Trial Outcomes & Findings for A Study of Atezolizumab Compared With Chemotherapy in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor211] (NCT NCT02302807)

NCT ID: NCT02302807

Last Updated: 2019-08-01

Results Overview

OS was defined as time from randomization to death from any cause.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

931 participants

Primary outcome timeframe

Between randomization and death due to any cause, up to approximately 25 months after first participant enrolled

Results posted on

2019-08-01

Participant Flow

Participant milestones

Participant milestones
Measure	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Overall Study STARTED	464	467
Overall Study Received Treatment	443	459
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	464	467

Reasons for withdrawal

Reasons for withdrawal
Measure	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Overall Study Withdrawal by Subject	28	11
Overall Study Lost to Follow-up	4	6
Overall Study Death	397	385
Overall Study Study Terminated By Sponsor	35	64
Overall Study Physician Decision	0	1

Baseline Characteristics

A Study of Atezolizumab Compared With Chemotherapy in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor211]

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=464 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=467 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.	Total n=931 Participants Total of all reporting groups
Age, Continuous	66.1 Years STANDARD_DEVIATION 9.3 • n=5 Participants	65.9 Years STANDARD_DEVIATION 9.6 • n=7 Participants	66.0 Years STANDARD_DEVIATION 9.4 • n=5 Participants
Sex: Female, Male Female	103 Participants n=5 Participants	110 Participants n=7 Participants	213 Participants n=5 Participants
Sex: Female, Male Male	361 Participants n=5 Participants	357 Participants n=7 Participants	718 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants n=5 Participants	13 Participants n=7 Participants	29 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	368 Participants n=5 Participants	363 Participants n=7 Participants	731 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	80 Participants n=5 Participants	91 Participants n=7 Participants	171 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	55 Participants n=5 Participants	63 Participants n=7 Participants	118 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	336 Participants n=5 Participants	335 Participants n=7 Participants	671 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	70 Participants n=5 Participants	68 Participants n=7 Participants	138 Participants n=5 Participants

PRIMARY outcome

Timeframe: Between randomization and death due to any cause, up to approximately 25 months after first participant enrolled

Population: Intent To Treat (ITT) was defined as all randomized participants, irrespective of whether the assigned treatment was actually received.

OS was defined as time from randomization to death from any cause.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=118 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=116 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=309 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab n=316 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=464 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=467 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Overall Survival (OS)	10.6 Months Interval 8.4 to 12.2	11.1 Months Interval 8.6 to 15.5	8.2 Months Interval 7.4 to 9.5	8.9 Months Interval 8.2 to 10.9	8.0 Months Interval 7.2 to 8.6	8.6 Months Interval 7.8 to 9.6

SECONDARY outcome

Timeframe: Up to approximately 25 months after first participant enrolled

Population: Intent To Treat (ITT) was defined as all randomized participants, irrespective of whether the assigned treatment was actually received.

PFS was defined as the time between the date of randomization and the date of first documented progression of disease (PD) or death, whichever occurred first. PD was determined on the basis of investigator assessment with use of RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters had to demonstrate an absolute increase of \>/= 5 millimeters (mm).

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=464 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=467 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=118 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab n=116 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=309 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=316 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Progression-free Survival (PFS) as Determined by the Investigator With Use of RECIST v1.1	4.0 months Interval 3.4 to 4.2	2.1 months Interval 2.1 to 2.2	4.2 months Interval 3.7 to 5.0	2.4 months Interval 2.1 to 4.2	4.1 months Interval 3.6 to 4.2	2.1 months Interval 2.1 to 2.2

SECONDARY outcome

Timeframe: Up to approximately 25 months after first participant enrolled

Population: DOR analyses was performed on the subset of patients who achieved an objective response.

DOR was defined as the time from first occurrence of a CR or PR, whichever came first, to first documented PD or death, whichever occurred first. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=96 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=71 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=34 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab n=30 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=68 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=51 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Unconfirmed Duration of Response (DOR) as Determined by the Investigator With Use of RECIST v1.1	5.3 months Interval 4.2 to 6.3	21.7 months Interval 9.9 to 21.7	6.4 months Interval 4.2 to 8.3	13.0 months Interval 6.6 to The DOR data was not mature at the time of clinical cutoff (i.e., majority of the responders are still ongoing), so the upper confidence interval was not estimable.	5.5 months Interval 4.2 to 7.4	13 months Interval 6.9 to The DOR data was not mature at the time of clinical cutoff (i.e., majority of the responders are still ongoing), so the upper confidence interval was not estimable.

SECONDARY outcome

Timeframe: Up to approximately 46 months after first participant enrolled

Population: Safety analyses was performed on all randomized patients who received any amount of study treatment, with patients grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=443 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=459 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=112 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab n=114 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=297 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=312 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Percentage of Participants With Adverse Events (AEs)	98.2 percentage	95.0 percentage	98.2 percentage	96.5 percentage	98.7 percentage	96.2 percentage

SECONDARY outcome

Timeframe: Predose (0 hours) on Day 1 of Cycles 1, 2, 3, 4 and every 8 cycles thereafter; at treatment discontinuation (up to 25 months); at 120 days after last dose of atezolizumab (up to 25 months; each cycle is 21 days)

Population: ATA evaluable population is defined as patients who received atezolizumab treatment and had at least one post-treatment ATA result.

Participants were considered post-baseline ATA positive if they had post-baseline ATAs to Atezolizumab that were treatment-induced or treatment-enhanced. Participants had treatment-induced ATAs if they had a baseline-negative ATA result and developed ATAs at any time after initial drug administration. Participants had treatment-enhanced ATAs if they had a baseline-positive ATA result that showed an enhanced signal that was \>/= 0.60 titer units at any time after initial drug initiation.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=427 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=289 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=106 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Percentage of Participants With Post-Baseline Anti-therapeutic Antibodies (ATA) to Atezolizumab	33.3 percentage of participants	35.0 percentage of participants	33.0 percentage of participants	—	—	—

SECONDARY outcome

Population: The PK-evaluable population is defined as patients who received atezolizumab treatment and had at least one measureable PK concentration.

Cmin was measured for all participants that received at least one dose of Atezolizumab.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=467 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 24, day 1	190 mcg/mL Standard Deviation 98.7	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 32, day 1	223 mcg/mL Standard Deviation 87.4	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 2, day 1	67.5 mcg/mL Standard Deviation 29.1	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 3, day 1	95.1 mcg/mL Standard Deviation 46.5	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 4, day 1	122 mcg/mL Standard Deviation 56.9	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 8, day 1	159 mcg/mL Standard Deviation 72.4	—	—	—	—	—
Minimum Observed Serum Atezolizumab Concentration (Cmin) Cycle 16, day 1	190 mcg/mL Standard Deviation 94.7	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 25 months after first participant enrolled

Population: ORR analyses was performed on all randomized patients who had measureable disease at baseline

ORR was defined as the percentage of participants, who had an objective response. Objective response was defined as either a complete response (CR) or partial response (PR) as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Objective response in this study did not need to be a confirmed response. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. ORR=CR+PR

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=461 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=462 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy n=116 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab n=113 Participants PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=306 Participants Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=312 Participants Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Percentage of Participants With Unconfirmed Objective Response Rate (ORR) as Determined by the Investigator With Use of Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)	20.8 Percentage of participants Interval 17.21 to 24.82	15.4 Percentage of participants Interval 12.2 to 18.99	29.3 Percentage of participants Interval 21.23 to 38.48	26.5 Percentage of participants Interval 18.68 to 35.68	22.2 Percentage of participants Interval 17.69 to 27.3	16.3 Percentage of participants Interval 12.42 to 20.93

SECONDARY outcome

Timeframe: 30 minutes post dose on Day 1 of Cycles 1

Population: The PK-evaluable population is defined as patients who received atezolizumab treatment and had at least one measureable PK concentration.

Cmax was measured for all participants that received at least one dose of Atezolizumab.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=467 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Maximum Observed Serum Atezolizumab Concentration (Cmax)	334 mcg/mL Standard Deviation 125	—	—	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)

Population: All randomized patients with non-missing baseline assessment and at least one non-missing post-baseline assessment.

The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=381 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=408 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Baseline (Cycle 1, Day 1)	61.49 units of a scale Standard Deviation 22.30	64.19 units of a scale Standard Deviation 21.72	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 2, Day 1	-5.47 units of a scale Standard Deviation 20.02	-6.18 units of a scale Standard Deviation 20.07	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 3, Day 1	-3.76 units of a scale Standard Deviation 22.34	-4.67 units of a scale Standard Deviation 20.89	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 4, Day 1	-1.48 units of a scale Standard Deviation 19.71	-0.53 units of a scale Standard Deviation 20.23	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 12, Day 1	-3.95 units of a scale Standard Deviation 24.33	-0.56 units of a scale Standard Deviation 22.31	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 20, Day 1	-2.27 units of a scale Standard Deviation 16.28	1.10 units of a scale Standard Deviation 21.88	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline: Cycle 28, Day 1	-11.67 units of a scale Standard Deviation 7.45	-5.26 units of a scale Standard Deviation 33.82	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale Change from baseline:Treatment Discont. Visit	-10.77 units of a scale Standard Deviation 24.15	-16.71 units of a scale Standard Deviation 24.39	—	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)

Population: All randomized patients with non-missing baseline assessment and at least one non-missing post-baseline assessment.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=381 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=408 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Baseline (Cycle 1, Day 1)	74.23 units of a scale Standard Deviation 22.55	76.37 units of a scale Standard Deviation 19.66	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Treatment Discont. Visit	-15.58 units of a scale Standard Deviation 25.67	-20.19 units of a scale Standard Deviation 25.52	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 28, Day 1	-18.67 units of a scale Standard Deviation 24.68	3.51 units of a scale Standard Deviation 20.53	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 2, Day 1	-4.80 units of a scale Standard Deviation 15.70	-7.56 units of a scale Standard Deviation 18.24	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 3, Day 1	-5.64 units of a scale Standard Deviation 17.37	-7.06 units of a scale Standard Deviation 19.62	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 4, Day 1	-4.41 units of a scale Standard Deviation 16.25	-3.81 units of a scale Standard Deviation 17.49	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 12, Day 1	-6.97 units of a scale Standard Deviation 20.20	0.89 units of a scale Standard Deviation 16.23	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale Change from baseline: Cycle 20, Day 1	-3.03 units of a scale Standard Deviation 11.30	3.48 units of a scale Standard Deviation 13.56	—	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)

Population: All randomized patients with non-missing baseline assessment and at least one non-missing post-baseline assessment.

Outcome measures

Outcome measures
Measure	IC2/3 Chemotherapy n=381 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC2/3 Atezolizumab n=408 Participants PD-L1 immunohistochemistry (IHC) score of IC2/3	IC1/2/3 Chemotherapy PD-L1 immunohistochemistry (IHC) score of IC1/2/3	IC1/2/3 Atezolizumab PD-L1 immunohistochemistry (IHC) score of IC1/2/3	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Participants randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigators choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 were administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Fatigue Symptom: Baseline (Cycle 1, Day 1)	34.67 units of a scale Standard Deviation 26.66	32.87 units of a scale Standard Deviation 23.88	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Fatigue Symptom: Cycle 2, Day 1	10.71 units of a scale Standard Deviation 23.13	10.56 units of a scale Standard Deviation 21.82	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Cycle 3, Day 1	11.04 units of a scale Standard Deviation 25.48	9.41 units of a scale Standard Deviation 24.80	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Cycle 4, Day 1	7.48 units of a scale Standard Deviation 22.63	3.67 units of a scale Standard Deviation 23.57	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Cycle 12, Day 1	5.70 units of a scale Standard Deviation 27.44	-0.95 units of a scale Standard Deviation 23.27	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Cycle 20, Day 1	11.11 units of a scale Standard Deviation 28.97	-8.05 units of a scale Standard Deviation 21.97	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Cycle 28, Day 1	15.56 units of a scale Standard Deviation 16.85	-12.28 units of a scale Standard Deviation 28.42	—	—	—	—
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale Change from baseline: Treatment Discont. Visit	17.27 units of a scale Standard Deviation 28.15	19.60 units of a scale Standard Deviation 25.95	—	—	—	—

Adverse Events

Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)

Serious events: 189 serious events

Other events: 417 other events

Deaths: 393 deaths

Atezolizumab

Serious events: 192 serious events

Other events: 413 other events

Deaths: 379 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) n=443 participants at risk Participants randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 will be administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.	Atezolizumab n=459 participants at risk Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
Blood and lymphatic system disorders Anaemia	28.0% 124/443 • Number of events 142 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	19.6% 90/459 • Number of events 94 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Blood and lymphatic system disorders Neutropenia	12.9% 57/443 • Number of events 75 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	1.1% 5/459 • Number of events 6 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Abdominal Pain	13.1% 58/443 • Number of events 63 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	11.3% 52/459 • Number of events 60 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Abdominal Pain Upper	6.1% 27/443 • Number of events 32 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.0% 23/459 • Number of events 23 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Constipation	36.8% 163/443 • Number of events 221 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	28.5% 131/459 • Number of events 147 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Diarrhoea	21.2% 94/443 • Number of events 115 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	21.1% 97/459 • Number of events 145 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Dry Mouth	1.8% 8/443 • Number of events 8 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	6.5% 30/459 • Number of events 36 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Nausea	30.9% 137/443 • Number of events 171 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	23.1% 106/459 • Number of events 124 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Stomatitis	7.9% 35/443 • Number of events 41 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	2.8% 13/459 • Number of events 16 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Gastrointestinal disorders Vomiting	18.3% 81/443 • Number of events 108 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	12.0% 55/459 • Number of events 67 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Asthenia	24.2% 107/443 • Number of events 144 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	20.0% 92/459 • Number of events 108 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Fatigue	30.7% 136/443 • Number of events 162 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	28.1% 129/459 • Number of events 153 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Mucosal Inflammation	10.6% 47/443 • Number of events 64 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.9% 27/459 • Number of events 30 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Oedema Peripheral	8.1% 36/443 • Number of events 43 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	11.3% 52/459 • Number of events 59 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Pain	7.0% 31/443 • Number of events 34 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.2% 24/459 • Number of events 24 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
General disorders Pyrexia	14.0% 62/443 • Number of events 76 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	20.3% 93/459 • Number of events 128 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Infections and infestations Nasopharyngitis	2.5% 11/443 • Number of events 15 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.9% 27/459 • Number of events 43 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Infections and infestations Urinary Tract Infection	13.1% 58/443 • Number of events 76 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	18.3% 84/459 • Number of events 141 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Investigations Blood Creatinine Increased	2.5% 11/443 • Number of events 12 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	7.8% 36/459 • Number of events 38 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Investigations Neutrophil Count Decreased	5.9% 26/443 • Number of events 49 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	0.00% 0/459 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Investigations Weight Decreased	10.2% 45/443 • Number of events 46 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	10.2% 47/459 • Number of events 47 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Metabolism and nutrition disorders Decreased Appetite	25.5% 113/443 • Number of events 136 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	29.4% 135/459 • Number of events 147 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Metabolism and nutrition disorders Hypokalaemia	5.2% 23/443 • Number of events 26 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	3.5% 16/459 • Number of events 17 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Musculoskeletal and connective tissue disorders Arthralgia	13.5% 60/443 • Number of events 79 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	10.2% 47/459 • Number of events 66 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Musculoskeletal and connective tissue disorders Back Pain	11.5% 51/443 • Number of events 53 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	17.4% 80/459 • Number of events 95 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Musculoskeletal and connective tissue disorders Bone Pain	5.4% 24/443 • Number of events 28 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.2% 24/459 • Number of events 27 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Musculoskeletal and connective tissue disorders Myalgia	12.4% 55/443 • Number of events 68 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.4% 25/459 • Number of events 27 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Musculoskeletal and connective tissue disorders Pain in Extremity	10.8% 48/443 • Number of events 55 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	8.1% 37/459 • Number of events 46 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Dizziness	6.8% 30/443 • Number of events 32 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	6.3% 29/459 • Number of events 29 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Dysgeusia	5.6% 25/443 • Number of events 27 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	2.6% 12/459 • Number of events 14 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Headache	5.9% 26/443 • Number of events 35 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	8.3% 38/459 • Number of events 44 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Neuropathy Peripheral	12.4% 55/443 • Number of events 67 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	1.7% 8/459 • Number of events 9 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Paraesthesia	6.5% 29/443 • Number of events 32 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	3.9% 18/459 • Number of events 18 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Nervous system disorders Peripheral Sensory Neuropathy	9.3% 41/443 • Number of events 43 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	1.3% 6/459 • Number of events 7 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Psychiatric disorders Anxiety	5.4% 24/443 • Number of events 24 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.9% 27/459 • Number of events 27 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Psychiatric disorders Insomnia	9.5% 42/443 • Number of events 42 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	9.8% 45/459 • Number of events 48 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Renal and urinary disorders Haematuria	5.9% 26/443 • Number of events 32 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	9.8% 45/459 • Number of events 60 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Respiratory, thoracic and mediastinal disorders Cough	6.8% 30/443 • Number of events 36 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	12.9% 59/459 • Number of events 69 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.4% 46/443 • Number of events 50 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	13.5% 62/459 • Number of events 70 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Skin and subcutaneous tissue disorders Alopecia	28.2% 125/443 • Number of events 127 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	0.22% 1/459 • Number of events 1 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Skin and subcutaneous tissue disorders Pruritus	4.3% 19/443 • Number of events 27 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	13.9% 64/459 • Number of events 86 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Skin and subcutaneous tissue disorders Rash	6.3% 28/443 • Number of events 37 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	11.8% 54/459 • Number of events 72 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)
Vascular disorders Hypertension	4.5% 20/443 • Number of events 22 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)	5.0% 23/459 • Number of events 24 • From the first study drug to the data cutoff date: 8 Nov 2018 (up to 46 months)