Trial Outcomes & Findings for Xentuzumab (BI 836845) Plus Afatinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC) (NCT NCT02191891)

NCT ID: NCT02191891

Last Updated: 2025-06-25

Results Overview

DLT Criteria: Common Terminology Criteria for Adverse Events(CTCAE) CTCAE Grade (G) 4 neutropenia lasting ≥7 days; Febrile neutropenia with a single/sustained temperature of ≥38.3°C for \>1 hour; Documented infection with absolute neutrophil count (ANC) \<1.0 x 109/L; G 3/4 thrombocytopenia associated with bleeding requiring platelet transfusion; G 2/higher decrease in cardiac left ventricular function; G 2 diarrhea lasting for ≥7 days; G ≥3 diarrhea; G≥3 nausea/vomiting; G≥3 skin rash; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>5 x Upper limit of normal (ULN)/\>baseline value +4 x ULN; G≥3 fatigue/asthenia lasting for \>7 days; G≥3 hyperglycemia lasting \>48 hours; All other non-hematologic adverse events(AEs) of G≥3 (except alopecia, infusion reaction, and allergic reaction) that led to an interruption of afatinib/xentuzumab for \>14 days until recovery to baseline/G 1; Any other study drug-related toxicity considered significant enough to qualify as DLT.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

32 participants

Primary outcome timeframe

During the first treatment course, up to 28 days.

Results posted on

2025-06-25

Participant Flow

Patients with epidermal growth factor receptor (EGFR) mutant lung cancer were recruited in this multi-centre, open-label, phase Ib clinical trial. The trial consisted of a dose confirmation part (Part A) and an expansion cohort (Part B), where Part A and Part B were conducted sequentially.

All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (all patients) met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.

Participant milestones

Participant milestones
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 20 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 30 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 40 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Overall Study STARTED	4	12	4	2	10
Overall Study COMPLETED	0	0	0	0	0
Overall Study NOT COMPLETED	4	12	4	2	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 20 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 30 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 40 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Overall Study Withdrawal by Subject	0	1	0	0	1
Overall Study Adverse Event	0	1	0	0	2
Overall Study Disease Progression	4	10	4	2	7

Baseline Characteristics

Xentuzumab (BI 836845) Plus Afatinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A n=4 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A n=12 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 20 mg - Part B n=4 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 30 mg - Part B n=2 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B).	Xentuzumab + Afatinib 40 mg - Part B n=10 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).	Total n=32 Participants Total of all reporting groups
Age, Continuous	61.75 Years STANDARD_DEVIATION 9.11 • n=5 Participants	59.08 Years STANDARD_DEVIATION 10.16 • n=7 Participants	57.75 Years STANDARD_DEVIATION 9.5 • n=5 Participants	68.00 Years STANDARD_DEVIATION 2.83 • n=4 Participants	56.60 Years STANDARD_DEVIATION 9.94 • n=21 Participants	59.03 Years STANDARD_DEVIATION 9.52 • n=10 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	8 Participants n=21 Participants	17 Participants n=10 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	7 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants	15 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	12 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	10 Participants n=21 Participants	32 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	12 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	10 Participants n=21 Participants	32 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants

PRIMARY outcome

Timeframe: During the first treatment course, up to 28 days.

Population: Maximum Tolerated Dose (MTD) Set (MS): this patient set defined the set of patients in Part A who were fully evaluable for determination of the MTD in the first treatment course.

Outcome measures

Outcome measures
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A n=3 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A n=12 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Number of Patients With Dose Limiting Toxicities (DLT) - Part A	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: During the first treatment course, up to 28 days.

Population: Maximum Tolerated Dose (MTD) Set (MS): this patient set defined the set of patients in Part A who were fully evaluable for determination of the MTD in the first treatment course.

Maximum tolerated dose (MTD) of Xentuzumab in combination with Afatinib, in patients with non-small cell lung cancer with progression following prior treatment, based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. MTD was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period.

Outcome measures

Outcome measures
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A n=15 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Maximum Tolerated Dose (MTD) - Part A	40 Milligrams (mg)	—	—

PRIMARY outcome

Timeframe: Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.

Population: Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1).

OR was defined as best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.

Outcome measures

Outcome measures
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A n=4 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A n=2 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part B n=10 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Number of Participants With Objective Response (OR) - Part B	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Population: Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1).

DC was defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.

Outcome measures

Outcome measures
Measure	Xentuzumab + Afatinib 30 Milligram (mg) - Part A n=4 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part A n=2 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Xentuzumab + Afatinib 40 mg - Part B n=10 Participants Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).
Number of Participants With Disease Control (DC) - Part B	2 Participants	2 Participants	6 Participants

SECONDARY outcome

Population: TS - Patients with objective response (There were no patients with objective response in the expansion cohort)

Time to OR, defined as the time from first treatment administration until first documented CR or PR. For patients with OR, time to OR was summarised on a patient level.

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: TS - Patients with objective response (There were no patients with objective response in the expansion cohort)

Duration of OR, defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR - Part B. For patients with OR, duration of OR was summarised on a patient level.

Outcome measures

Outcome data not reported

Adverse Events

Xentuzumab + Afatinib 20 mg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Xentuzumab + Afatinib 30 mg

Serious events: 2 serious events

Other events: 6 other events

Deaths: 1 deaths

Xentuzumab + Afatinib 40 mg

Serious events: 8 serious events

Other events: 20 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Xentuzumab + Afatinib 20 mg n=4 participants at risk Patients received intravenous infusion of Xentuzumab 1000 mg delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet.	Xentuzumab + Afatinib 30 mg n=6 participants at risk Patients received intravenous infusion of Xentuzumab 1000 mg delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet.	Xentuzumab + Afatinib 40 mg n=22 participants at risk Patients received intravenous infusion of Xentuzumab 1000 mg delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet.
Cardiac disorders Pericardial effusion	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	16.7% 1/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Gastrointestinal disorders Ascites	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Gastrointestinal disorders Intestinal perforation	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Gastrointestinal disorders Peritoneal haemorrhage	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
General disorders Chest pain	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Immune system disorders Hypersensitivity	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	16.7% 1/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Infections and infestations Peritonitis	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Infections and infestations Pneumonia	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Psychiatric disorders Delirium	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	16.7% 1/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/4 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	0.00% 0/6 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.	4.5% 1/22 • From first administration of trial medication until end of the follow-up period, up to 1247 days. Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1). As per protocol safety data was collected according to dose groups.