Urothelial Cancer
Conditions
Keywords
Bladder cancer, Urologic neoplasms, urothelial carcinoma, PD-L1, programmed cell death protein, maintenance treatment
Brief summary
The main purpose of this study is to compare maintenance treatment with avelumab plus best supportive care (BSC) with BSC alone, to determine if avelumab has an effect on survival in patients with locally advanced or metastatic urothelial cancer that did not worsen during or following completion of first-line chemotherapy.
Interventions
BIOLOGICALAvelumab
1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles
OTHERBest Supportive Care
BSC will be administered as deemed appropriate by the treating physician, and could include treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-tumor therapy, however local radiotherapy of isolated lesions with palliative intent is acceptable.
BIOLOGICALFollowing the planned interim analysis for this study: Avelumab
1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium * Stage IV disease at the start of first-line chemotherapy * Measurable disease (per RECIST v1.1) prior to the start of first-line chemotherapy * Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin * No evidence of progressive disease following completion of first-line chemotherapy (i.e., ongoing CR, PR, or SD per RECIST v1.1 guidelines )
Exclusion criteria
* Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization * Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA 4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways * Persisting toxicity related to prior therapy (Grade \>1 NCI CTCAE v4.0); however, alopecia, sensory neuropathy (Grade 2 or less), or other (Grade 2 or less) adverse events not constituting a safety risk based on the investigator's judgement are acceptable. * Patients with known symptomatic central nervous system (CNS) metastases requiring steroids * Diagnosis of any other malignancy within 5 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months) | Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by Investigator | From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months) | Investigator assessed PFS: Duration from randomization to first documentation of PD or death, whichever occurred first. PD as per RECIST version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included 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. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started a new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments. |
| Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months) | BICR assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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. |
| Percentage of Participants With Objective Response as Assessed by Investigator | From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months) | Investigator assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of CR or PR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and 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. |
| Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR) | From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months) | TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR), which was confirmed subsequently. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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. |
| Time to Tumor Response (TTR) as Assessed by Investigator | From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months) | TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and 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. |
| Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) | First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (for a maximum duration of 41 months) | BICR assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Any pathological lymph nodes reduced 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 for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. |
| Duration of Response (DOR) as Assessed by Investigator | First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (for a maximum duration of 41 months) | Investigator assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Additionally, normalization of tumor marker levels and any pathological lymph nodes reduced 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 for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. |
| Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR) | From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months) | Disease Control (DC) was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) as assessed by BICR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. |
| Percentage of Participants With Disease Control (DC) as Assessed by Investigator | From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months) | DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD as assessed by Investigator. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Additionally, normalization of tumor marker levels and 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. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | For Avelumab + Best Supportive Care (BSC)'' group: Day1 up to 90 days after last dose of study drug; for BSC group: Day1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months for both groups) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent AEs are events between first dose of study drug and up to 90 days after last dose of study drug or end of treatment (EOT) visit, that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | For Avelumab + Best Supportive Care (BSC)'' group: Day1 up to 90 days after last dose of study drug; for BSC group: Day1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months for both groups) | Hematology (Anemia G3: hemoglobin\<8.0 grams per deciliter \[g/dL\],\<4.9 millimoles (mmol)/liter (L),\<80 g/L, transfusion indicated, Grade 4 \[G4\]: life-threatening consequences, urgent intervention indicated, Grade 5 \[G5\]: death; platelet count decreased-G3:\<50.0 to 25.0\*10\^9/L, G4: \<25.0\*10\^9/L; lymphocyte count decreased-G3:\<0.5-0.2\*10\^9/L, G4:\<0.2\*10\^9/L; neutrophil count decreased-G3:\<1.0 to 0.5\*10\^9 /L, G4:\<0.5\*10\^9/L). Chemistry (creatinine increased-G3:\>3.0 to 6.0\*upper limit of normal \[ULN\], G4:\>6.0\*ULN; serum amylase increased, lipase increased-G3:\>2.0- 5.0\*ULN, G4:\>5.0\*ULN. Aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\]-G3:\>5.0 to 20.0\*ULN, G4:\>20.0\*ULN\]. Blood bilirubin increased-\[G3:\>3.0 to 10.0\*ULN, G4:\>10.0\*ULN\], Creatine phosphokinase \[CPK\] increased- \[G3:\>5.0 to 10.0\*ULN, G4:\>10.0\*ULN\], Hyperglycemia-\[G3:\>250 to 500 mg/dL; \>13.9 to 27.8 mmol/L hospitalization indicated, G4:\>500 mg/DL; \>27.8 mmol/L life-threatening consequences\]). |
| Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days) | Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). |
| Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months) | BICR assessed PFS: Duration from randomization until disease progression (PD) or death. PD as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (included 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. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments. |
| Maximum Plasma Concentration (Cmax) of Avelumab | End of avelumab infusion on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 (each cycle=28 days) | The Lower Limit of Quantitation (LLQ) of avelumab was 0.20 micrograms (mcg)/milliliter (mL). Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm. |
| Predose Plasma Concentration (Ctrough) of Avelumab | Pre-dose (0 hour) on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 (each cycle=28 days) | The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm. |
| Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months) | ADA against avelumab in serum samples was determined and reported separately for ADA never positive and ADA ever positive participants. Participants were considered ADA ever-positive if they had at least one positive ADA result at any time point during study and were otherwise considered negative. Data for this outcome measure was not planned to be collected and analyzed for reporting arm Best Supportive Care, since avelumab was not administered in this arm. |
| Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months) | Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum of ADA titer (60, 180, 540, 1620, 4860, 14580, and 131220) are reported. |
| Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status | From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months) | nAb against avelumab in serum samples was determined and reported separately for nAb never positive and nAb ever positive participants. Participants were considered nAb ever-positive if they had at least one positive nAb result at any time point during study and were otherwise considered negative. |
| Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Up to 41 months at the time of the analysis | PD-L1 assessment was performed using immunohistochemistry on pre-treatment tumor tissue samples. Participants were classified as having PD-L1 -positive status if at least one of the following three criteria were met: at least 25% of tumor cells stained for PD-L1, at least 25% of immune cells stained for PD-L1 if more than 1% of the tumor area contained immune cells, or 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells. |
| Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes) | Up to approximately 60 months | Number of Participants With CD8 T Lymphocytes (Cytotoxic T lymphocytes) were presented in this outcome. |
| Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | Baseline, Day 1 of Cycle 6 (1 cycle=28 days) | NCCN-FACT FBlSI-18 is an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. 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 and general function/well-being subscale with 2 items. Participants rated their level of symptoms for each item using 5-point scale ranging from 0=not at all to 4=very much. Items that were negatively framed, and the scores were reversed for analysis so that higher scores= good quality of life. Overall score: total of 18 items, ranging from 0=severely symptomatic to 72=asymptomatic. Higher scores= better functioning or lower symptom burden. |
| Time to Deterioration (TTD) Based on National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores | From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months) | NCCN-FACT FBlSI-18: an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. 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. Participants rated their level of symptoms for each item using 5-point scale ranging: 0=not at all to 4=very much. For items negatively framed, scores were reversed for analysis so that higher scores= good quality of life. DRS-P score: total 9 items, ranging from 0=severely symptomatic to 36= asymptomatic. Higher scores=better functioning or lower symptom burden. TTD: time from randomization to first time participant's score showed 3 point or greater decrease from baseline in FBlSI-DRS-P subscale for 2 consecutive assessments. |
| Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | Baseline, Day 1 of Cycle 6 (1 cycle=28 days) | The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). Published UK weights was used to create a single summary utility score. Utility scores range from -0.594 to 1, with low scores representing lower health status. |
| Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | Baseline, Day 1 of Cycle 6 (1 cycle=28 days) | The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state. |
| Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days) | Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Czechia, Denmark, France, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Russia, Serbia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study included only those participants who did not show evidence of disease progression after completion of at least 4 and not more than 6 cycles of first-line platinum-containing chemotherapy (prior to this study).
Participants by arm
| Arm | Count |
|---|---|
| Avelumab + Best Supportive Care (BSC) Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | 350 |
| Best Supportive Care As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | 350 |
| Total | 700 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 221 | 242 |
| Overall Study | Lost to Follow-up | 3 | 9 |
| Overall Study | No Longer Meets Eligibility Criteria | 3 | 0 |
| Overall Study | Other | 13 | 0 |
| Overall Study | Progressive Disease | 7 | 5 |
| Overall Study | Study terminated by sponsor | 74 | 75 |
| Overall Study | Withdrawal by Subject | 12 | 18 |
Baseline characteristics
| Characteristic | Best Supportive Care | Total | Avelumab + Best Supportive Care (BSC) |
|---|---|---|---|
| Age, Continuous | 67.7 Years STANDARD_DEVIATION 9.2 | 67.44 Years STANDARD_DEVIATION 9.4 | 67.20 Years STANDARD_DEVIATION 9.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 30 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 298 Participants | 584 Participants | 286 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 40 Participants | 86 Participants | 46 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 81 Participants | 156 Participants | 75 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 31 Participants | 72 Participants | 41 Participants |
| Race (NIH/OMB) White | 238 Participants | 470 Participants | 232 Participants |
| Sex: Female, Male Female | 75 Participants | 159 Participants | 84 Participants |
| Sex: Female, Male Male | 275 Participants | 541 Participants | 266 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 225 / 344 | 242 / 345 |
| other Total, other adverse events | 321 / 344 | 214 / 345 |
| serious Total, serious adverse events | 111 / 344 | 73 / 345 |
Outcome results
Primary
Overall Survival (OS)
Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Time frame: From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Overall Survival (OS) | 21.4 months |
| Best Supportive Care | Overall Survival (OS) | 14.3 months |
p-value: 0.000595% CI: [0.556, 0.863]Log Rank
Secondary
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6
The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). Published UK weights was used to create a single summary utility score. Utility scores range from -0.594 to 1, with low scores representing lower health status.
Time frame: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)
Population: The full analysis set included all participants who were randomized. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | Baseline | 0.814 units on a scale | Standard Deviation 0.1794 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | Change at Day 1 of Cycle 6 | -0.029 units on a scale | Standard Deviation 0.1919 |
| Best Supportive Care | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | Baseline | 0.792 units on a scale | Standard Deviation 0.2013 |
| Best Supportive Care | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | Change at Day 1 of Cycle 6 | -0.020 units on a scale | Standard Deviation 0.1684 |
Secondary
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6
The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state.
Time frame: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)
Population: The full analysis set included all participants who were randomized. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | Baseline | 74.9 units on a scale | Standard Deviation 18.87 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | Change at Day 1 of Cycle 6 | 1.6 units on a scale | Standard Deviation 17.74 |
| Best Supportive Care | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | Baseline | 74.9 units on a scale | Standard Deviation 16.34 |
| Best Supportive Care | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | Change at Day 1 of Cycle 6 | 0.2 units on a scale | Standard Deviation 14.74 |
Secondary
Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6
NCCN-FACT FBlSI-18 is an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. 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 and general function/well-being subscale with 2 items. Participants rated their level of symptoms for each item using 5-point scale ranging from 0=not at all to 4=very much. Items that were negatively framed, and the scores were reversed for analysis so that higher scores= good quality of life. Overall score: total of 18 items, ranging from 0=severely symptomatic to 72=asymptomatic. Higher scores= better functioning or lower symptom burden.
Time frame: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)
Population: The full analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | Change at Day 1 of Cycle 6 | 1.0 units on a scale | Standard Deviation 8.25 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | Baseline | 53.3 units on a scale | Standard Deviation 9.59 |
| Best Supportive Care | Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | Change at Day 1 of Cycle 6 | 1.6 units on a scale | Standard Deviation 8.35 |
| Best Supportive Care | Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | Baseline | 52.7 units on a scale | Standard Deviation 9.31 |
Secondary
Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit
Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP).
Time frame: Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days)
Population: Safety set analyzed. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment: Sitting SBP | -0.9 millimeters of mercury | Standard Deviation 18.99 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1: Sitting DBP | -1.7 millimeters of mercury | Standard Deviation 10.36 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1): Sitting SBP | 131.3 millimeters of mercury | Standard Deviation 17.34 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1: Sitting SBP | -1.9 millimeters of mercury | Standard Deviation 16.1 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1: Sitting SBP | -0.6 millimeters of mercury | Standard Deviation 16.54 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1: Sitting SBP | -1.9 millimeters of mercury | Standard Deviation 15.49 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1: Sitting DBP | -0.9 millimeters of mercury | Standard Deviation 9.37 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1: Sitting DBP | -1.7 millimeters of mercury | Standard Deviation 9.97 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1: Sitting DBP | -1.1 millimeters of mercury | Standard Deviation 10.6 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1: Sitting DBP | -1.2 millimeters of mercury | Standard Deviation 10.89 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1: Sitting DBP | -0.7 millimeters of mercury | Standard Deviation 10.9 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment: Sitting DBP | -0.1 millimeters of mercury | Standard Deviation 12.09 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1: Sitting SBP | -2.2 millimeters of mercury | Standard Deviation 14.85 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1: Sitting SBP | -2.3 millimeters of mercury | Standard Deviation 15.77 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1: Sitting SBP | -1.8 millimeters of mercury | Standard Deviation 16.13 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1): Sitting DBP | 75.7 millimeters of mercury | Standard Deviation 10.81 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1: Sitting SBP | 3.3 millimeters of mercury | Standard Deviation 16.81 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1: Sitting DBP | -0.0 millimeters of mercury | Standard Deviation 9.06 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1: Sitting DBP | -1.0 millimeters of mercury | Standard Deviation 10.22 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment: Sitting DBP | -1.7 millimeters of mercury | Standard Deviation 10.23 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1: Sitting SBP | -0.3 millimeters of mercury | Standard Deviation 13.79 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1: Sitting DBP | -1.1 millimeters of mercury | Standard Deviation 10.89 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1: Sitting SBP | 1.0 millimeters of mercury | Standard Deviation 14.94 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1: Sitting SBP | 1.9 millimeters of mercury | Standard Deviation 15.85 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1: Sitting SBP | 1.3 millimeters of mercury | Standard Deviation 16.54 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1: Sitting DBP | 0.2 millimeters of mercury | Standard Deviation 9.95 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment: Sitting SBP | -0.3 millimeters of mercury | Standard Deviation 16.78 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1): Sitting DBP | 77.0 millimeters of mercury | Standard Deviation 10.48 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1: Sitting SBP | 2.7 millimeters of mercury | Standard Deviation 19.86 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1: Sitting DBP | -1.6 millimeters of mercury | Standard Deviation 9.38 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1): Sitting SBP | 130.6 millimeters of mercury | Standard Deviation 16.32 |
| Best Supportive Care | Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1: Sitting DBP | -1.0 millimeters of mercury | Standard Deviation 9.9 |
Secondary
Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
Time frame: Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days)
Population: Safety set analyzed. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1) | 76.1 beats per minute | Standard Deviation 12.84 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1 | -0.8 beats per minute | Standard Deviation 11.54 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1 | 0.3 beats per minute | Standard Deviation 11.81 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1 | -0.2 beats per minute | Standard Deviation 12.1 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1 | -0.5 beats per minute | Standard Deviation 12.84 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1 | 0.4 beats per minute | Standard Deviation 12.32 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1 | -0.6 beats per minute | Standard Deviation 11.89 |
| Avelumab + Best Supportive Care (BSC) | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment | 2.5 beats per minute | Standard Deviation 12.25 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at End of Treatment | 1.4 beats per minute | Standard Deviation 12.45 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Baseline (C1D1) | 77.1 beats per minute | Standard Deviation 12.95 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 5, Day 1 | -1.0 beats per minute | Standard Deviation 11.45 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 4, Day 1 | -0.1 beats per minute | Standard Deviation 11.26 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 7, Day 1 | -2.6 beats per minute | Standard Deviation 11.48 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 2, Day 1 | 0.1 beats per minute | Standard Deviation 9.98 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 6, Day 1 | -2.6 beats per minute | Standard Deviation 10.52 |
| Best Supportive Care | Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Change at Cycle 3, Day 1 | -0.4 beats per minute | Standard Deviation 10.2 |
Secondary
Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)
BICR assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Any pathological lymph nodes reduced 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 for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD.
Time frame: First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (for a maximum duration of 41 months)
Population: Analysis was performed on subset of randomized participants, who had objective response, as assessed by BICR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) | NA months |
| Best Supportive Care | Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) | NA months |
Secondary
Duration of Response (DOR) as Assessed by Investigator
Investigator assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Additionally, normalization of tumor marker levels and any pathological lymph nodes reduced 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 for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD.
Time frame: First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (for a maximum duration of 41 months)
Population: Analysis was performed on subset of randomized participants, who had objective response, as assessed by Investigator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Duration of Response (DOR) as Assessed by Investigator | 25.6 months |
| Best Supportive Care | Duration of Response (DOR) as Assessed by Investigator | NA months |
Secondary
Maximum Plasma Concentration (Cmax) of Avelumab
The Lower Limit of Quantitation (LLQ) of avelumab was 0.20 micrograms (mcg)/milliliter (mL). Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm.
Time frame: End of avelumab infusion on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 (each cycle=28 days)
Population: Avelumab pharmacokinetic (PK) parameter analysis set: all participants who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'n' signifies participants evaluable for this OM at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 7, Day 1 | 191.9 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 86.2 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 9, Day 1 | 168.9 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 84.4 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 1, Day 1 | 192.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 68.4 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 1, Day 15 | 216.2 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 49.6 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 2, Day 1 | 201.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 54.5 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 2, Day 15 | 208.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 60.2 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 3, Day 1 | 213.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 39.6 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 3, Day 15 | 213.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 52.7 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 5, Day 1 | 197.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 67.7 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 11, Day 1 | 203.4 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 51.6 |
| Avelumab + Best Supportive Care (BSC) | Maximum Plasma Concentration (Cmax) of Avelumab | Cycle 13, Day 1 | 222.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 30.3 |
Secondary
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab
Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum of ADA titer (60, 180, 540, 1620, 4860, 14580, and 131220) are reported.
Time frame: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
Population: The immunogenicity analysis set included participants who had received at least one dose of study drug and who had ADA ever-positive results. Here Overall number of participants analyzed signifies participants who had data available for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 60 | 4 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 180 | 14 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 540 | 19 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 1620 | 10 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 4860 | 11 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 14580 | 7 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | 131220 | 1 Participants |
Secondary
Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status
ADA against avelumab in serum samples was determined and reported separately for ADA never positive and ADA ever positive participants. Participants were considered ADA ever-positive if they had at least one positive ADA result at any time point during study and were otherwise considered negative. Data for this outcome measure was not planned to be collected and analyzed for reporting arm Best Supportive Care, since avelumab was not administered in this arm.
Time frame: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
Population: The immunogenicity analysis set included all participants who had received at least one dose of study drug and who had at least one ADA sample collected for avelumab in the avelumab containing arm.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | Never-positive | 278 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | Ever-positive | 66 Participants |
Secondary
Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes)
Number of Participants With CD8 T Lymphocytes (Cytotoxic T lymphocytes) were presented in this outcome.
Time frame: Up to approximately 60 months
Population: Biomarker analysis set is a subset of the safety analysis set and included participants who have at least one baseline biomarker assessment performed. Here, 'Overall Number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes) | 148 Participants |
| Best Supportive Care | Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes) | 134 Participants |
Secondary
Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Hematology (Anemia G3: hemoglobin\<8.0 grams per deciliter \[g/dL\],\<4.9 millimoles (mmol)/liter (L),\<80 g/L, transfusion indicated, Grade 4 \[G4\]: life-threatening consequences, urgent intervention indicated, Grade 5 \[G5\]: death; platelet count decreased-G3:\<50.0 to 25.0\*10\^9/L, G4: \<25.0\*10\^9/L; lymphocyte count decreased-G3:\<0.5-0.2\*10\^9/L, G4:\<0.2\*10\^9/L; neutrophil count decreased-G3:\<1.0 to 0.5\*10\^9 /L, G4:\<0.5\*10\^9/L). Chemistry (creatinine increased-G3:\>3.0 to 6.0\*upper limit of normal \[ULN\], G4:\>6.0\*ULN; serum amylase increased, lipase increased-G3:\>2.0- 5.0\*ULN, G4:\>5.0\*ULN. Aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\]-G3:\>5.0 to 20.0\*ULN, G4:\>20.0\*ULN\]. Blood bilirubin increased-\[G3:\>3.0 to 10.0\*ULN, G4:\>10.0\*ULN\], Creatine phosphokinase \[CPK\] increased- \[G3:\>5.0 to 10.0\*ULN, G4:\>10.0\*ULN\], Hyperglycemia-\[G3:\>250 to 500 mg/dL; \>13.9 to 27.8 mmol/L hospitalization indicated, G4:\>500 mg/DL; \>27.8 mmol/L life-threatening consequences\]).
Time frame: For Avelumab + Best Supportive Care (BSC)'' group: Day1 up to 90 days after last dose of study drug; for BSC group: Day1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months for both groups)
Population: Safety analysis set included all participants who had received at least one dose of study drug on arm 'Avelumab+BSC' or completed C1D1 on arm 'BSC'. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'Number analyzed (n)' = Participants evaluable for this outcome measure for each specified row.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Lymphocyte Count Decreased | 20 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Lipase Increased | 37 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | ALT Increased | 11 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Platelet Count Decreased | 3 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | AST Increased | 6 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Neutrophil Count Decreased | 7 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Blood Bilirubin Increased | 0 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Creatinine Increased | 7 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | CPK Increased | 9 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Anemia | 16 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Hyperglycemia | 28 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Serum Amylase Increased | 25 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Hyperglycemia | 16 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Lipase Increased | 22 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Anemia | 12 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Platelet Count Decreased | 1 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Lymphocyte Count Decreased | 11 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Creatinine Increased | 5 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Serum Amylase Increased | 9 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | ALT Increased | 3 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | AST Increased | 3 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Blood Bilirubin Increased | 3 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | CPK Increased | 0 Participants |
| Best Supportive Care | Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Neutrophil Count Decreased | 0 Participants |
Secondary
Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status
nAb against avelumab in serum samples was determined and reported separately for nAb never positive and nAb ever positive participants. Participants were considered nAb ever-positive if they had at least one positive nAb result at any time point during study and were otherwise considered negative.
Time frame: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
Population: The immunogenicity analysis set included all participants who had received at least one dose of study drug and who had at least one nAb sample collected for avelumab in the avelumab containing arm.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status | Never-positive | 284 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status | Ever-positive | 60 Participants |
Secondary
Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)
PD-L1 assessment was performed using immunohistochemistry on pre-treatment tumor tissue samples. Participants were classified as having PD-L1 -positive status if at least one of the following three criteria were met: at least 25% of tumor cells stained for PD-L1, at least 25% of immune cells stained for PD-L1 if more than 1% of the tumor area contained immune cells, or 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells.
Time frame: Up to 41 months at the time of the analysis
Population: The full analysis set included all randomized participants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Positive | 189 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Negative | 139 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Unknown | 22 Participants |
| Best Supportive Care | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Positive | 169 Participants |
| Best Supportive Care | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Negative | 131 Participants |
| Best Supportive Care | Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | Unknown | 50 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent AEs are events between first dose of study drug and up to 90 days after last dose of study drug or end of treatment (EOT) visit, that were absent before treatment or that worsened relative to pretreatment state.
Time frame: For Avelumab + Best Supportive Care (BSC)'' group: Day1 up to 90 days after last dose of study drug; for BSC group: Day1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months for both groups)
Population: Safety analysis set included all participants who had received at least one dose of study drug on arm 'Avelumab+BSC' or completed Cycle 1 Day (C1D1) on arm 'BSC'.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 5 | 7 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 1 | 37 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 2 | 113 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 3 | 163 Participants |
| Avelumab + Best Supportive Care (BSC) | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 4 | 18 Participants |
| Best Supportive Care | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 4 | 8 Participants |
| Best Supportive Care | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 3 | 58 Participants |
| Best Supportive Care | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 1 | 76 Participants |
| Best Supportive Care | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 5 | 24 Participants |
| Best Supportive Care | Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Grade 2 | 104 Participants |
Secondary
Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR)
Disease Control (DC) was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) as assessed by BICR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.
Time frame: From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR) | 41.1 percentage of participants |
| Best Supportive Care | Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR) | 27.4 percentage of participants |
Secondary
Percentage of Participants With Disease Control (DC) as Assessed by Investigator
DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD as assessed by Investigator. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Additionally, normalization of tumor marker levels and 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. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.
Time frame: From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Percentage of Participants With Disease Control (DC) as Assessed by Investigator | 50.9 percentage of participants |
| Best Supportive Care | Percentage of Participants With Disease Control (DC) as Assessed by Investigator | 34.0 percentage of participants |
Secondary
Percentage of Participants With Objective Response as Assessed by Investigator
Investigator assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of CR or PR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and 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.
Time frame: From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Percentage of Participants With Objective Response as Assessed by Investigator | 12.3 percentage of participants |
| Best Supportive Care | Percentage of Participants With Objective Response as Assessed by Investigator | 3.4 percentage of participants |
Secondary
Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
BICR assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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.
Time frame: From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | 9.7 percentage of participants |
| Best Supportive Care | Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | 1.4 percentage of participants |
Secondary
Predose Plasma Concentration (Ctrough) of Avelumab
The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm.
Time frame: Pre-dose (0 hour) on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 (each cycle=28 days)
Population: Avelumab PK parameter analysis set: all participants who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'n' signifies participants evaluable for this OM at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 2, Day 1 | 25.2 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 64.2 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 2, Day 15 | 26.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 65.4 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 3, Day 1 | 26.4 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 76.2 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 1, Day 1 | 3.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 247.6 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 1, Day 15 | 22.2 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 48.6 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 3, Day 15 | 25.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 85.2 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 5, Day 1 | 26.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 67.5 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 7, Day 1 | 29.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 60.2 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 9, Day 1 | 32.4 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 55.9 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 11, Day 1 | 29.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 68.9 |
| Avelumab + Best Supportive Care (BSC) | Predose Plasma Concentration (Ctrough) of Avelumab | Cycle 13, Day 1 | 32.4 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 54.9 |
Secondary
Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)
BICR assessed PFS: Duration from randomization until disease progression (PD) or death. PD as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (included 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. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments.
Time frame: From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | 3.7 months |
| Best Supportive Care | Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | 2.0 months |
Secondary
Progression-Free Survival (PFS) as Assessed by Investigator
Investigator assessed PFS: Duration from randomization to first documentation of PD or death, whichever occurred first. PD as per RECIST version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included 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. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started a new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments.
Time frame: From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Progression-Free Survival (PFS) as Assessed by Investigator | 5.5 months |
| Best Supportive Care | Progression-Free Survival (PFS) as Assessed by Investigator | 2.1 months |
Secondary
Time to Deterioration (TTD) Based on National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores
NCCN-FACT FBlSI-18: an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. 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. Participants rated their level of symptoms for each item using 5-point scale ranging: 0=not at all to 4=very much. For items negatively framed, scores were reversed for analysis so that higher scores= good quality of life. DRS-P score: total 9 items, ranging from 0=severely symptomatic to 36= asymptomatic. Higher scores=better functioning or lower symptom burden. TTD: time from randomization to first time participant's score showed 3 point or greater decrease from baseline in FBlSI-DRS-P subscale for 2 consecutive assessments.
Time frame: From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months)
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Time to Deterioration (TTD) Based on National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores | NA months |
| Best Supportive Care | Time to Deterioration (TTD) Based on National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores | 13.8 months |
p-value: 0.913Log Rank
Secondary
Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR)
TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR), which was confirmed subsequently. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. 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.
Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants. Here, 'Overall Number of participants analyzed (N)' signifies participants who were evaluable for this outcome measure (OM).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR) | 2.0 months |
| Best Supportive Care | Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR) | 2.0 months |
Secondary
Time to Tumor Response (TTR) as Assessed by Investigator
TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and 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.
Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)
Population: The full analysis set included all randomized participants. Here, 'Overall Number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Best Supportive Care (BSC) | Time to Tumor Response (TTR) as Assessed by Investigator | 2.0 months |
| Best Supportive Care | Time to Tumor Response (TTR) as Assessed by Investigator | 1.9 months |