Trial Outcomes & Findings for A Study to Assess Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in Participants With Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer (NCT NCT01565083)

NCT ID: NCT01565083

Last Updated: 2016-11-22

Results Overview

Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis \[SA\] of at least (\>/=) 15 millimeter \[mm\]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (\<) 10 mm for nodal TLs/ non-TLs. PR: \>/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 213 participants
• Primary outcome timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
• Results posted on: 2016-11-22

Participant Flow

Due to non-randomized nature of the study (single infusion cohort started enrollment only after separate infusion cohort recruitment was completed) and different baseline characteristics of participants, the comparison between the 2 cohorts was not performed. Hence, the efficacy and safety results for the 2 cohorts should be considered separately.

Participant milestones

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab intravenous (IV) infusion at a loading dose of 840 milligrams (mg) on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg per kilogram (mg/kg) on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg per meter-squared (mg/m\^2) on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Overall Study STARTED	106	107
Overall Study COMPLETED	73	68
Overall Study NOT COMPLETED	33	39

Reasons for withdrawal

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab intravenous (IV) infusion at a loading dose of 840 milligrams (mg) on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg per kilogram (mg/kg) on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg per meter-squared (mg/m\^2) on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Overall Study Withdrawal by Subject	6	4
Overall Study Lost to Follow-up	2	7
Overall Study Death	22	23
Overall Study Other	3	5

Baseline Characteristics

A Study to Assess Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in Participants With Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer

Baseline characteristics by cohort

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Total n=213 Participants Total of all reporting groups
Age, Continuous	56.9 years STANDARD_DEVIATION 11.80 • n=5 Participants	55.6 years STANDARD_DEVIATION 13.17 • n=7 Participants	56.2 years STANDARD_DEVIATION 12.50 • n=5 Participants
Sex: Female, Male Female	106 Participants n=5 Participants	106 Participants n=7 Participants	212 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population. Only participants with measurable disease at baseline were included in the analysis.

Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis [SA] of at least (>/=) 15 millimeter [mm]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (<) 10 mm for nodal TLs/ non-TLs. PR: >/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=89 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=91 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	74.2 percentage of participants Interval 63.8 to 82.9	63.7 percentage of participants Interval 53.0 to 73.6

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population. Only participants with measurable disease at baseline were included in the analysis.

For participants with a BOR of CR or PR, time to response = (Date of first confirmed CR/PR - Date of first study treatment) + 1. For participants without a CR or PR, time to response = (Date of adequate last tumor assessment - Date of first study treatment) + 1. For participant with no tumor assessment (or if all assessments were progressive disease [PD]) the censoring day was set to date of first study treatment +1. CR: the disappearance of all TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR: >/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=89 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=91 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Time to Response as Assessed by Investigator According to RECIST v 1.1	2.1 months Interval 2.0 to 2.2	2.2 months Interval 2.1 to 4.4

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population. Only participants with a BOR of CR or PR and with measurable disease at baseline were included in the analysis.

DOR, in participants with a BOR of CR or PR, was defined as the period from the date of initial PR or CR until the date of PD or death from any cause. Participants with no documented PD or death after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively (regardless of the response at intermediate assessments). CR: the disappearance of all TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR: >/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=66 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=58 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1	13.3 months Interval 10.6 to 16.2	11.8 months Interval 7.5 to 17.9

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population

PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause was reported.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From Any Cause	69.8 percentage of participants	67.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population

PFS was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause, whichever occurred first. Participants with no PFS events were censored at the time of the last evaluable tumor assessment. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or died due to any cause were considered as having an event. The median PFS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1	14.3 months Interval 11.2 to 17.5	11.5 months Interval 10.3 to 15.8

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population

PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 was reported.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1	67.9 percentage of participants	61.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)

Population: ITT population

TTP was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1. Participants who did not have a radio-graphically documented PD and had died due to reason other than PD were censored on the last available tumor assessment prior to the death date. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 were considered as having an event. The median TTP was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1	14.9 months Interval 11.3 to 17.9	12.8 months Interval 10.4 to 17.1

SECONDARY outcome

Timeframe: Baseline until death (up to approximately 3.5 years)

Population: ITT population

Percentage of participants who died due to any cause was reported.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Percentage of Participants Who Died From Any Cause	21.7 percentage of participants	21.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline until death (up to approximately 3.5 years)

Population: ITT population

OS was defined as the time from first intake of any study medication to the date of death, regardless of the cause of death. Participants who were known to be alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study treatment, and participants with no post-baseline information were censored at the date of first study treatment plus 1 day. Participants who died due to any cause were considered as having an event. The median OS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Overall Survival (OS)	NA months Median and corresponding CI could not be calculated due to low number of participants who had an event.	NA months Median and corresponding CI could not be calculated due to low number of participants who had an event.

SECONDARY outcome

Timeframe: Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)

Population: ITT population. Here, 'Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.

EQ-5D VAS: participant rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=102 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=102 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Baseline (n = 102, 102)	69.7 units on a scale Standard Deviation 22.74	68.6 units on a scale Standard Deviation 23.58
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 3 (n = 83, 90)	0.9 units on a scale Standard Deviation 19.31	1.7 units on a scale Standard Deviation 23.16
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 6 (n=68, 82)	1.0 units on a scale Standard Deviation 23.59	4.3 units on a scale Standard Deviation 24.49
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 9 (n=67, 68)	2.2 units on a scale Standard Deviation 23.00	6.6 units on a scale Standard Deviation 26.29
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 12 (n=53, 59)	-1.4 units on a scale Standard Deviation 30.19	6.8 units on a scale Standard Deviation 23.59
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 15 (n=43, 43)	6.3 units on a scale Standard Deviation 19.34	8.1 units on a scale Standard Deviation 24.45
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 18 (n=32, 28)	5.7 units on a scale Standard Deviation 21.83	6.5 units on a scale Standard Deviation 22.12
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 21 (n=30, 27)	3.2 units on a scale Standard Deviation 20.00	1.3 units on a scale Standard Deviation 28.50
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 24 (n=25, 26)	3.1 units on a scale Standard Deviation 17.06	2.8 units on a scale Standard Deviation 23.16
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 27 (n=21, 24)	5.9 units on a scale Standard Deviation 18.79	1.1 units on a scale Standard Deviation 20.16
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 30 (n=18, 19)	5.4 units on a scale Standard Deviation 19.87	9.5 units on a scale Standard Deviation 19.68
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 33 (n=15, 15)	2.9 units on a scale Standard Deviation 24.03	13.4 units on a scale Standard Deviation 19.65
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 36 (n=14, 7)	4.8 units on a scale Standard Deviation 17.37	7.3 units on a scale Standard Deviation 21.72
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 39 (n=6, 1)	15.8 units on a scale Standard Deviation 19.85	50.0 units on a scale Standard Deviation NA Standard deviation data was not available because only 1 participant was evaluable at indicated time point.
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 42 (n=2, 0)	-5.0 units on a scale Standard Deviation 14.14	NA units on a scale Standard Deviation NA Data was not available because no participant was evaluable at indicated time point.
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score Change at Cycle 45 (n=1, 0)	5.0 units on a scale Standard Deviation NA Standard deviation data was not available because only 1 participant was evaluable at indicated time point.	NA units on a scale Standard Deviation NA Data was not available because no participant was evaluable at indicated time point.

SECONDARY outcome

Timeframe: Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)

Population: ITT population. Here, 'Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.

FACT-B questionnaire is used for assessment of health-related QoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and breast cancer subscale (9 items) ranging from 0 to 36; high subscale score represents a better QoL. All single-item measures ranges from 0='Not at all' to 4='Very much'. Total possible score ranged from 0 to 144. High scale score represents a better QoL.

Outcome measures

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=100 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=100 Participants Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Baseline (n = 100, 100)	76.7 units on a scale Standard Deviation 13.46	78.5 units on a scale Standard Deviation 16.06
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 3 (n = 82, 90)	-1.96 units on a scale Standard Deviation 10.872	-2.57 units on a scale Standard Deviation 13.159
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 6 (n=70, 79)	-0.97 units on a scale Standard Deviation 12.749	0.47 units on a scale Standard Deviation 13.724
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 9 (n=65, 60)	1.44 units on a scale Standard Deviation 13.189	-0.42 units on a scale Standard Deviation 14.602
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 12 (n=52, 51)	0.40 units on a scale Standard Deviation 12.057	0.51 units on a scale Standard Deviation 14.510
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 15 (n=43, 44)	2.72 units on a scale Standard Deviation 10.989	0.09 units on a scale Standard Deviation 13.713
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 18 (n=32, 32)	4.58 units on a scale Standard Deviation 11.801	0.51 units on a scale Standard Deviation 16.512
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 21 (n=29, 24)	3.22 units on a scale Standard Deviation 13.178	-0.23 units on a scale Standard Deviation 16.116
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 24 (n= 26, 23)	1.19 units on a scale Standard Deviation 10.660	-1.03 units on a scale Standard Deviation 14.546
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 27 (n=20, 22)	4.91 units on a scale Standard Deviation 9.900	0.55 units on a scale Standard Deviation 14.185
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 30 (n=18, 24)	3.96 units on a scale Standard Deviation 11.082	-0.26 units on a scale Standard Deviation 17.381
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 33 (n=14, 17)	5.75 units on a scale Standard Deviation 13.272	1.76 units on a scale Standard Deviation 19.179
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 36 (n=15, 13)	1.26 units on a scale Standard Deviation 9.210	2.74 units on a scale Standard Deviation 14.354
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 39 (n=6, 6)	-3.68 units on a scale Standard Deviation 16.866	7.33 units on a scale Standard Deviation 20.992
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 42 (n=4, 0)	-0.17 units on a scale Standard Deviation 10.599	NA units on a scale Standard Deviation NA Data was not available because no participant was evaluable at indicated time point.
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score Change at Cycle 45 (n=1, 0)	1.00 units on a scale Standard Deviation NA Standard deviation data was not available because only 1 participant was evaluable at indicated time point.	NA units on a scale Standard Deviation NA Data was not available because no participant was evaluable at indicated time point.

Adverse Events

Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion

Serious events: 32 serious events

Other events: 103 other events

Deaths: 0 deaths

Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion

Serious events: 44 serious events

Other events: 106 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 participants at risk Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 participants at risk Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Blood and lymphatic system disorders Febrile neutropenia	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Blood and lymphatic system disorders Leukopenia	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Blood and lymphatic system disorders Neutropenia	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Arrhythmia	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Atrial fibrillation	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Cardiac failure	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Left ventricular dysfunction	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Myocardial infarction	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Supraventricular tachycardia	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Tachycardia	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Abdominal hernia obstructive	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Abdominal pain	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Constipation	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Diarrhoea	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Nausea	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Oesophagitis	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Pancreatitis acute	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Fatigue	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Malaise	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Pyrexia	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Immune system disorders Drug hypersensitivity	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Immune system disorders Hypersensitivity	4.7% 5/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Device related infection	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Erysipelas	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Gastroenteritis	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Implant site infection	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Influenza	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Meningitis	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Nosocomial infection	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Pneumonia	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	3.7% 4/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Sepsis	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Septic shock	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Urinary tract infection	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Injury, poisoning and procedural complications Infusion related reaction	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Injury, poisoning and procedural complications Wound dehiscence	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Blood creatine phosphokinase increased	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Ejection fraction decreased	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastrointestinal stromal tumour	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine tumour	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Paraparesis	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Sensorimotor disorder	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Syncope	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Psychiatric disorders Depression	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Psychiatric disorders Psychotic disorder	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Renal and urinary disorders Acute kidney injury	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Renal and urinary disorders Haematuria	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.00% 0/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Deep vein thrombosis	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Jugular vein thrombosis	0.00% 0/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	0.93% 1/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.

Other adverse events

Measure	Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion n=106 participants at risk Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).	Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion n=107 participants at risk Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
Blood and lymphatic system disorders Anaemia	34.0% 36/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	17.8% 19/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Blood and lymphatic system disorders Leukopenia	22.6% 24/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	15.0% 16/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Blood and lymphatic system disorders Neutropenia	50.9% 54/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	57.0% 61/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Cardiac disorders Tachycardia	2.8% 3/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Eye disorders Cataract	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Eye disorders Lacrimation increased	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Abdominal pain	14.2% 15/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	17.8% 19/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Abdominal pain upper	18.9% 20/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	20.6% 22/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Constipation	33.0% 35/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	32.7% 35/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Diarrhoea	57.5% 61/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	57.9% 62/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Dry mouth	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Dyspepsia	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	14.0% 15/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Haemorrhoids	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	3.7% 4/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Nausea	49.1% 52/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	41.1% 44/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Stomatitis	17.9% 19/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	24.3% 26/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Gastrointestinal disorders Vomiting	32.1% 34/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	23.4% 25/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Asthenia	39.6% 42/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	27.1% 29/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Chest pain	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	9.3% 10/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Chills	28.3% 30/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	13.1% 14/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Extravasation	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Fatigue	34.0% 36/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	38.3% 41/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Influenza like illness	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	8.4% 9/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Mucosal inflammation	15.1% 16/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	24.3% 26/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Oedema peripheral	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	12.1% 13/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Pain	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	11.2% 12/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
General disorders Pyrexia	33.0% 35/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	20.6% 22/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Immune system disorders Hypersensitivity	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	3.7% 4/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Conjunctivitis	7.5% 8/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Cystitis	7.5% 8/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	15.0% 16/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Gastroenteritis	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Influenza	10.4% 11/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	3.7% 4/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Nasopharyngitis	18.9% 20/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	14.0% 15/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Paronychia	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Rhinitis	13.2% 14/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Sinusitis	3.8% 4/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Upper respiratory tract infection	4.7% 5/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	14.0% 15/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Infections and infestations Urinary tract infection	10.4% 11/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	12.1% 13/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Injury, poisoning and procedural complications Radiation skin injury	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Alanine aminotransferase increased	7.5% 8/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	10.3% 11/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Aspartate aminotransferase increased	3.8% 4/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	9.3% 10/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Ejection fraction decreased	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	1.9% 2/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Gamma-glutamyltransferase increased	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	8.4% 9/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Weight decreased	20.8% 22/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	20.6% 22/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Investigations Weight increased	0.94% 1/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Metabolism and nutrition disorders Decreased appetite	21.7% 23/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	22.4% 24/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Metabolism and nutrition disorders Hypocalcaemia	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	4.7% 5/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Metabolism and nutrition disorders Hypokalaemia	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	4.7% 5/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Arthralgia	17.0% 18/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	15.0% 16/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Back pain	17.0% 18/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	25.2% 27/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Bone pain	12.3% 13/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Muscle spasms	19.8% 21/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	26.2% 28/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Myalgia	18.9% 20/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	10.3% 11/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Neck pain	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Musculoskeletal and connective tissue disorders Pain in extremity	13.2% 14/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	27.1% 29/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Dizziness	3.8% 4/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	15.0% 16/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Dysgeusia	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Headache	14.2% 15/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	25.2% 27/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Neuropathy peripheral	10.4% 11/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	21.5% 23/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Paraesthesia	18.9% 20/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	8.4% 9/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Peripheral sensory neuropathy	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	9.3% 10/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Nervous system disorders Polyneuropathy	4.7% 5/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Psychiatric disorders Anxiety	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	9.3% 10/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Psychiatric disorders Depression	9.4% 10/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Psychiatric disorders Insomnia	9.4% 10/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	17.8% 19/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Renal and urinary disorders Dysuria	2.8% 3/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Cough	17.0% 18/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	22.4% 24/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.3% 12/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	24.3% 26/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Epistaxis	13.2% 14/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	19.6% 21/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Nasal dryness	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Nasal inflammation	2.8% 3/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	12.3% 13/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	4.7% 5/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	4.7% 5/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	6.5% 7/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Alopecia	25.5% 27/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	26.2% 28/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Dry skin	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	11.2% 12/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Erythema	8.5% 9/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Nail disorder	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	5.6% 6/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Onychoclasis	1.9% 2/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Pruritus	11.3% 12/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	8.4% 9/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Skin and subcutaneous tissue disorders Rash	23.6% 25/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	11.2% 12/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Hot flush	6.6% 7/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	4.7% 5/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Hypertension	7.5% 8/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	29.0% 31/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Hypotension	5.7% 6/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	2.8% 3/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
Vascular disorders Phlebitis	2.8% 3/106 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.	7.5% 8/107 • Day 1 until 28 days after last study treatment (up to approximately 3.5 years) Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.

Additional Information

Medical Communications

Hoffmann-La Roche

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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