Trial Outcomes & Findings for Afatinib Monotherapy in Patients With ERBB-deregulated Metastatic Urothelial Tract Carcinoma After Failure of Platinum Based Chemotherapy (NCT NCT02780687)

Last Updated: 2020-11-18

Results Overview

Progression-free survival at 6 months for Cohort A was defined as the number of patients who were alive and without disease progression at 24-week tumour assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated. Progression is defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since the treatment started, together with an absolute increase in the sum of LD of at least 5 millimeter OR The appearance of one or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

42 participants

Primary outcome timeframe

From start of treatment till assesment at week 24.

Results posted on

2020-11-18

Participant Flow

This study was a Phase II open label single arm exploratory trial of oral afatinib monotherapy following platinum failure for patients with advanced/metastatic urothelial tract carcinoma with genetic alterations in ERBB receptors.

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	Cohort A Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.	Cohort B Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Overall Study STARTED	34	8
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	34	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort A Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.	Cohort B Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	2	1
Overall Study Switched to commercial program (in CTP)	2	0
Overall Study progressive disease	29	6

Baseline Characteristics

Afatinib Monotherapy in Patients With ERBB-deregulated Metastatic Urothelial Tract Carcinoma After Failure of Platinum Based Chemotherapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.	Cohort B n=8 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.	Total n=42 Participants Total of all reporting groups
Age, Continuous	66.4 years STANDARD_DEVIATION 10.3 • n=99 Participants	70.0 years STANDARD_DEVIATION 6.9 • n=107 Participants	67.1 years STANDARD_DEVIATION 9.8 • n=206 Participants
Sex: Female, Male Female	4 Participants n=99 Participants	2 Participants n=107 Participants	6 Participants n=206 Participants
Sex: Female, Male Male	30 Participants n=99 Participants	6 Participants n=107 Participants	36 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) White	34 Participants n=99 Participants	8 Participants n=107 Participants	42 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Biomarker status ERBB2 mutation	8 Participants n=99 Participants	0 Participants n=107 Participants	8 Participants n=206 Participants
Biomarker status ERBB3 mutation	11 Participants n=99 Participants	0 Participants n=107 Participants	11 Participants n=206 Participants
Biomarker status ERBB2 amplification	20 Participants n=99 Participants	0 Participants n=107 Participants	20 Participants n=206 Participants
Biomarker status EGFR amplification	3 Participants n=99 Participants	8 Participants n=107 Participants	11 Participants n=206 Participants

PRIMARY outcome

Timeframe: From start of treatment till assesment at week 24.

Population: The treated set (TS) included all patients who took at least 1 afatinib dose. The aim of the study was to investigate patients with ERBB-deregulated tumours (cohort A), patients with EGFR amplification (cohort B) were therefore not included in the endpoint.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Number of Participants With Progression-free Survival at Six Months (PFS6) in Cohort A Without progression/death at 24th week	4 Participants

SECONDARY outcome

Timeframe: Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.

Confirmed objective response by investigator review for Cohort A was defined as the number of participants with confirmed complete response (CR, disappearance of all target lesions) or confirmed partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Number of Participants With Confirmed Objective Response (ORR) in Cohort A Objective response	2 Participants

SECONDARY outcome

Progression-free survival was defined as the time (months) from the date of the first afatinib administration to the date of disease progression or death (if the patient died without progression). The date of progression for the primary analyses was determined based on investigator assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to RECIST version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated. Progression is defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since the treatment started, together with an absolute increase in the sum of LD of at least 5 millimeter OR The appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Progression-free Survival (PFS) in Cohort A	9.8 Weeks Interval 7.9 to 16.0

SECONDARY outcome

Timeframe: From start of treatment of afatinib until death from any cause, i.e. up to approximately 20 Months.

Overall survival (OS) defined as the time from start of treatment of afatinib until death from any cause.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Overall Survival (OS) in Cohort A	30.1 Weeks Interval 17.4 to 47.0

SECONDARY outcome

Disease control was calculated as the number of participants with complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD), or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for PD (Progression) taking as reference the smallest SoD since the treatment started). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Number of Participants With Disease Control (DCR) in Cohort A Yes	17 Participants
Number of Participants With Disease Control (DCR) in Cohort A No	17 Participants

SECONDARY outcome

For patients with disease control, duration of disease control was defined as the time from afatinib treatment start to disease progression (or death if the patient died before progression). Disease control was defined as a having a complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD), or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for PD taking as reference the smallest SoD since the treatment started). Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Duration of Disease Control in Cohort A	22.7 Weeks Interval 15.1 to 36.1

SECONDARY outcome

Number of patients with tumour shrinkage, tumour shrinkage from baseline was defined by the maximum percentage decrease from baseline in the sum of the longest diameters of target lesions. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.

Outcome measures

Outcome measures
Measure	Cohort A n=34 Participants Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Number of Patients With Tumour Shrinkage in Cohort A Patients with Shrinkage	9 Participants

Adverse Events

Cohort A

Serious events: 15 serious events

Other events: 34 other events

Deaths: 26 deaths

Cohort B

Serious events: 6 serious events

Other events: 8 other events

Deaths: 7 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	Cohort A n=34 participants at risk Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.	Cohort B n=8 participants at risk Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
Blood and lymphatic system disorders Anaemia	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Cardiac disorders Acute coronary syndrome	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Cardiac disorders Cardiac failure	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Gastrointestinal disorders Diarrhoea	11.8% 4/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	25.0% 2/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Gastrointestinal disorders Dysphagia	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Gastrointestinal disorders Nausea	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Gastrointestinal disorders Vomiting	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
General disorders Asthenia	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
General disorders Pain	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
General disorders Pyrexia	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Escherichia pyelonephritis	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Infected skin ulcer	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Influenza	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Pelvic abscess	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Respiratory tract infection	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Urinary tract infection	11.8% 4/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Infections and infestations Urinary tract infection bacterial	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Metabolism and nutrition disorders Cachexia	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Musculoskeletal and connective tissue disorders Back pain	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Musculoskeletal and connective tissue disorders Fistula	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Musculoskeletal and connective tissue disorders Musculoskeletal disorder	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Nervous system disorders Ischaemic stroke	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Nervous system disorders Sciatica	0.00% 0/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Renal and urinary disorders Acute kidney injury	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	12.5% 1/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Renal and urinary disorders Renal failure	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.9% 1/34 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.	0.00% 0/8 • From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months. The treated set (TS) included all patients who took at least 1 afatinib dose.