Trial Outcomes & Findings for A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Treatment of Physician's Choice in Subjects With Advanced Non-Small Cell Lung Cancer (NCT NCT01454934)

Last Updated: 2023-06-22

Results Overview

The OS was defined as the time in months from the date of randomization to the date of death, regardless of cause. In the absence of confirmation of death, the participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. The two treatment arms were compared using the log-rank test, stratified by histology, TPC option, and geographic region; and the treatment difference between eribulin mesylate and TPC was tested at a significance level of 0.05 (2-sided). Kaplan-Meier (K-M) survival probabilities for each arm were plotted over time. The treatment effect was estimated by fitting a Cox Proportional Hazards model to the OS times including treatment arm as a factor and histology, TPC option and geographic region as strata.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

540 participants

Primary outcome timeframe

Randomization (Day 1) until date of death from any cause, or 37 months

Results posted on

2023-06-22

Participant Flow

A total of 735 participants were screened. Of these, 195 screen failed due to failure to meet inclusion/exclusion criteria, adverse events, withdrawal of consent, or other reason and were not randomized into the study. A total of 540 participants were randomized into the study. Of these, 3 were discontinued prior to treatment.

Participant milestones

Participant milestones
Measure	Arm A: Eribulin Mesylate Eribulin mesylate (1.4 milligram per square meter \[mg/m\^2\]) was administered intravenously (IV) over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed Treatment of Physician's Choice (TPC): Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Overall Study STARTED	270	270
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	270	270

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Eribulin Mesylate Eribulin mesylate (1.4 milligram per square meter \[mg/m\^2\]) was administered intravenously (IV) over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed Treatment of Physician's Choice (TPC): Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Overall Study Clinical progression	28	25
Overall Study Other	6	17
Overall Study Adverse Event	28	24
Overall Study Withdrawn consent	2	5
Overall Study Withdrawal by Subject	11	15
Overall Study Disease progression	194	181
Overall Study Lost to Follow-up	0	1
Overall Study Not treated	1	2

Baseline Characteristics

A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Treatment of Physician's Choice in Subjects With Advanced Non-Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Eribulin Mesylate n=270 Participants Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=270 Participants TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).	Total n=540 Participants Total of all reporting groups
Age, Continuous	61.4 Years STANDARD_DEVIATION 9.62 • n=5 Participants	60.8 Years STANDARD_DEVIATION 9.32 • n=7 Participants	61.1 Years STANDARD_DEVIATION 9.47 • n=5 Participants
Sex: Female, Male Female	107 Participants n=5 Participants	101 Participants n=7 Participants	208 Participants n=5 Participants
Sex: Female, Male Male	163 Participants n=5 Participants	169 Participants n=7 Participants	332 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization (Day 1) until date of death from any cause, or 37 months

Population: Full analysis set included all randomized participants.

Outcome measures

Outcome measures
Measure	Arm A: Eribulin Mesylate n=270 Participants Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=270 Participants TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Overall Survival (OS)	9.5 months Interval 7.4 to 11.4	9.5 months Interval 8.5 to 11.3

SECONDARY outcome

Timeframe: Randomization (Day 1) until date of disease progression or death (whichever occurred first), or 37 months

Population: Full analysis set included all randomized participants.

PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first. The difference in PFS (based on the tumor response evaluation as determined by the investigator) between eribulin mesylate and TPC was evaluated using the log rank test, stratified by histology, TPC option, and geographic region, tested at an alpha level of 0.05 (2-sided). PFS censoring rules will be defined in the SAP and follow Federal Department of Agriculture (FDA) guidance.

Outcome measures

Outcome measures
Measure	Arm A: Eribulin Mesylate n=270 Participants Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=270 Participants TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST)	3.0 months Interval 2.6 to 3.9	2.8 months Interval 2.6 to 3.6

SECONDARY outcome

Timeframe: Randomization (Day 1) to CR or PR

Population: Full analysis set included all randomized participants.

The ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per RECIST criteria. The ORR was estimated by study arm based on the tumor response evaluation as determined by the investigator, according to RECIST 1.1. Participants with unknown response were treated as non-responders. The statistical difference in ORR between treatment arms was evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with histology, TPC option, and geographic region as strata, tested at an alpha level of 0.05 (2-sided). The 95 percent confidence interval (CI) was calculated using Clopper Pearson method.

Outcome measures

Outcome measures
Measure	Arm A: Eribulin Mesylate n=270 Participants Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=270 Participants TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Objective Response Rate (ORR)	12.2 percentage of participants Interval 8.6 to 16.7	15.2 percentage of participants Interval 11.1 to 20.0

Adverse Events

Arm A: Eribulin Mesylate

Serious events: 96 serious events

Other events: 254 other events

Deaths: 28 deaths

Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed

Serious events: 86 serious events

Other events: 261 other events

Deaths: 21 deaths

Serious adverse events

Other adverse events

Additional Information

Eisai Medical Information

Eisai Inc.

Phone: 1-888-274-2378

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Arm A: Eribulin Mesylate n=269 participants at risk Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=268 participants at risk TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Blood and lymphatic system disorders Anaemia	0.74% 2/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.75% 2/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Febrile neutropenia	1.1% 3/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	2.6% 7/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Leukocytosis	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Leukopenia	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Neutropenia	1.5% 4/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	1.1% 3/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Acute coronary syndrome	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Angina unstable	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Atrial fibrillation	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Cardiac failure	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Coronary artery thrombosis	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Myocardial ischaemia	0.74% 2/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Cardiac disorders Supraventricular tachycardia	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Abdominal pain	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.75% 2/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Constipation	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Diarrhoea	0.74% 2/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Dysphagia	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Gastric ulcer	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Gastritis	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Ileus	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Large intestinal obstruction	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Nausea	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Stomatitis	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Vomiting	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Asthenia	0.74% 2/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	1.1% 3/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Chest pain	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Device failure	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Face oedema	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Fatigue	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	1.1% 3/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders General physical health deterioration	4.8% 13/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	4.5% 12/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Non-cardiac chest pain	0.74% 2/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Pain	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Pyrexia	1.1% 3/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	1.1% 3/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Hepatobiliary disorders Hepatic cirrhosis	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.00% 0/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Immune system disorders Hypersensitivity	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Infections and infestations Bronchitis	0.00% 0/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.75% 2/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Infections and infestations Bronchopneumonia	0.37% 1/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	0.37% 1/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.

Other adverse events
Measure	Arm A: Eribulin Mesylate n=269 participants at risk Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.	Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed n=268 participants at risk TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
Blood and lymphatic system disorders Anaemia	21.9% 59/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	26.9% 72/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Leukopenia	10.0% 27/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	10.4% 28/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Blood and lymphatic system disorders Neutropenia	34.2% 92/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	27.6% 74/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Abdominal Pain	4.8% 13/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.1% 19/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Abdominal Pain Upper	6.3% 17/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	6.3% 17/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Constipation	23.4% 63/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	23.5% 63/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Diarrhoea	14.1% 38/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	16.8% 45/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Nausea	27.1% 73/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	29.1% 78/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Stomatitis	16.0% 43/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	12.7% 34/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Gastrointestinal disorders Vomiting	10.8% 29/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	14.2% 38/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Asthenia	21.9% 59/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	20.9% 56/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Fatigue	24.5% 66/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	23.1% 62/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Malaise	8.2% 22/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	10.8% 29/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Oedema peripheral	14.9% 40/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	11.6% 31/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
General disorders Pyrexia	17.5% 47/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	18.7% 50/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Infections and infestations Upper respiratory tract infection	4.8% 13/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	5.2% 14/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Investigations Alanine aminotransferase increased	7.1% 19/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	8.6% 23/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Investigations Aspartate aminotransferase increased	6.3% 17/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	6.3% 17/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Investigations Neutrophil count decreased	22.3% 60/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	21.6% 58/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Investigations Weight decreased	7.4% 20/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	5.6% 15/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Investigations White blood cell count decreased	20.4% 55/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	21.3% 57/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Metabolism and nutrition disorders Decreased appetite	36.4% 98/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	25.4% 68/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Arthralgia	5.6% 15/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	6.7% 18/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Back pain	8.9% 24/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.8% 21/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Muscle Spasms	5.2% 14/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	2.6% 7/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Muscular Weakness	5.2% 14/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	3.4% 9/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.1% 19/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	9.0% 24/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	8.2% 22/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	5.2% 14/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Myalgia	10.4% 28/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	9.7% 26/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Musculoskeletal and connective tissue disorders Pain in extremity	4.8% 13/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	5.2% 14/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Nervous system disorders Dizziness	5.2% 14/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.1% 19/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Nervous system disorders Dysgeusia	9.3% 25/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	6.0% 16/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Nervous system disorders Headache	13.0% 35/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.8% 21/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Nervous system disorders Paraesthesia	7.8% 21/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	2.2% 6/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Nervous system disorders Peripheral sensory neuropathy	16.4% 44/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	9.0% 24/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Psychiatric disorders Insomnia	5.9% 16/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.5% 20/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Respiratory, thoracic and mediastinal disorders Cough	15.6% 42/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	15.7% 42/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Respiratory, thoracic and mediastinal disorders Dyspnoea	21.2% 57/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	19.4% 52/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Respiratory, thoracic and mediastinal disorders Haemoptysis	7.1% 19/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	7.5% 20/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
Respiratory, thoracic and mediastinal disorders Productive cough	5.9% 16/269 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.	5.2% 14/268 • Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were collected from the first dose of study treatment to thirty days after final dose of study medication. Participants were followed for approximately 37 months. Safety analysis set included all randomized participants who received at least one dose of study treatment. AEs were graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.