Trial Outcomes & Findings for Study of Rovalpituzumab Tesirine (SC16LD6.5) for Third-Line and Later Treatment of Subjects With Relapsed or Refractory Delta-Like Protein 3-Expressing Small Cell Lung Cancer (NCT NCT02674568)

NCT ID: NCT02674568

Last Updated: 2021-07-30

Results Overview

Objective response is defined as a participant with the best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, prior to receiving any subsequent anticancer therapy and retreatment, and is confirmed by a consecutive response assessment at least 4 weeks (28 days) from the initial determination of CR/PR. Analyzed based on response assessments from both the Independent Review Committee (IRC) and investigators. CR: disappearance of all target lesions.Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 342 participants
• Primary outcome timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks
• Results posted on: 2021-07-30

Participant Flow

A total of 342 participants were enrolled; 3 participants were not dosed.

Participant milestones

Measure	Rovalpituzumab Tesirine 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (every 6 weeks; Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.
Overall Study STARTED	339
Overall Study Delta-like Protein 3 (DLL3) High	238
Overall Study DLL3 Positive	287
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	339

Reasons for withdrawal

Measure	Rovalpituzumab Tesirine 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (every 6 weeks; Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.
Overall Study Withdrawal by Subject	5
Overall Study Death	303
Overall Study Physician Decision	2
Overall Study Lost to Follow-up	9
Overall Study Other, Not Specified	20

Baseline Characteristics

Study of Rovalpituzumab Tesirine (SC16LD6.5) for Third-Line and Later Treatment of Subjects With Relapsed or Refractory Delta-Like Protein 3-Expressing Small Cell Lung Cancer

Baseline characteristics by cohort

Measure	Rovalpituzumab Tesirine n=339 Participants 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.
Age, Continuous	61.9 years STANDARD_DEVIATION 9.36 • n=5 Participants
Sex: Female, Male Female	169 Participants n=5 Participants
Sex: Female, Male Male	170 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	272 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	57 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	11 Participants n=5 Participants
Race (NIH/OMB) White	265 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	56 Participants n=5 Participants

PRIMARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug.

Objective response is defined as a participant with the best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, prior to receiving any subsequent anticancer therapy and retreatment, and is confirmed by a consecutive response assessment at least 4 weeks (28 days) from the initial determination of CR/PR. Analyzed based on response assessments from both the Independent Review Committee (IRC) and investigators.

CR: disappearance of all target lesions.Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=238 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=287 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Objective Response Rate IRC	15.5 percentage of participants Interval 11.2 to 20.8	14.6 percentage of participants Interval 10.8 to 19.3	—
Objective Response Rate Investigator	19.3 percentage of participants Interval 14.5 to 24.9	18.8 percentage of participants Interval 14.5 to 23.8	—

PRIMARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug.

Overall survival is defined as the time from the first dose date to death for any reason. Participants who were alive at the clinical data cut-off were censored at the last known alive date. Based on Kaplan-Meier estimates.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=238 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=287 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Overall Survival	5.3 months Interval 4.7 to 5.8	5.3 months Interval 4.7 to 5.8	—

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug.

Overall response rate is defined as the percentage of participants with a response of CR or PR, regardless of confirmation, per RECIST v 1.1 prior to receiving any subsequent anticancer therapy and retreatment. Any participants not exhibiting a response (CR or PR) as defined above were considered non-responders. Analyzed based on response assessments from both the IRC and investigators.

CR: disappearance of all target lesions.Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=238 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=287 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Overall Response Rate IRC	23.1 percentage of participants Interval 17.9 to 29.0	22.0 percentage of participants Interval 17.3 to 27.2	—
Overall Response Rate Investigator	26.9 percentage of participants Interval 21.4 to 33.0	25.8 percentage of participants Interval 20.8 to 31.3	—

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug and had an objective response.

Duration of objective response is defined as the time from the date of first documented CR or PR of participants with a confirmed response to the documented date of progressive disease (PD) or death, whichever occurred first. Participants who neither progressed nor died are censored at the last evaluable disease assessment. Analyzed based on response assessments from both the IRC and investigators. Based on Kaplan-Meier estimates.

CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression.)

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=46 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=54 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Duration of Objective Response IRC	4.0 months Interval 3.0 to 4.2	4.1 months Interval 3.0 to 4.2	—
Duration of Objective Response Investigator	4.0 months Interval 2.9 to 4.2	4.0 months Interval 2.9 to 4.3	—

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug.

Progression-free survival is defined as the time from the first dose date to the documented date of PD or death, whichever occurred first. Participants who neither progressed nor died were censored at the last evaluable disease assessment. Analyzed based on response assessments from both the IRC and investigators. Based on Kaplan-Meier estimates.

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression.)

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=238 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=287 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Progression-Free Survival IRC	3.8 months Interval 3.3 to 4.1	3.8 months Interval 3.3 to 4.0	—
Progression-Free Survival Investigator	3.9 months Interval 3.3 to 4.1	3.9 months Interval 3.3 to 4.0	—

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug.

Clinical benefit rate is defined as the percentage of participants with an overall response of CR or PR or stable disease (SD) with SD of a minimum duration of 42 days from the first dose date. Analyzed based on response assessments from both the IRC and investigators.

CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression.)

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=238 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=287 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Clinical Benefit Rate IRC	73.9 percentage of participants Interval 67.9 to 79.4	72.1 percentage of participants Interval 66.6 to 77.2	—
Clinical Benefit Rate Investigator	71.0 percentage of participants Interval 64.8 to 76.7	68.6 percentage of participants Interval 62.9 to 74.0	—

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: Modified Intent to Treat Population: all participants who received any amount of study drug with best overall response of CR or PR or SD.

Duration of clinical benefit is defined as time from the date of first documented CR or PR or SD of ≥ 42 days from first dose date (-7 days to allow for scheduled visit window per the protocol) to the documented date PD or death, whichever occurs first. Analyzed based on response assessments from both the IRC and investigators.

CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=176 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=207 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Duration of Clinical Benefit IRC	2.9 months Interval 2.8 to 3.2	2.9 months Interval 2.8 to 3.0	—
Duration of Clinical Benefit Investigator	3.0 months Interval 2.9 to 3.3	3.0 months Interval 2.9 to 3.2	—

SECONDARY outcome

Timeframe: Cycle 1: Day 1, 30 minutes pre-infusion; Day 1, 30 minutes post-infusion; Day 3; Day 15; Day 29. Cycle 2: Day 1, 30 minutes pre-infusion; Day 1, 30 minutes post-infusion; Day 3; Day 15; Day 29; End of Treatment (up to Day 29).

Population: Pharmacokinetic Analysis Population: all participants who receive at least 1 dose of study treatment and at least 1 post-baseline blood sample following a dose of study treatment and had an assessment at given time point.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=329 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive n=20 Participants 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 n=2 Participants 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 1: Day 1, 30 minutes pre-infusion	180.9 ng/mL Standard Deviation 1215.03	236.6 ng/mL Standard Deviation 923.44	148.2 ng/mL Standard Deviation 81.81
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 1: Day 1, 30 minutes post-infusion	7611.6 ng/mL Standard Deviation 1980.49	6365.5 ng/mL Standard Deviation 1763.08	6690.0 ng/mL Standard Deviation 2050.61
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 1: Day 3	4535.2 ng/mL Standard Deviation 1398.49	3740.5 ng/mL Standard Deviation 1454.87	4630.0 ng/mL Standard Deviation 1866.76
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 1: Day 15	1472.8 ng/mL Standard Deviation 573.90	1323.3 ng/mL Standard Deviation 504.33	1390.0 ng/mL Standard Deviation 381.84
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 1: Day 29	816.3 ng/mL Standard Deviation 379.15	793.8 ng/mL Standard Deviation 322.90	956.5 ng/mL Standard Deviation 61.52
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 2: Day 1, 30 minutes pre-infusion	532.2 ng/mL Standard Deviation 592.90	518.6 ng/mL Standard Deviation 226.45	601.0 ng/mL Standard Deviation NA 1 participant was analyzed.
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 2: Day 1, 30 minutes post-infusion	7535.6 ng/mL Standard Deviation 1928.74	6602.7 ng/mL Standard Deviation 1508.23	7880.0 ng/mL Standard Deviation NA 1 participant was analyzed.
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 2: Day 3	4791.1 ng/mL Standard Deviation 1373.70	4670.8 ng/mL Standard Deviation 1539.65	3840.0 ng/mL Standard Deviation NA 1 participant was analyzed.
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 2: Day 15	1845.5 ng/mL Standard Deviation 688.47	1857.7 ng/mL Standard Deviation 599.65	2030.0 ng/mL Standard Deviation NA 1 participant was analyzed.
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit Cycle 2: Day 29	1029.3 ng/mL Standard Deviation 362.28	1077.7 ng/mL Standard Deviation 362.33	1300.0 ng/mL Standard Deviation NA 1 participant was analyzed.
Rovalpituzumab Tesirine Antibody-Drug Conjugate Plasma Concentrations by Study Visit End of Treatment	558.5 ng/mL Standard Deviation 296.09	686.9 ng/mL Standard Deviation 354.68	679.5 ng/mL Standard Deviation 64.35

SECONDARY outcome

Timeframe: up to 122.4 weeks; mean (SD) duration of follow-up was 29.0 (23.77) weeks

Population: All participants who received rovalpituzumab tesirine and had at least one sample screened for ATA against rovalpituzumab tesirine antibody-drug conjugate concentration.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=336 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Number of Anti-Therapeutic Antibody (ATA) Positive Participants Positive After First Dose of Study Drug	3 Participants	—	—
Number of Anti-Therapeutic Antibody (ATA) Positive Participants Positive at Any Study Visit	11 Participants	—	—

SECONDARY outcome

Timeframe: From first dose of study drug through the end of the initial treatment period (84 ± 6 days)

Population: Safety analysis population: all participants who received any amount of study drug.

An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: is fatal or life-threatening; results in death or hospitalization; is disabling/incapacitating or a congenital anomaly/birth defect; is medically significant. AE severity was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 terminology: grade 1=mild; grade 2=moderate; grade 3=severe; grade 4 life-threatening; grade 5=death. TEAEs were defined as AEs that were newly occurring or worsened following study treatment.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=339 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment TEAE Leading to Drug WIthdrawal	25 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment TEAE Leading to Dose Interruption	33 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment TEAE Leading to Dose Reduction	32 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment TEAE Reasonably Possibly Related to Study Drug	308 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment Fatal AE	34 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment Any TEAE	335 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment Treatment Emergent SAE	171 Participants	—	—
Number of Participants With Treatment-Related Adverse Events (TEAEs) During Initial Treatment TEAE Maximum Severity Grade 3/4	179 Participants	—	—

SECONDARY outcome

Timeframe: From first dose of study drug through the end of the initial treatment period (84 ± 6 days)

Population: Safety analysis population: all participants who received any amount of study drug.

TEAEs were defined as AEs that were newly occurring or worsened following study treatment.

Outcome measures

Measure	Rovalpituzumab Tesirine: DLL3 High n=339 Participants 'DLL3 High' (tumors with ≥75% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: DLL3 Positive 'DLL3 Positive' (tumors with ≥25% of cells expressing DLL3) participants received 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.	Rovalpituzumab Tesirine: Re-Treatment 2 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of retreatment Cycle 2
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Any TEAE	335 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Fatigue	129 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Photosensitivity Reaction	123 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Pleural effusion	113 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Oedema peripheral	105 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Decreased appetite	102 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Nausea	88 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Dyspnoea	83 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Thrombocytopenia	83 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Constipation	75 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Vomiting	59 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Anaemia	58 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Cough	54 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Hypoalbuminaemia	52 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Pericardial effusion	50 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Abdominal pain	50 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Asthenia	50 Participants	—	—
Number of Participants With TEAEs Occurring in at Least 10% of All Participants During Initial Treatment Diarrhoea	47 Participants	—	—

Adverse Events

Rovalpituzumab Tesirine

Serious events: 178 serious events

Other events: 322 other events

Deaths: 303 deaths

Serious adverse events

Measure	Rovalpituzumab Tesirine n=339 participants at risk 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.59% 2/339 • Number of events 5 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Blood and lymphatic system disorders Anaemia	2.1% 7/339 • Number of events 7 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Blood and lymphatic system disorders Febrile neutropenia	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Blood and lymphatic system disorders Thrombocytopenia	3.2% 11/339 • Number of events 13 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Atrial fibrillation	1.8% 6/339 • Number of events 6 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Cardiac arrest	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Cardiac failure congestive	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Cardiac tamponade	1.2% 4/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Cardiopulmonary failure	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Pericardial effusion	4.1% 14/339 • Number of events 19 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Sinus bradycardia	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Abdominal pain	2.7% 9/339 • Number of events 10 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Ascites	1.2% 4/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Colitis	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Constipation	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Diarrhoea	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Intestinal ischaemia	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Intestinal obstruction	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Nausea	2.1% 7/339 • Number of events 8 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Pancreatitis	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Small intestinal obstruction	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Vomiting	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Asthenia	1.2% 4/339 • Number of events 6 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Fatigue	1.5% 5/339 • Number of events 5 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Gait disturbance	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders General physical health deterioration	2.4% 8/339 • Number of events 14 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Generalised oedema	2.4% 8/339 • Number of events 10 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Oedema peripheral	2.4% 8/339 • Number of events 10 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Pain	0.88% 3/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Pyrexia	0.88% 3/339 • Number of events 3 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Cholangitis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Drug-induced liver injury	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Hepatic pain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Hepatocellular injury	0.88% 3/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Hepatotoxicity	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Hepatobiliary disorders Hyperbilirubinaemia	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Bacterial infection	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Bronchitis	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Cellulitis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Cerebral toxoplasmosis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Clostridium difficile colitis	0.59% 2/339 • Number of events 3 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Device related infection	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Diverticulitis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Infection	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Infective exacerbation of chronic obstructive airways disease	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Lung infection	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Oesophageal candidiasis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Pneumonia	3.5% 12/339 • Number of events 16 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Pulmonary sepsis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Respiratory tract infection	0.88% 3/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Sepsis	1.8% 6/339 • Number of events 8 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Septic shock	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Urinary tract infection	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Fall	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Femur fracture	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Head injury	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Humerus fracture	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Ligament sprain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Pneumonitis chemical	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Injury, poisoning and procedural complications Tracheal haemorrhage	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Alanine aminotransferase increased	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Blood uric acid increased	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Ejection fraction decreased	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Liver function test increased	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Platelet count decreased	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Decreased appetite	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Dehydration	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Diabetes mellitus	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Hypoalbuminaemia	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Hypokalaemia	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Hyponatraemia	1.8% 6/339 • Number of events 6 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Back pain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Flank pain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Myalgia	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Spinal pain	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to pancreas	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Nervous system disorders Hemiparesis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Nervous system disorders Seizure	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Nervous system disorders Spinal cord compression	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Product Issues Device occlusion	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Psychiatric disorders Confusional state	1.5% 5/339 • Number of events 5 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Psychiatric disorders Delirium	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Psychiatric disorders Disorientation	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Psychiatric disorders Mental status changes	1.2% 4/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Renal and urinary disorders Acute kidney injury	0.88% 3/339 • Number of events 3 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Renal and urinary disorders Haematuria	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Renal and urinary disorders Renal failure	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Renal and urinary disorders Renal impairment	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.2% 4/339 • Number of events 4 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Haemothorax	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Obstructive airways disorder	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pleural effusion	14.5% 49/339 • Number of events 62 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.88% 3/339 • Number of events 3 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.29% 1/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.1% 7/339 • Number of events 11 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Tracheal stenosis	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Dermatitis exfoliative	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Erythema	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Photosensitivity reaction	1.8% 6/339 • Number of events 7 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Capillary leak syndrome	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Deep vein thrombosis	0.59% 2/339 • Number of events 2 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Haemorrhage	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Hypertension	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Hypotension	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Intermittent claudication	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Orthostatic hypotension	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Peripheral ischaemia	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Superior vena cava syndrome	0.88% 3/339 • Number of events 3 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Venous thrombosis limb	0.29% 1/339 • Number of events 1 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.

Other adverse events

Measure	Rovalpituzumab Tesirine n=339 participants at risk 0.3 mg/kg rovalpituzumab tesirine administered intravenously on Day 1 of each 42-day cycle (Q6W) for 2 cycles. An additional 2 cycles of rovalpituzumab tesirine (retreatment) was permitted for eligible participants.
Blood and lymphatic system disorders Anaemia	15.9% 54/339 • Number of events 88 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Blood and lymphatic system disorders Thrombocytopenia	21.5% 73/339 • Number of events 140 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Cardiac disorders Pericardial effusion	11.2% 38/339 • Number of events 40 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Abdominal distension	5.9% 20/339 • Number of events 21 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Abdominal pain	12.4% 42/339 • Number of events 59 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Constipation	21.8% 74/339 • Number of events 87 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Diarrhoea	13.6% 46/339 • Number of events 50 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Nausea	24.2% 82/339 • Number of events 101 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Gastrointestinal disorders Vomiting	17.7% 60/339 • Number of events 75 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Asthenia	14.2% 48/339 • Number of events 81 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Face oedema	9.4% 32/339 • Number of events 32 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Fatigue	36.9% 125/339 • Number of events 170 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Non-cardiac chest pain	5.6% 19/339 • Number of events 21 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
General disorders Oedema peripheral	29.8% 101/339 • Number of events 136 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Infections and infestations Urinary tract infection	8.0% 27/339 • Number of events 32 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Alanine aminotransferase increased	5.9% 20/339 • Number of events 33 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Aspartate aminotransferase increased	5.9% 20/339 • Number of events 27 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Investigations Weight decreased	9.4% 32/339 • Number of events 36 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Decreased appetite	30.7% 104/339 • Number of events 124 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Dehydration	5.6% 19/339 • Number of events 22 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Hypoalbuminaemia	15.9% 54/339 • Number of events 70 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Metabolism and nutrition disorders Hypokalaemia	5.6% 19/339 • Number of events 23 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Back pain	8.8% 30/339 • Number of events 36 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Musculoskeletal and connective tissue disorders Myalgia	6.5% 22/339 • Number of events 27 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Nervous system disorders Dizziness	9.7% 33/339 • Number of events 37 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Nervous system disorders Headache	5.3% 18/339 • Number of events 18 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Psychiatric disorders Insomnia	7.7% 26/339 • Number of events 26 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Cough	16.5% 56/339 • Number of events 67 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea	24.5% 83/339 • Number of events 107 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Respiratory, thoracic and mediastinal disorders Pleural effusion	20.4% 69/339 • Number of events 84 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Dry skin	7.4% 25/339 • Number of events 28 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Erythema	8.8% 30/339 • Number of events 37 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Photosensitivity reaction	35.1% 119/339 • Number of events 199 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Skin and subcutaneous tissue disorders Rash	7.7% 26/339 • Number of events 30 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.
Vascular disorders Hypotension	5.6% 19/339 • Number of events 21 • From first dose of study drug through the end of treatment (EOT; 42 ± 3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever was later) or 30 days after last study treatment, whichever was later. Mean (SD) duration of follow-up (ie, from the first dose date to the last known date alive or death date) was 29.0 (23.77) weeks.

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