Trial Outcomes & Findings for A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer (NCT NCT00976989)

NCT ID: NCT00976989

Last Updated: 2017-02-06

Results Overview

Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 225 participants
• Primary outcome timeframe: From baseline up to approximately 3.5 years
• Results posted on: 2017-02-06

Participant Flow

This study included 3 periods: Neoadjuvant (pre-operative) period and surgery, adjuvant (post-operative) period and post-treatment follow-up period.

Participant milestones

Measure	T+P Concomitant Anthracycline-based Chemotherapy 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Study STARTED	73	75	77
Overall Study COMPLETED	60	63	60
Overall Study NOT COMPLETED	13	12	17

Reasons for withdrawal

Measure	T+P Concomitant Anthracycline-based Chemotherapy 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Study Violation of Selection Criteria at Entry	1	0	1
Overall Study Death	5	7	10
Overall Study Refused Treatment	4	3	5
Overall Study Failure to Return	2	1	0
Overall Study Recurrence of Disease	0	1	0
Overall Study Other	1	0	1

Baseline Characteristics

A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer

Baseline characteristics by cohort

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	Total n=225 Participants Total of all reporting groups
Age, Continuous	49.6 years STANDARD_DEVIATION 11.41 • n=5 Participants	50.5 years STANDARD_DEVIATION 10.70 • n=7 Participants	50.6 years STANDARD_DEVIATION 10.58 • n=5 Participants	50.6 years STANDARD_DEVIATION 10.86 • n=4 Participants
Gender Female	73 Participants n=5 Participants	75 Participants n=7 Participants	77 Participants n=5 Participants	225 Participants n=4 Participants
Gender Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: From baseline up to approximately 3.5 years

Population: Safety population included all participants who were randomized and received study drug.

Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator	0 percentage of participants	2.7 percentage of participants	1.3 percentage of participants

PRIMARY outcome

Timeframe: From baseline up to approximately 18 weeks

Population: Safety population included all participants who were randomized and received study drug.

Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of <50% during the pre-operative (neoadjuvant) period.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Safety: Percentage of Participants With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period	5.6 percentage of participants	5.3 percentage of participants	3.9 percentage of participants

SECONDARY outcome

Timeframe: At surgery, after 18 weeks (6 cycles) of treatment

Population: Intent to treat (ITT) population included all participants who were randomized to treatment.

pCR is defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. pCR is evaluated after 6 cycles of treatment and surgery or following withdrawal from the study whichever occurs sooner.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Percentage of Participants With Complete Pathological Response (pCR)	61.6 percentage of participants Interval 49.5 to 72.8	57.3 percentage of participants Interval 45.4 to 68.7	66.2 percentage of participants Interval 54.6 to 76.6

SECONDARY outcome

Timeframe: During each 3-week cycle of 6 total cycles: up to 18 weeks

Population: ITT population included all participants who were randomized to treatment.

Tumor response is defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) and is identified as per local practice. Clinical response rate is defined as the percentage of participants who achieve a response of CR or PR at any time pre-surgery. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by mammogram or magnetic resonance imaging (MRI) and clinical breast examination (CBE), CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Clinical Response Rate	91.8 percentage of participants	94.7 percentage of participants	89.6 percentage of participants

SECONDARY outcome

Timeframe: Up to 18 weeks

Population: ITT population included all participants who were randomized to treatment.

Time to clinical response is defined as the time from the date of first dose received to the first date of assessment of clinical response. Clinical response is defined as a response of CR or PR at any time pre-surgery. Per RECIST v1.0 for target lesions and assessed by mammogram or MRI and CBE, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Time to Clinical Response	3.6 weeks Interval 3.0 to 6.0	6.3 weeks Interval 6.0 to 7.0	4.9 weeks Interval 4.0 to 6.0

SECONDARY outcome

Timeframe: At approximately 18 weeks

Population: Number of participants analyzed represents the participants with T2-3 tumors for whom mastectomy was planned.

This is the percentage of participants who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer, as these participants received mastectomy irrespective of their response to neoadjuvant (pre-operative) treatment.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=46 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=36 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=37 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Percentage of Participants Achieving Breast Conserving Surgery	21.7 percentage of participants	16.7 percentage of participants	27.0 percentage of participants

SECONDARY outcome

Timeframe: From baseline to end of study up to 5 years

Population: ITT population included all participants who were randomized to treatment.

Overall survival (OS) was defined as the time from randomization to the date of death from any cause. Participants who were alive or lost to follow-up were censored at the last known alive date. Participants with no post-baseline information were censored at the date of randomization plus one day.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Percentage of Participants Without an Overall Survival (OS) Event	93.2 percentage of participants	90.7 percentage of participants	87.0 percentage of participants

SECONDARY outcome

Timeframe: From baseline to end of study up to 5 years

Population: ITT population included all participants who were randomized to treatment. Number of participants analyzed is total number of participants evaluable during each period.

The DFS was defined as the time from the first date of no disease (i.e., date of surgery) to the first documentation of progressive disease (PD) or death. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Any evidence of contralateral disease in situ was not considered as PD. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be disease-free.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=69 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=67 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=72 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event	85.5 percentage of participants	88.1 percentage of participants	84.7 percentage of participants

SECONDARY outcome

Timeframe: From baseline to end of study up to 5 years

Population: ITT population included all participants who were randomized to treatment.

Progression-free survival was defined as the time from the date of randomization to the first documentation of PD or death from any cause, whichever occurred first. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be free from PD. Participants without post-baseline assessments but known to be alive were censored at the time of randomization plus one day.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=73 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=77 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event	86.3 percentage of participants	85.3 percentage of participants	81.8 percentage of participants

SECONDARY outcome

Timeframe: From Baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)

Population: Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable during each period.

Percentage of participants with signs or symptoms of cardiac events.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD) Neoadjuvant Period (n=72, 75, 76)	1.4 percentage of participants	2.7 percentage of participants	0 percentage of participants
Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD) Adjuvant Period (n= 68, 65, 67)	0 percentage of participants	0 percentage of participants	1.5 percentage of participants
Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD) Follow-up Period (n=70, 75, 74)	0 percentage of participants	1.3 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: From baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)

Population: Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable during each period.

Percentage of participants with LVEF events without signs or symptoms of cardiac events.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events Neoadjuvant Period (n=72, 75, 76)	5.6 percentage of participants	4.0 percentage of participants	2.6 percentage of participants
Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events Adjuvant Period (n= 66, 64, 63)	3.0 percentage of participants	0 percentage of participants	4.8 percentage of participants
Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events Follow-up Period (n=21, 18, 23)	0 percentage of participants	11.1 percentage of participants	4.3 percentage of participants

SECONDARY outcome

Timeframe: From baseline up to approximately 3.5 years

Population: Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable.

Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage.

Outcome measures

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=71 Participants 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=72 Participants FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=73 Participants Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Safety: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures	-6.6 percentage (ejection fraction) Standard Deviation 5.15	-8.4 percentage (ejection fraction) Standard Deviation 5.66	-7.0 percentage (ejection fraction) Standard Deviation 6.48

Adverse Events

T+P Concomitant Anthracycline-based Chemotherapy

Serious events: 23 serious events

Other events: 72 other events

Deaths: 0 deaths

T+P Sequential Anthracycline-based Chemotherapy

Serious events: 18 serious events

Other events: 73 other events

Deaths: 0 deaths

T+P Concomitant Non-Anthracycline Chemotherapy

Serious events: 31 serious events

Other events: 76 other events

Deaths: 0 deaths

Serious adverse events

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 participants at risk 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 participants at risk FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 participants at risk Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Blood and lymphatic system disorders Febrile Neutropenia	13.9% 10/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	14.5% 11/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Neutropenia	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Leukopenia	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Pneumonia	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Neutropenic infection	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Wound infection	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Anal abscess	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Appendicitis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Catheter site infection	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Clostridium difficile colitis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Clostridium difficile infection	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Cystitis	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Device related infection	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Device related sepsis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Gastroenteritis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Infection	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Lung Abscess	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Neutropenic sepsis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Pseudomembranous colitis	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Pyelonephritis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Urinary tract infection	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Diarrhoea	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Vomiting	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Nausea	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Cardiac disorders Left ventricular dysfunction	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Cardiac disorders Cardiovascular disorder	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Cardiac disorders Conduction disorder	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Dehydration	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Mucosal inflammation	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Chest pain	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders General physical health deterioration	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Pyrexia	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Immune system disorders Drug hypersensitivity	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Immune system disorders Anaphylactic reaction	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Breast mass	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Breast necrosis	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Ovarian cyst	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Vaginal haemorrhage	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Injury, poisoning and procedural complications Post procedural haematoma	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Injury, poisoning and procedural complications Seroma	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Cerebrovascular accident	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Epilepsy	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Psychiatric disorders Panic attack	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.

Other adverse events

Measure	T+P Concomitant Anthracycline-based Chemotherapy n=72 participants at risk 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	T+P Sequential Anthracycline-based Chemotherapy n=75 participants at risk FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	T+P Concomitant Non-Anthracycline Chemotherapy n=76 participants at risk Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Musculoskeletal and connective tissue disorders Myalgia	19.4% 14/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	21.3% 16/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.5% 8/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Back pain	15.3% 11/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Nasopharyngitis	8.3% 6/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	11.8% 9/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	15.3% 11/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Bone pain	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Headache	27.8% 20/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	20.0% 15/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	21.1% 16/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Dysgeusia	11.1% 8/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.3% 10/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	21.1% 16/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Dizziness	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	19.7% 15/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Neuropathy peripheral	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.5% 8/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Peripheral sensory neuropathy	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Paraesthesia	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	11.8% 9/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Nervous system disorders Polyneuropathy	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	18.1% 13/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.2% 10/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	11.1% 8/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.3% 10/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	14.5% 11/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Upper respiratory tract infection	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.3% 10/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	3.9% 3/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Urinary tract infection	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Rhinitis	8.3% 6/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Cystitis	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Psychiatric disorders Insomnia	16.7% 12/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	17.3% 13/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	22.4% 17/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Psychiatric disorders Depression	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Psychiatric disorders Anxiety	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Vascular disorders Hot Flush	15.3% 11/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.2% 10/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Vascular disorders Hypertension	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Vascular disorders Lymphoedema	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Investigations Haemoglobin decreased	8.3% 6/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Investigations Alanine aminotransferase increased	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.5% 8/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Investigations Aspartate aminotransferase increased	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Investigations Weight decreased	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Cough	13.9% 10/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.2% 10/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	8.0% 6/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	11.8% 9/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Diarrhoea	63.9% 46/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	58.7% 44/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	72.4% 55/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Nausea	52.8% 38/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	54.7% 41/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	44.7% 34/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Vomiting	40.3% 29/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	36.0% 27/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	39.5% 30/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Dyspepsia	26.4% 19/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	22.4% 17/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Constipation	19.4% 14/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	24.0% 18/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	17.1% 13/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Stomatitis	13.9% 10/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	17.3% 13/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	11.8% 9/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Abdominal pain upper	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	8.0% 6/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Abdominal pain	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Dry mouth	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.5% 8/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Haemorrhoids	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Abdominal distension	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Gastrointestinal disorders Oral pain	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Alopecia	48.6% 35/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	52.0% 39/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	55.3% 42/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Rash	23.6% 17/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	26.3% 20/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Nail disorder	12.5% 9/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.2% 10/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Erythema	13.9% 10/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	14.5% 11/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Dry skin	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.5% 8/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Palmar -plantar erythrodysaesthesia syndrome	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Pruritus	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Skin reaction	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	3.9% 3/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Dermatitis	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Hyperhidrosis	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Night sweats	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Fatigue	41.7% 30/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	37.3% 28/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	43.4% 33/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Mucosal inflammation	23.6% 17/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	20.0% 15/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	15.8% 12/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Pyrexia	15.3% 11/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	12.0% 9/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	19.7% 15/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Asthenia	12.5% 9/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	18.7% 14/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	13.2% 10/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Oedema peripheral	13.9% 10/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	11.8% 9/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Pain	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.3% 7/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Chills	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Chest pain	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Influenza like illness	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.7% 5/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Oedema	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Malaise	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Axillary pain	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	6.6% 5/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Neutropenia	50.0% 36/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	44.0% 33/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	48.7% 37/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Anaemia	19.4% 14/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	38.2% 29/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Leukopenia	22.2% 16/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	16.0% 12/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	17.1% 13/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Thrombocytopenia	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	30.3% 23/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Blood and lymphatic system disorders Febrile neutropenia	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Musculoskeletal and connective tissue disorders Arthralgia	25.0% 18/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	24.0% 18/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	14.5% 11/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Metabolism and nutrition disorders Decreased appetite	20.8% 15/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	21.1% 16/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Injury, poisoning and procedural complications Radiation skin injury	15.3% 11/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	18.7% 14/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Injury, poisoning and procedural complications Seroma	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Eye disorders Lacrimation increased	12.5% 9/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Conjunctivitis	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Eye disorders Eyelid oedema	1.4% 1/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Cardiac disorders Left ventricular dysfunction	9.7% 7/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	10.7% 8/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Cardiac disorders Palpitations	4.2% 3/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Breast pain	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	7.9% 6/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Reproductive system and breast disorders Vulvovaginal dryness	0.00% 0/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	1.3% 1/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Immune system disorders Drug hypersensitivity	8.3% 6/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.7% 2/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Renal and urinary disorders Dysuria	2.8% 2/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	0.00% 0/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	9.2% 7/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
Infections and infestations Influenza	6.9% 5/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	5.3% 4/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	2.6% 2/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.
General disorders Chest discomfort	5.6% 4/72 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	4.0% 3/75 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.	3.9% 3/76 • Up to approximately 5 years Safety population included all participants who were randomized and received study drug.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER