LUX-Bladder 1: Afatinib Monotherapy in Patients With ERBB-deregulated Metastatic Urothelial Tract Carcinoma After Failure of Platinum Based Chemotherapy

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02780687
• Collaborator: (none)
• Enrollment: 42
• Locations: 30
• Arm: 1
• Actual Duration (Months): 38.8
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess the anti-tumour activity and safety of afatinib monotherapy in patients with urothelial tract carcinoma carrying ERBB2 or ERBB3 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors) mutations or ERBB2 amplifications (Cohort A), and EGFR (Epidermal Growth Factor Receptor) amplification positive tumours (Cohort B), progressing despite previous platinum based chemotherapy, and thereby to improve their prognosis.

The antitumour activity of afatinib monotherapy in these patients will be assessed by progression free survival rate at 6 months (PFS6). This will be the primary endpoint of the trial. A key secondary endpoint will also be defined, the objective response rate (ORR).

Condition or Disease	Intervention/Treatment	Phase
Urologic Neoplasms	Drug: Afatinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: LUX-Bladder 1: 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.
• Actual Study Start Date: Jun 9, 2016
• Actual Primary Completion Date: Sep 24, 2018
• Actual Study Completion Date: Sep 2, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afatinib	Drug: Afatinib

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Progression-free Survival at Six Months (PFS6) in Cohort A [From start of treatment till assesment at week 24.]

   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.

Secondary Outcome Measures

1. Number of Participants With Confirmed Objective Response (ORR) in Cohort A [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.

2. Progression-free Survival (PFS) in Cohort A [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.]

   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.

3. Overall Survival (OS) in Cohort A [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.

4. Number of Participants With Disease Control (DCR) in Cohort A [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.]

   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.

5. Duration of Disease Control in Cohort A [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.]

   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.

6. Number of Patients With Tumour Shrinkage in Cohort A [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.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Recurrent or metastatic urothelial cancer

• Patients must have failed prior platinum based treatment (adjuvant or 1st line)

• Archival tissue sample available for biomarker testing at pre-screening and tissue banking.

• Patients should complete a pre-screening biomarker analysis and should fulfill the following: for Cohort A tumour should show a ERBB2 (epidermal growth factor family receptor 2) or ERBB3 mutation, or ERBB2 gene amplification; for Cohort B tumour should show EGFR (Epidermal Growth Factor Receptor) amplification.

• Further inclusion criteria apply

Exclusion criteria:

• Prior use of EGFR, ERBB2 or ERBB3 targeted treatment

• Chemotherapy within 4 weeks prior to the start of study treatment. Biological therapy or investigational agents within 4 weeks prior to the start of study treatment or prior to passing 5 half-lives, i.e. systemic clearance, whatever comes first

• Known brain metastases or signs hereof, uncontrolled spinal cord compression or leptomeningeal carcinomatosis

• Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	INS Bergonié	Bordeaux		France	33076
2	CTR Leon Berard	Lyon		France	69373
3	INS Cancérologie du Gard	Nîmes		France	30029
4	HOP Saint-Louis	Paris		France	75010
5	HOP Cochin	Paris		France	75014
6	HOP Européen G. Pompidou	Paris		France	75015
7	HOP Foch	Suresnes		France	92150
8	INS Universitaire du Cancer	Toulouse		France	31059
9	INS Gustave Roussy	Villejuif		France	94805
10	Ospedale San Donato di Arezzo	Arezzo		Italy	52100
11	A.O. San Camillo Forlanini	Roma		Italy	00152
12	Hospital Germans Trias i Pujol	Badalona		Spain	08916
13	Hospital del Mar	Barcelona		Spain	08003
14	Hospital Santa Creu i Sant Pau	Barcelona		Spain	08025
15	Hospital Clínic de Barcelona	Barcelona		Spain	08036
16	Hospital Vall d'Hebron	Barcelona		Spain	08038
17	Hospital Universitario de Elche	Elche		Spain	03202
18	Hospital Universitari de Girona Doctor Josep Trueta	Girona		Spain	17007
19	Hospital Duran i Reynals	L'Hospitalet de Llobregat		Spain	08908
20	Hospital Universitario Lucus Augusti	Lugo		Spain	27003
21	Hospital Ramón y Cajal	Madrid		Spain	28034
22	Hospital Clínico San Carlos	Madrid		Spain	28040
23	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
24	Hospital La Paz	Madrid		Spain	28046
25	CIO Clara Campal	Madrid		Spain	28050
26	Hospital Son Espases	Palma de Mallorca		Spain	07010
27	CS Parc Taulí	Sabadell		Spain	08208
28	Hospital Virgen Macarena	Sevilla		Spain	41009
29	Hospital Virgen del Rocío	Sevilla		Spain	41013
30	Instituto Valenciano de Oncología	Valencia		Spain	46009

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Mar 13, 2017
• Statistical Analysis Plan - Oct 1, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02780687
• Other Study ID Numbers: 1200.261; 2015-005427-10
• First Posted: May 23, 2016
• Last Update Posted: Nov 18, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Urologic Neoplasms; Afatinib

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	34	8
COMPLETED	0	0
NOT COMPLETED	34	8

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	34	8	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.4 (10.3)	70.0 (6.9)	67.1 (9.8)
Sex: Female, Male (Count of Participants)
Female	4 11.8%	2 25%	6 14.3%
Male	30 88.2%	6 75%	36 85.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	34 100%	8 100%	42 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Biomarker status (Number) [Number]
ERBB2 mutation	8 23.5%	0 0%	8 19%
ERBB3 mutation	11 32.4%	0 0%	11 26.2%
ERBB2 amplification	20 58.8%	0 0%	20 47.6%
EGFR amplification	3 8.8%	8 100%	11 26.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Progression-free Survival at Six Months (PFS6) in Cohort A
Description	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.
Time Frame	From start of treatment till assesment at week 24.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Without progression/death at 24th week	4 11.8%

2. Secondary Outcome

Title	Number of Participants With Confirmed Objective Response (ORR) in Cohort A
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Objective response	2 5.9%

3. Secondary Outcome

Title	Progression-free Survival (PFS) in Cohort A
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Median (95% Confidence Interval) [Weeks]	9.8

4. Secondary Outcome

Title	Overall Survival (OS) in Cohort A
Description	Overall survival (OS) defined as the time from start of treatment of afatinib until death from any cause.
Time Frame	From start of treatment of afatinib until death from any cause, i.e. up to approximately 20 Months.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Median (95% Confidence Interval) [Weeks]	30.1

5. Secondary Outcome

Title	Number of Participants With Disease Control (DCR) in Cohort A
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Yes	17 50%
No	17 50%

6. Secondary Outcome

Title	Duration of Disease Control in Cohort A
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Median (95% Confidence Interval) [Weeks]	22.7

7. Secondary Outcome

Title	Number of Patients With Tumour Shrinkage in Cohort A
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort A
Arm/Group Description	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.
Measure Participants	34
Patients with Shrinkage	9 26.5%

Adverse Events

Time Frame	From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months.
Adverse Event Reporting Description	The treated set (TS) included all patients who took at least 1 afatinib dose.
Arm/Group Title	Cohort A		Cohort B
Arm/Group Description	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.		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.
All Cause Mortality
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/34 (76.5%)		7/8 (87.5%)
Serious Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/34 (44.1%)		6/8 (75%)
Blood and lymphatic system disorders
Anaemia	1/34 (2.9%)		0/8 (0%)
Cardiac disorders
Acute coronary syndrome	0/34 (0%)		1/8 (12.5%)
Cardiac failure	0/34 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Diarrhoea	4/34 (11.8%)		2/8 (25%)
Dysphagia	1/34 (2.9%)		0/8 (0%)
Intestinal obstruction	0/34 (0%)		1/8 (12.5%)
Nausea	1/34 (2.9%)		0/8 (0%)
Vomiting	1/34 (2.9%)		0/8 (0%)
General disorders
Asthenia	1/34 (2.9%)		0/8 (0%)
Pain	1/34 (2.9%)		0/8 (0%)
Pyrexia	1/34 (2.9%)		1/8 (12.5%)
Infections and infestations
Escherichia pyelonephritis	1/34 (2.9%)		0/8 (0%)
Infected skin ulcer	1/34 (2.9%)		0/8 (0%)
Influenza	1/34 (2.9%)		0/8 (0%)
Pelvic abscess	1/34 (2.9%)		0/8 (0%)
Respiratory tract infection	0/34 (0%)		1/8 (12.5%)
Urinary tract infection	4/34 (11.8%)		1/8 (12.5%)
Urinary tract infection bacterial	1/34 (2.9%)		0/8 (0%)
Metabolism and nutrition disorders
Cachexia	1/34 (2.9%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/34 (2.9%)		0/8 (0%)
Fistula	1/34 (2.9%)		0/8 (0%)
Groin pain	0/34 (0%)		1/8 (12.5%)
Musculoskeletal disorder	1/34 (2.9%)		0/8 (0%)
Osteonecrosis of jaw	1/34 (2.9%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/34 (2.9%)		1/8 (12.5%)
Nervous system disorders
Ischaemic stroke	1/34 (2.9%)		0/8 (0%)
Sciatica	0/34 (0%)		1/8 (12.5%)
Renal and urinary disorders
Acute kidney injury	1/34 (2.9%)		1/8 (12.5%)
Renal failure	1/34 (2.9%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/34 (2.9%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/34 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Anaemia	10/34 (29.4%)		2/8 (25%)
Gastrointestinal disorders
Abdominal pain	2/34 (5.9%)		0/8 (0%)
Constipation	10/34 (29.4%)		1/8 (12.5%)
Diarrhoea	23/34 (67.6%)		5/8 (62.5%)
Dry mouth	1/34 (2.9%)		1/8 (12.5%)
Dyspepsia	3/34 (8.8%)		0/8 (0%)
Faeces soft	0/34 (0%)		1/8 (12.5%)
Glossitis	0/34 (0%)		1/8 (12.5%)
Nausea	9/34 (26.5%)		1/8 (12.5%)
Stomatitis	9/34 (26.5%)		2/8 (25%)
Vomiting	7/34 (20.6%)		1/8 (12.5%)
General disorders
Asthenia	19/34 (55.9%)		3/8 (37.5%)
Malaise	1/34 (2.9%)		1/8 (12.5%)
Mucosal inflammation	10/34 (29.4%)		3/8 (37.5%)
Oedema peripheral	2/34 (5.9%)		1/8 (12.5%)
Pain	3/34 (8.8%)		1/8 (12.5%)
Pyrexia	7/34 (20.6%)		1/8 (12.5%)
Xerosis	3/34 (8.8%)		1/8 (12.5%)
Infections and infestations
Clostridium difficile infection	0/34 (0%)		1/8 (12.5%)
Folliculitis	1/34 (2.9%)		1/8 (12.5%)
Paronychia	3/34 (8.8%)		3/8 (37.5%)
Respiratory tract infection	2/34 (5.9%)		0/8 (0%)
Skin candida	0/34 (0%)		1/8 (12.5%)
Urinary tract infection	6/34 (17.6%)		3/8 (37.5%)
Injury, poisoning and procedural complications
Fall	2/34 (5.9%)		0/8 (0%)
Investigations
Alanine aminotransferase increased	0/34 (0%)		2/8 (25%)
Aspartate aminotransferase increased	0/34 (0%)		1/8 (12.5%)
Blood creatine phosphokinase increased	2/34 (5.9%)		0/8 (0%)
Blood creatinine increased	2/34 (5.9%)		1/8 (12.5%)
Blood lactate dehydrogenase increased	1/34 (2.9%)		1/8 (12.5%)
Platelet count decreased	0/34 (0%)		1/8 (12.5%)
Transaminases increased	0/34 (0%)		1/8 (12.5%)
Weight decreased	1/34 (2.9%)		1/8 (12.5%)
Metabolism and nutrition disorders
Cachexia	2/34 (5.9%)		0/8 (0%)
Decreased appetite	15/34 (44.1%)		2/8 (25%)
Hyperkalaemia	1/34 (2.9%)		1/8 (12.5%)
Hypoalbuminaemia	0/34 (0%)		1/8 (12.5%)
Hypokalaemia	2/34 (5.9%)		0/8 (0%)
Hypomagnesaemia	4/34 (11.8%)		1/8 (12.5%)
Hyponatraemia	2/34 (5.9%)		1/8 (12.5%)
Hypophosphataemia	2/34 (5.9%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back pain	7/34 (20.6%)		0/8 (0%)
Bone pain	2/34 (5.9%)		0/8 (0%)
Pain in extremity	3/34 (8.8%)		0/8 (0%)
Nervous system disorders
Dysgeusia	2/34 (5.9%)		1/8 (12.5%)
Neuropathy peripheral	2/34 (5.9%)		0/8 (0%)
Paraesthesia	2/34 (5.9%)		0/8 (0%)
Speech disorder	0/34 (0%)		1/8 (12.5%)
Psychiatric disorders
Insomnia	2/34 (5.9%)		1/8 (12.5%)
Renal and urinary disorders
Dysuria	0/34 (0%)		1/8 (12.5%)
Haematuria	2/34 (5.9%)		0/8 (0%)
Leukocyturia	2/34 (5.9%)		0/8 (0%)
Oliguria	0/34 (0%)		1/8 (12.5%)
Proteinuria	2/34 (5.9%)		0/8 (0%)
Renal failure	3/34 (8.8%)		0/8 (0%)
Reproductive system and breast disorders
Pelvic pain	2/34 (5.9%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/34 (5.9%)		1/8 (12.5%)
Haemoptysis	1/34 (2.9%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Dermatitis	2/34 (5.9%)		1/8 (12.5%)
Dermatitis acneiform	4/34 (11.8%)		1/8 (12.5%)
Dry skin	3/34 (8.8%)		1/8 (12.5%)
Pruritus	5/34 (14.7%)		2/8 (25%)
Rash	11/34 (32.4%)		1/8 (12.5%)
Skin erosion	0/34 (0%)		1/8 (12.5%)
Skin lesion	2/34 (5.9%)		1/8 (12.5%)
Skin toxicity	4/34 (11.8%)		1/8 (12.5%)
Vascular disorders
Hypotension	2/34 (5.9%)		0/8 (0%)

Limitations/Caveats

Duration of confirmed objective response was not analysed because only 2 patients showed a confirmed objective response. Instead, duration of disease control was analysed.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.