Change at FU Month 6: Role Functioning	7.4 (25.8)	3.6 (26.7)
Change at FU Month 12: Role Functioning	8.0 (27.5)	4.6 (25.5)
Baseline: Social Functioning	77.1 (24.1)	76.8 (23.2)
Change at Cycle 5: Social Functioning	4.0 (22.5)	1.6 (23.8)
Change at Cycle 11: Social Functioning	5.8 (24.0)	2.5 (23.6)
Change at FU Month 6: Social Functioning	8.5 (23.7)	6.5 (26.1)
Change at FU Month 12: Social Functioning	9.5 (25.1)	7.4 (26.4)
Baseline: Global Health Status	71.2 (19.3)	71.4 (18.0)
Change at Cycle 5: Global Health Status	0.6 (18.9)	-1.9 (19.6)
Change at Cycle 11: Global Health Status	1.7 (17.8)	-0.5 (19.9)
Change at FU Month 6: Global Health Status	2.5 (19.3)	2.0 (19.2)
Change at FU Month 12: Global Health Status	3.2 (19.5)	2.8 (20.1)

9. Secondary Outcome

Title	Change From Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)
Description	EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL.
Time Frame	Baseline, Cycle 5, 11, Follow-up Month 6, Follow-up Month 12

Outcome Measure Data

Analysis Population Description

Randomized Patient Population of patients with both a baseline assessment and at least one post-baseline assessment are included in the analysis.

Arm/Group Title	Trastuzumab	Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.	Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
Measure Participants	743	743
Baseline: Body Image	69.8 (28.5)	67.5 (28.5)
Change at Cycle 5: Body Image	1.5 (20.5)	4.6 (22.7)
Change at Cycle 11: Body Image	3.4 (24.4)	5.7 (23.9)
Change at FU Month 6: Body Image	3.6 (25.1)	7.8 (25.8)
Change at FU Month 12: Body Image	6.2 (27.1)	6.1 (27.2)
Baseline: FP	51.3 (31.2)	50.1 (31.7)
Change at Cycle 5: FP	2.6 (28.3)	6.5 (29.9)
Change at Cycle 11: FP	6.3 (30.0)	6.1 (31.4)
Change at FU Month 6: FP	7.7 (33.5)	8.1 (34.6)
Change at FU Month 12: FP	8.1 (31.1)	8.2 (33.0)
Baseline: Sexual Enjoyment	50.9 (28.8)	52.3 (28.5)
Change at Cycle 5: Sexual Enjoyment	2.3 (26.4)	-1.9 (24.6)
Change at Cycle 11: Sexual Enjoyment	4.4 (27.5)	4.4 (24.5)
Change at FU Month 6: Sexual Enjoyment	3.2 (28.1)	0.3 (27.5)
Change at FU Month 12: Sexual Enjoyment	5.6 (26.0)	1.8 (26.2)
Baseline: Sexual Function	20.2 (23.6)	22.0 (23.4)
Change at Cycle 5: Sexual Function	3.3 (20.0)	2.3 (20.0)
Change at Cycle 11: Sexual Function	3.1 (20.8)	1.9 (20.3)
Change at FU Month 6: Sexual Function	5.1 (23.9)	4.3 (23.1)
Change at FU Month 12: Sexual Function	5.9 (23.7)	5.2 (22.7)
Baseline: Arm Symptoms	24.6 (21.1)	24.5 (21.0)
Change at Cycle 5: Arm Symptoms	-2.8 (20.9)	-2.6 (23.0)
Change at Cycle 11: Arm Symptoms	-2.6 (21.2)	0.2 (24.2)
Change at FU Month 6: Arm Symptoms	-3.0 (23.5)	-1.3 (24.2)
Change at FU Month 12: Arm Symptoms	-5.7 (22.8)	-1.5 (22.6)
Baseline: Breast Symptoms	22.7 (19.1)	21.4 (17.9)
Change at Cycle 5: Breast Symptoms	-1.1 (20.3)	-1.1 (19.1)
Change at Cycle 11: Breast Symptoms	-3.7 (19.8)	-0.6 (19.5)
Change at FU Month 6: Breast Function	-6.5 (20.0)	-2.2 (19.7)
Change at Follow-up Month 12: Breast Function	-8.3 (19.9)	-3.8 (19.2)
Baseline: Systemic Therapy Side Effects (SE)	16.7 (13.7)	16.9 (14.1)
Change at Cycle 5: Systemic Therapy SE	0.7 (13.0)	5.5 (15.3)
Change at Cycle 11: Systemic Therapy SE	1.2 (12.2)	4.2 (15.4)
Change at FU Month 6: Systemic Therapy SE	1.9 (13.9)	1.1 (15.3)
Change at FU Month 12: Systemic Therapy SE	1.3 (13.9)	1.4 (16.3)
Baseline: Upset by Hair Loss Item	40.3 (35.6)	50.7 (38.4)
Change at Cycle 5: Upset by Hair Loss Item	-5.1 (38.1)	-17.6 (39.3)
Change at Cycle 11: Upset by Hair Loss Item	-28.6 (45.0)	-14.3 (33.9)
Change at FU Month 6: Upset by Hair Loss Item	-12.0 (47.0)	-15.2 (42.1)
Change at FU Month 12: Upset by Hair Loss Item	-2.9 (37.5)	-14.3 (41.6)

10. Secondary Outcome

Title	Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (Including Total Trastuzumab and DM1)
Description	Blood and serum samples for measurement of trastuzumab emtansine, total trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab emtansine arm.
Time Frame	Cycle (C) 1, Day (D) 1 and C4D1 of pre-infusion, C1D1 and C4D1 post-infusion, C2D1 and C5D1 pre-infusion and study treatment termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Serum Concentrations (AUC) of Trastuzumab
Description	Serum blood samples were collected for trastuzumab measurement prior to dosing and 15-30 minutes post infusion for Cycle 1 and Cycle 4. Additional serum samples were collected at study treatment termination.
Time Frame	C1D1 and C4D1 of post-infusion and study treatment termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Plasma Concentrations of DM1
Time Frame	Day 1 on Cycles 1 and 4. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Trastuzumab Emtansine Exposure
Time Frame	Day 1 on Cycles 1, 2, 4 and 5, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Anti-trastuzumab Emtansine Antibody (ATA)
Time Frame	Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Anti-trastuzumab Antibody (ATA)
Time Frame	Day 1 on Cycles 1, and 4, at study treatment termination and 3-4 months after last dose of trastuzumab emtansine. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From baseline to primary clinical cutoff date of approximately 64 months
Adverse Event Reporting Description	Safety population was analyzed.
Arm/Group Title	Trastuzumab		Trastuzumab Emtansine
Arm/Group Description	Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.		Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
All Cause Mortality
	Trastuzumab		Trastuzumab Emtansine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/720 (7.8%)		42/740 (5.7%)
Serious Adverse Events
	Trastuzumab		Trastuzumab Emtansine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/720 (8.1%)		94/740 (12.7%)
Cardiac disorders
Cardiac Failure	2/720 (0.3%)	2	2/740 (0.3%)	2
Atrial Fibrillation	1/720 (0.1%)	1	0/740 (0%)	0
Pericarditis	1/720 (0.1%)	1	0/740 (0%)	0
Eye disorders
Vision Blurred	0/720 (0%)	0	1/740 (0.1%)	1
Gastrointestinal disorders
Vomiting	2/720 (0.3%)	3	3/740 (0.4%)	4
Abdominal Pain	1/720 (0.1%)	2	3/740 (0.4%)	3
Diarrhoea	1/720 (0.1%)	1	1/740 (0.1%)	1
Nausea	1/720 (0.1%)	2	1/740 (0.1%)	1
Colitis	0/720 (0%)	0	1/740 (0.1%)	1
Haemorrhoids	1/720 (0.1%)	1	0/740 (0%)	0
Ileal Perforation	0/720 (0%)	0	1/740 (0.1%)	1
Impaired gastric Emptying	0/720 (0%)	0	1/740 (0.1%)	1
Large Intestinal Obstruction	0/720 (0%)	0	1/740 (0.1%)	1
Pancreatitis	1/720 (0.1%)	1	0/740 (0%)	0
General disorders
Non-Cardiac Chest pain	2/720 (0.3%)	2	3/740 (0.4%)	3
Influenza Like Illness	1/720 (0.1%)	1	0/740 (0%)	0
Pyrexia	0/720 (0%)	0	1/740 (0.1%)	1
Systemic Inflammatory Response Syndrome	1/720 (0.1%)	1	0/740 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/720 (0.1%)	1	1/740 (0.1%)	1
Nodular Regenerative Hyperplasia	0/720 (0%)	0	2/740 (0.3%)	2
Gallbladder Polyp	1/720 (0.1%)	1	0/740 (0%)	0
Hepatic Cyst	0/720 (0%)	0	1/740 (0.1%)	1
Hepatitis	0/720 (0%)	0	1/740 (0.1%)	1
Immune system disorders
Hypersensitivity	0/720 (0%)	0	4/740 (0.5%)	4
Infections and infestations
Mastitis	6/720 (0.8%)	7	8/740 (1.1%)	8
Device Related Infection	0/720 (0%)	0	6/740 (0.8%)	6
Bronchitis	1/720 (0.1%)	1	3/740 (0.4%)	3
Pneumonia	1/720 (0.1%)	1	3/740 (0.4%)	3
Skin Infection	2/720 (0.3%)	2	2/740 (0.3%)	2
Lung Infection	1/720 (0.1%)	1	2/740 (0.3%)	2
Urinary Tract Infection	2/720 (0.3%)	2	1/740 (0.1%)	1
Wound Infection	2/720 (0.3%)	2	1/740 (0.1%)	1
Appendicitis	0/720 (0%)	0	2/740 (0.3%)	2
Cellulitis	1/720 (0.1%)	1	1/740 (0.1%)	1
Gastroenteritis	0/720 (0%)	0	2/740 (0.3%)	2
Abscess Intestinal	0/720 (0%)	0	1/740 (0.1%)	1
Cystitis	1/720 (0.1%)	1	0/740 (0%)	0
Diverticulitis	0/720 (0%)	0	1/740 (0.1%)	1
Enterocolitis Infections	1/720 (0.1%)	1	0/740 (0%)	0
Implant Site Cellulitis	1/720 (0.1%)	1	0/740 (0%)	0
Infected Seroma	0/720 (0%)	0	1/740 (0.1%)	1
Influenza	0/720 (0%)	0	1/740 (0.1%)	1
Perirectal Abscess	1/720 (0.1%)	1	0/740 (0%)	0
Staphylococcal Bacteraemia	0/720 (0%)	0	1/740 (0.1%)	1
Tonsillitis	0/720 (0%)	0	1/740 (0.1%)	1
Vestibular Neuronitis	1/720 (0.1%)	1	0/740 (0%)	0
Vulvitis	0/720 (0%)	0	1/740 (0.1%)	1
Injury, poisoning and procedural complications
Wound Dehiscence	1/720 (0.1%)	1	3/740 (0.4%)	3
Post Procedural haemorrhage	1/720 (0.1%)	1	1/740 (0.1%)	1
Radiation Pneumonitis	0/720 (0%)	0	2/740 (0.3%)	2
Tibia Fracture	0/720 (0%)	0	2/740 (0.3%)	2
Ankle Fracture	1/720 (0.1%)	1	0/740 (0%)	0
Femur Fracture	1/720 (0.1%)	1	0/740 (0%)	0
Limb Fracture	1/720 (0.1%)	1	0/740 (0%)	0
Seroma	1/720 (0.1%)	1	0/740 (0%)	0
Wound Complication	1/720 (0.1%)	1	0/740 (0%)	0
Wrist Fracture	1/720 (0.1%)	1	0/740 (0%)	0
Investigations
Platelet Count Decreased	0/720 (0%)	0	10/740 (1.4%)	10
Aspartate Aminotransferase Increased	0/720 (0%)	0	1/740 (0.1%)	1
Ejection Fraction Decreased	1/720 (0.1%)	1	0/740 (0%)	0
Troponin T Increased	0/720 (0%)	0	1/740 (0.1%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/720 (0.1%)	1	0/740 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/720 (0.1%)	1	0/740 (0%)	0
Muscular Weakness	1/720 (0.1%)	1	0/740 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer Stage 1	0/720 (0%)	0	1/740 (0.1%)	1
Endometrial Adenocarcinoma	1/720 (0.1%)	1	0/740 (0%)	0
Intraductal Proliferative Breast Lesion	1/720 (0.1%)	1	0/740 (0%)	0
Pituitary Tumour Benign	0/720 (0%)	0	1/740 (0.1%)	1
Nervous system disorders
Peripheral Sensory Neuropathy	0/720 (0%)	0	3/740 (0.4%)	3
Peripheral Motor Neuropathy	0/720 (0%)	0	2/740 (0.3%)	2
Syncope	0/720 (0%)	0	2/740 (0.3%)	2
Dizziness	0/720 (0%)	0	1/740 (0.1%)	1
Haemorrhage intracranial	0/720 (0%)	0	1/740 (0.1%)	1
Neuralgia	0/720 (0%)	0	1/740 (0.1%)	1
Paraesthesia	1/720 (0.1%)	1	0/740 (0%)	0
Psychiatric disorders
Anxiety	0/720 (0%)	0	1/740 (0.1%)	2
Suicidal Ideation	0/720 (0%)	0	1/740 (0.1%)	1
Renal and urinary disorders
Acute Kidney Injury	0/720 (0%)	0	1/740 (0.1%)	1
Bladder Pain	1/720 (0.1%)	1	0/740 (0%)	0
Reproductive system and breast disorders
Ovarian Cyst	1/720 (0.1%)	1	0/740 (0%)	0
Menorrhagia	0/720 (0%)	0	1/740 (0.1%)	1
Uterine Haemorrhage	1/720 (0.1%)	1	0/740 (0%)	0
Uterine Obstruction	1/720 (0.1%)	1	0/740 (0%)	0
Uterine Prolapse	1/720 (0.1%)	1	0/740 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/720 (0%)	0	2/740 (0.3%)	2
Pneumonitis	0/720 (0%)	0	2/740 (0.3%)	2
Aspiration	0/720 (0%)	0	1/740 (0.1%)	1
Chronic Obstructive Pulmonary	0/720 (0%)	0	1/740 (0.1%)	1
Dyspnoea	1/720 (0.1%)	1	0/740 (0%)	0
Pleural Effusion	0/720 (0%)	0	1/740 (0.1%)	1
Pulmonary fibrosis	0/720 (0%)	0	1/740 (0.1%)	1
Skin and subcutaneous tissue disorders
Photosensitivity reaction	1/720 (0.1%)	1	0/740 (0%)	0
Telangiectasia	1/720 (0.1%)	1	0/740 (0%)	0
Vascular disorders
Embolism	3/720 (0.4%)	3	1/740 (0.1%)	1
Hypertension	1/720 (0.1%)	1	1/740 (0.1%)	1
Haematoma	1/720 (0.1%)	1	0/740 (0%)	0
Other (Not Including Serious) Adverse Events
	Trastuzumab		Trastuzumab Emtansine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	634/720 (88.1%)		719/740 (97.2%)
Blood and lymphatic system disorders
Anaemia	60/720 (8.3%)	79	74/740 (10%)	89
Eye disorders
lacrimation Increased	13/720 (1.8%)	13	41/740 (5.5%)	44
Gastrointestinal disorders
Nausea	93/720 (12.9%)	111	308/740 (41.6%)	438
Constipation	59/720 (8.2%)	66	126/740 (17%)	152
Diarrhoea	89/720 (12.4%)	116	91/740 (12.3%)	117
Vomiting	37/720 (5.1%)	45	106/740 (14.3%)	139
Dry Mouth	9/720 (1.3%)	9	100/740 (13.5%)	109
Stomatitis	27/720 (3.8%)	29	80/740 (10.8%)	96
Abdominal Pain	42/720 (5.8%)	48	55/740 (7.4%)	66
General disorders
Fatigue	243/720 (33.8%)	276	366/740 (49.5%)	456
Influenza like Illness	86/720 (11.9%)	96	100/740 (13.5%)	138
Pain	92/720 (12.8%)	113	93/740 (12.6%)	114
Pyrexia	29/720 (4%)	32	76/740 (10.3%)	98
Oedema Peripheral	52/720 (7.2%)	56	29/740 (3.9%)	33
Chills	14/720 (1.9%)	16	39/740 (5.3%)	57
Infections and infestations
Upper Respiratory Tract Infection	53/720 (7.4%)	65	58/740 (7.8%)	69
Urinary Tract Infection	37/720 (5.1%)	39	64/740 (8.6%)	79
Injury, poisoning and procedural complications
Radiation Skin Injury	199/720 (27.6%)	208	188/740 (25.4%)	198
Investigations
Aspartate Aminotransferase Increased	40/720 (5.6%)	44	209/740 (28.2%)	253
Platelet Count Decreased	17/720 (2.4%)	21	205/740 (27.7%)	256
Alanine Aminotransferase Increased	41/720 (5.7%)	51	171/740 (23.1%)	208
White Blood Cell Count Decreased	42/720 (5.8%)	62	61/740 (8.2%)	81
Neutrophil Count Decreased	36/720 (5%)	46	61/740 (8.2%)	78
Blood Alkaline Phosphatase Increased	13/720 (1.8%)	14	61/740 (8.2%)	68
Blood Bilirubin Increased	2/720 (0.3%)	2	49/740 (6.6%)	74
Metabolism and nutrition disorders
Decreased Appetite	16/720 (2.2%)	19	62/740 (8.4%)	70
Hypokalaemia	14/720 (1.9%)	20	48/740 (6.5%)	58
Musculoskeletal and connective tissue disorders
Arthralgia	148/720 (20.6%)	162	192/740 (25.9%)	221
Myalgia	80/720 (11.1%)	87	114/740 (15.4%)	125
Pain In Extremity	70/720 (9.7%)	81	86/740 (11.6%)	97
Back Pain	66/720 (9.2%)	73	53/740 (7.2%)	56
Bone Pain	35/720 (4.9%)	38	52/740 (7%)	55
Muscle Spasms	45/720 (6.3%)	45	33/740 (4.5%)	36
Nervous system disorders
Headache	122/720 (16.9%)	146	210/740 (28.4%)	287
Peripheral Sensory Neuropathy	50/720 (6.9%)	51	135/740 (18.2%)	146
Dizziness	57/720 (7.9%)	61	69/740 (9.3%)	76
Paraesthesia	40/720 (5.6%)	43	60/740 (8.1%)	72
Dysgeusia	11/720 (1.5%)	12	60/740 (8.1%)	61
Psychiatric disorders
Insomnia	86/720 (11.9%)	95	101/740 (13.6%)	110
Depression	44/720 (6.1%)	47	41/740 (5.5%)	44
Anxiety	42/720 (5.8%)	44	27/740 (3.6%)	29
Reproductive system and breast disorders
Breast pain	42/720 (5.8%)	50	53/740 (7.2%)	56
Respiratory, thoracic and mediastinal disorders
Cough	86/720 (11.9%)	93	100/740 (13.5%)	112
Epistaxis	25/720 (3.5%)	30	158/740 (21.4%)	220
Dyspnoea	52/720 (7.2%)	56	62/740 (8.4%)	69
Oropharyngeal Pain	33/720 (4.6%)	36	37/740 (5%)	39
Skin and subcutaneous tissue disorders
Pruritus	42/720 (5.8%)	44	51/740 (6.9%)	57
Dry Skin	36/720 (5%)	41	48/740 (6.5%)	52
Rash Maculo-Papular	26/720 (3.6%)	27	42/740 (5.7%)	49
Dermatitis Acneiform	21/720 (2.9%)	23	39/740 (5.3%)	44
Vascular disorders
Hot Flush	146/720 (20.3%)	154	95/740 (12.8%)	99
Lymphoedema	48/720 (6.7%)	51	37/740 (5%)	37
Hypertension	34/720 (4.7%)	38	41/740 (5.5%)	58

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.