A NON-INTERVENTIONAL STUDY ON AVELUMAB USE IN PATIENTS WITH ADVANCED OR METASTATIC UROTHELIAL CARCINOMA

OS from initiation of first-line chemotherapy was defined as the time from the date of first injection of the chemotherapy used in first line (before avelumab initiation) as reported in medical history to death due to any cause. Participants last known to be alive or lost to follow up were censored at date of last contact. Analysis was performed using Kaplan-Meier method with left truncature and right censoring to consider the participant 'immortality' time before avelumab initiation.

OS from initiation of first-line chemotherapy was defined as the time from the date of first injection of the chemotherapy used in first line (before avelumab initiation) as reported in medical history to death due to any cause. Participants last known to be alive or lost to follow up were censored at date of last contact. OS from initiation of first line chemotherapy according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure. Analysis was performed using Kaplan-Meier method with left truncature and right censoring to take into account the participant 'immortality' time before avelumab initiation.

PFS: time between first injection of avelumab and the date of disease progression (PD) or death from any cause, whichever occurred first. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (including baseline sum if that was smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 millimeters (mm). Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of treatment during study before any progression or death or who were lost to follow-up or had early study discontinuation without progression or death were censored at last contact date. Analysis was performed using Kaplan-Meier method.

PFS:time between first injection of avelumab and the date of PD or death from any cause, whichever occurred first. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study). In addition to relative increase of 20%,sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of treatment during study before any progression or death or who were lost to follow-up or had early study discontinuation without progression or death were censored at last contact date. PFS according to histology group:pure urothelial carcinoma,pure variant and urothelial carcinoma variant were reported. Kaplan-Meier method was used.

PFS2: time between first injection and date of PD or death from any cause, whichever occurred first. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study). In addition to relative increase of 20%,sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of second line of post-avelumab treatment during the study before any progression or death or who were lost to follow-up or had early study discontinuation without progression, death or 2nd line of post-avelumab treatment discontinuation were censored at last contact date. Analysis was performed using Kaplan-Meier method.

PFS2: time between first injection and date of PD or death from any cause, whichever occurred first. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. Unequivocal progression of pre-existing lesions or appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of 2nd line of post-avelumab treatment during study before any progression or death or who were lost to follow-up or had early study discontinuation without progression, death or 2nd line of post-avelumab treatment discontinuation were censored at last contact date. PFS according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported. Kaplan-Meier method was used.

ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) as a best response during the avelumab treatment. Responses to treatment were defined according to RECIST 1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions.

ORR was defined as the percentage of participants with a CR or PR as a best response during the avelumab treatment. Responses to treatment were defined according to RECIST 1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. ORR according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

DOR: time between beginning of response (CR or PR) and PD or death from any cause, whichever occurred first. CR: complete disappearance of all target and non-target lesions, with exception of nodal disease. Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier.

DOR: time between beginning of response (CR or PR) and PD or death from any cause, whichever occurred first. CR: complete disappearance of all target and non-target lesions, with exception of nodal disease. Any pathological lymph nodes (target or non-target) must have reduction in short axis to<10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions or appearance of any new unequivocal malignant lesion was also considered PD. DOR according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported. Kaplan-Meier method was used.

DOT was defined as the time between the first and last dose of avelumab. DOT was evaluated using survival analysis where first dose date was considered as date of first study treatment intake until permanent discontinuation of treatment or death due to any cause. Participants without permanent discontinuation reported at the end of study or who were lost to follow-up or had early permanent study discontinuation without stopping treatment were censored at the last contact date. Analysis was performed using Kaplan-Meier method.

DOT was defined as the time between the first and last dose of avelumab. DOT was evaluated using survival analysis where first dose date was considered as date of first study treatment intake until permanent discontinuation of treatment or death due to any cause. Participants without permanent discontinuation reported at the end of study or who were lost to follow-up or had early permanent study discontinuation without stopping treatment were censored at the last contact date. DOT according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure. Analysis was performed using Kaplan-Meier method.

The number of participants classified per progression type (new lesions; pre-existing lesions progression; pre-existing lesions progression and new lesions; undefined) were reported in this outcome measure.

The number of participants classified per progression type (new lesions; pre-existing lesions progression; pre-existing lesions progression and new lesions; undefined) were reported in this outcome measure. Number of participants classified per progression type according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

Duration of subsequent treatment was defined as the time from the first to last dose of subsequent treatment to avelumab. Participants without permanent discontinuation reported at the end of study or who were lost to follow-up or had early permanent study discontinuation without stopping treatment were censored at the last contact date. Analysis was performed using Kaplan-Meier method.

Duration of subsequent treatment was defined as the time from the first to last dose of subsequent treatment to avelumab. Participants without permanent discontinuation reported at the end of study or who were lost to follow-up or had early permanent study discontinuation without stopping treatment were censored at the last contact date. Duration of subsequent treatment according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure. Analysis was performed using Kaplan-Meier method.

PFS of subsequent treatment was defined as time between first injection of subsequent treatment and the date of PD or death from any cause, whichever occurred first. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study). In addition to relative increase of 20%,sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of treatment during study before any progression or death or who were lost to follow-up or had early study discontinuation without progression or death were censored at last contact date. Analysis was performed using Kaplan-Meier method.

PFS: time between first injection and date of PD or death from any cause, whichever occurred first. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study including baseline sum if that was smallest on study). In addition to relative increase of 20%,sum must have also demonstrated an absolute increase of at least 5mm. Unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy was also considered PD. Appearance of any new unequivocal malignant lesion was also considered PD. Participants with final discontinuation of treatment during study before any progression or death or who were lost to follow-up or had early study discontinuation without progression or death were censored at last contact date. PFS according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported. Kaplan-Meier method was used.

ORR of subsequent therapy was defined as the percentage of participants with a CR or PR as a best response during the subsequent treatment. Responses to treatment were defined according to RECIST 1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions.

ORR of subsequent therapy was defined as the percentage of participants with a CR or PR as a best response during the subsequent treatment. Responses to treatment were defined according to RECIST 1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. ORR of subsequent therapy according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

OS of subsequent treatment was defined as the time from the date of first injection of subsequent treatment to the date of death due to any cause. Participants last known to be alive or lost to follow-up were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

OS of subsequent treatment was defined as the time from the date of first injection of subsequent treatment to the date of death due to any cause. Participants last known to be alive or lost to follow-up were censored at date of last contact. OS of subsequent treatment according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure. Analysis was performed using Kaplan-Meier method.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. AEs included both serious AEs (SAEs) and all non-SAEs. SAE was defined as any untoward medical occurrence at any dose that met 1 or more of following criteria: resulted in death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or other important medical events.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. AEs included both SAEs and all non-SAEs. SAE was defined as any untoward medical occurrence at any dose that met 1 or more of following criteria: resulted in death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or other important medical events. AEs according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Severity of AEs were graded as according to NCI CTCAE v5.0 as: Grade 3= severe AE, Grade 4= life-threatening and Grade 5= death. Number of participants with any Grade 3, 4 or 5 were reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Severity of AEs were graded as according to NCI CTCAE v5.0 as: Grade 3= severe AE and Grade 4= life-threatening and Grade 5= death. Number of participants with any Grade 3, 4 or 5 AEs according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Number of participants With AEs leading to temporary/permanent discontinuation of avelumab were reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Number of participants With AEs leading to temporary/permanent discontinuation of avelumab according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Number of participants with AEs leading to death are reported in this outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product. The event need not necessarily have a causal relationship with the product treatment or usage. Number of participants with AEs leading to death according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

Number of participants who received at least one premedication with paracetamol among all avelumab injections were reported in this outcome measure.

Number of participants who received at least one premedication with paracetamol among all avelumab injections according to histology group: pure urothelial carcinoma, pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

Number of participants who received at least one premedication with antihistamines among all avelumab injections were reported in this outcome measure.

Number of participants who received at least one premedication with antihistamines among all avelumab injections according to histology group: pure urothelial carcinoma (UC), pure variant, urothelial carcinoma variant and missing were reported in this outcome measure.

The NCCN/FACT FBlSI-18 was a self-administered questionnaire to assess participant's bladder cancer-specific symptoms using a 'core' set of 18 questions. It included four subscales: Disease related symptoms-physical subscale with 9 items, disease related symptoms-emotional subscale with 2 items, treatment side effects subscale with 5 items, general function/well-being subscale with 2 items. The response to each of the 18 questions was evaluated using a 5-point scale ranging from 0='not at all' to 4='very much'. For items negatively framed, scores were reversed for analysis so that higher scores indicated a higher degree of bladder symptoms. Total score ranged from 0 to 72, where higher scores indicated a higher degree of bladder symptoms. This outcome measure was planned to be evaluated only in prospectively included participants. Baseline was defined as the time of avelumab initiation.

NCCN/FACT FBlSI-18: self-administered questionnaire to assess participant's bladder cancer-specific symptoms using a 'core' set of 18 questions. It included four subscales: Disease related symptoms-physical subscale with 9 items, disease related symptoms-emotional subscale with 2 items, treatment side effects subscale with 5 items, general function/well-being subscale with 2 items. Response to each of 18 questions was evaluated using a 5-point scale ranging from 0='not at all' to 4='very much'. For items negatively framed, scores were reversed for analysis so that higher scores indicated a higher degree of bladder symptoms. Total score ranged from 0 to 72, where higher scores indicated a higher degree of bladder symptoms. This outcome measure was planned to be evaluated only in prospectively included participants. Baseline=time of avelumab initiation. Change from Baseline in NCCN/FACT FBlSI-18 according to histology group: pure UC, pure variant and UC variant were reported.

The EQ-5D-5L was a participant-completed questionnaire with two parts: the EQ-5D index score and the visual analogue scale (VAS). The index score measures health across five dimensions-mobility, self-care, usual activities, pain/discomfort, and anxiety/depression-each rated on five severity levels from 1= no problems to 5= extreme problems. These responses form a five-digit health state score ranging from 11111 (no problems) to 55555 (extreme problems), which was then converted into a single utility EQ-5D-5L index score between 0 (death) and 1 (perfect health) using a weighted formula from the EQ-5D official website, where higher EQ-5D-5L scores signified better health. Baseline was defined as the time of avelumab initiation.

The EQ-5D-5L was a participant-completed questionnaire with two parts: the EQ-5D index score and the VAS. The index score measures health across five dimensions-mobility, self-care, usual activities, pain/discomfort, and anxiety/depression-each rated on five severity levels from 1= no problems to 5= extreme problems. These responses form a five-digit health state score ranging from 11111 (no problems) to 55555 (extreme problems), which was then converted into a single utility EQ-5D-5L index score between 0 (death) and 1 (perfect health) using a weighted formula from the EQ-5D official website, where higher EQ-5D-5L scores signified better health. Baseline was defined as the time of avelumab initiation. Change from Baseline in EQ-5D-5L Index Score according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure.

The EQ-5D-5L was a participant-completed questionnaire with two parts: the EQ-5D index score and the VAS. The EQ VAS records participants' self-rated health on a vertical scale ranging from 0= worst health you can imagine to 100= best health you can imagine, where higher scores signified better health. Baseline was defined as the time of avelumab initiation.

The EQ-5D-5L was a participant-completed questionnaire with two parts: the EQ-5D index score and the VAS. The EQ VAS records participants' self-rated health on a vertical scale ranging from 0= worst health you can imagine to 100= best health you can imagine, where higher scores signified better health. Baseline was defined as the time of avelumab initiation. Change from Baseline in EQ-5D-5L- VAS Score according to histology group: pure urothelial carcinoma, pure variant and urothelial carcinoma variant were reported in this outcome measure.