A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)

OS in Participants Irrespective of PD-L1 Expression

OS 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 the date of randomization to the date of death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months)

Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression

OR was defined as best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method.

Time frame: From date of randomization until PD (maximum up to approximately 26 months)

Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression

OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by investigator recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method.

Time frame: From date of randomization until PD (maximum up to approximately 89 months)

Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression

DC was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) according to RECIST v1.1 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. All lymph nodes must decrease to normal size (short axis\<10mm). 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 (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.

Time frame: From date of randomization until PD (maximum up to approximately 26 months)

Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression

DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD according to RECIST v1.1 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. All lymph nodes must decrease to normal size (short axis\<10mm). 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 (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.

Time frame: From date of randomization until PD (maximum up to approximately 89 months)

Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by BICR (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.

Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months)

TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by investigator (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.

Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 89 months)

Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

BICR assessed DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of objective tumor progression assessed by BICR or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months)

DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Investigator assessed DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of objective tumor progression (PD) assessed by investigator or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 89 months)

PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Investigator assessed PFS: time from the date of randomization to the date of the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: From date of randomization until PD, whichever occurred first (maximum up to approximately 89 months)

Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression

PFS2 is defined as the time (in months) from randomization to discontinuation of next-line treatment after first objective disease progression by investigator assessment, second objective disease progression by investigator assessment after initiation of next-line treatment, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: From date of randomization until PD or death, whichever occurred first (maximum up to approximately 89 months)

Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (V) 4.03

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period (time from the first dose of study treatment through 90 days after last dose of study treatment or start day of new anti-cancer drug therapy-1 day). As per NCI-CTCAE v4.03, grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death.

Time frame: From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

Number of Participants According to Grade Shift in Hematology Parameters

Following hematology parameters were assessed: hemoglobin decreased (anemia), hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell (WBC) decreased. Laboratory abnormalities were graded as per NCI- CTCAE v 4.03 where, grade(G) 0= non-missing lab value that does not meet either of G1 through 4 criteria, G1=mild, G2=moderate, G3=severe, G4=life-threatening consequences and G5=death. Baseline was defined as last assessment prior to first dose of study treatment. Number of participants with a baseline grade of 0 to 4 which shifted to G3-4 post-baseline are reported in this outcome measure. Only non-zero categories for any reporting arm are reported.

Time frame: From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

Number of Participants According to Grade Shift in Chemistry Parameters

Following chemistry parameters were assessed: alanine aminotransferase(ALT) increased, alkaline phosphatase(ALP) increased, aspartate aminotransferase(AST) increased, blood bilirubin increased, cholesterol high, creatinine phosphokinase(CPK) increased, creatinine increased, gamma glutamyl transferase(GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesmia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypokalemia, hypomagnesemia, hyponatremia, lipase increased and serum amylase increased. Laboratory abnormality graded as per NCI CTCAE v4.03; G0=non-missing lab value that does not meet either of G1 through 4 criteria, G1=mild, G2=moderate, G3=severe, G4=life-threatening consequences and G5=death. Number of participants with a baseline grade of 0 to 4 which shifted to G3-4 post-baseline are reported. Only non-zero categories for any reporting arm are reported.

Time frame: From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

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

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes.

Time frame: Baseline (pre-dose on Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum up to approximately 89 months) (each cycle=42 days)

Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit

Pulse rate was measured with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes.

Time frame: Baseline (pre-dose on Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum up to approximately 89 months) (each cycle=42 days)

Number of Participants Who Discontinued Treatment Due to Toxicity

Number of participants who discontinued treatment due to toxicity are reported in this outcome measure.

Time frame: From first dose of study treatment until discontinuation of study treatment (maximum up to approximately 89 months)

Time to Treatment Discontinuation/Failure Due to Toxicity

Time to treatment discontinuation/ failure due to toxicity was defined as the time from first dose of study treatment to discontinuation of study treatment due to an adverse event or death due to study treatment toxicity.

Time frame: From first dose of study treatment until discontinuation of study treatment (maximum up to approximately 89 months)

Trough Plasma Concentration (Ctrough) of Avelumab

Predose concentration during multiple dosing.

Time frame: Pre dose (0 hour) on Day 1, 15 and 29 of Cycle 1, Day 1 and 29 of Cycles 2, 3, 4 and Day 1 of Cycle 6

Ctrough of Axitinib

Predose concentration during multiple dosing.

Time frame: Pre dose (0 hour) on day 15 and 29 of cycle 1 (each cycle= 6 weeks)

Maximum Plasma Concentration (Cmax) of Axitinib

Time frame: 2 hours post-dose on Day 1, pre-dose and 2 hours post dose on Days 15 and 29 of Cycle 1

Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue

Tumor biospecimens from pre-treatment tissue samples were analyzed by immunohistochemistry for PD-L1 biomarker expression. Number of participants with positive PD-L1 biomarker expression are reported in this outcome measure.

Time frame: At screening

PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

PFS: time from the date of randomization to the date of the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months)

Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.

Time frame: From date of randomization until PD (maximum up to approximately 26 months)

Percentage of Participants With DC in Biomarker-Positive Subgroup

DC was defined as a best overall response of CR, PR, or stable disease (SD) according to the RECIST v.1.1 recorded from randomization until disease progression or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. SD was defined as PR that the sum increases by less than 20% from the nadir, (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.

Time frame: From date of randomization until PD or death, whichever occurred first (maximum up to approximately 26 months)

TTR in Biomarker-Positive Subgroup

TTR was defined as the time from randomization to the first documentation of objective tumor response (CR or PR) according to RECIST v1.1 which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.

Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months)

DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause, whichever occurred first. As per RECIST version 1.1, CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. PR: at least 30%\< in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD: defined as at least a 20% \> in sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.

Time frame: From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months)

Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib

Time frame: From start of treatment until 30 days after the end of avelumab treatment (maximum up to approximately 89 months)

Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS)

TTD was defined as the time from date of randomization to the first time the participant's score showed a 3-point or greater decrease in FKSI-DRS. FKSI was used to assess symptoms and quality of life (QoL) for those diagnosed with advanced kidney cancer and it consisted of 19 questions. A 9-item subscale of the FKSI known as FKSI-Disease Related Symptoms subscale (FKSI-DRS). This subscale included 9 items: lack of energy, pain, losing weight, bone pain, fatigue, shortness of breath, coughing, bothered by fevers, and hematuria. Each of the 9 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI-DRS score = sum of the 9 item scores; total range: 0 - 36; 0 (no symptoms) to 36 (very much); higher score indicated greater presence of symptoms.

Time frame: Date of randomization to the first time the participant's score showed a 3-point or greater decrease in FKSI-DRS (maximum up to approximately 26 months)

Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score

EQ-5D-5L is a 5-item participant-completed questionnaire designed to assess health status in terms of a single utility score. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Overall scores ranged from 0 to 1, with low scores representing a higher level of dysfunction. Published UK weights were used to create a single summary utility score. Utility scores range from -0.594 to 1, with higher scores representing better health status.

Time frame: Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months)

Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score

EQ-VAS records the participant's self-rated health status from 0 (worst imaginable health status) to 100 (best imaginable health status), where higher scores indicated better health status.

Time frame: Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months)