Carcinoma, Hepatocellular
Conditions
Keywords
Cancer, Hepatocellular carcinoma, Liver disease, Avelumab, Axitinib
Brief summary
To evaluate the safety, efficacy and PK of avelumab in combination with axitinib as first line treatment in patients with advanced HCC
Interventions
Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID.
Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on a prior tumor biopsy) or by imaging with serum α-fetoprotein (AFP) ≥400 ng/mL. * All patients must provide at least 1 archival tumor specimen. If archival tumor specimen is no longer available, de novo tumor biopsy will be required during screening. * HCC not amenable to local therapy. * Measurable disease according to RECIST v. 1.1. * Child Pugh Class A disease. * BCLC stage B or C disease. * No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. * ECOG performance status 0 or 1. * Adequate bone marrow function, renal and liver functions * Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) as assessed by multigated acquisition (MUGA) scan or echocardiogram (ECHO).
Exclusion criteria
* Prior systemic treatment for advanced HCC, including prior treatment with approved or investigational drugs. * Any prior locoregional therapy within 4 weeks and radiotherapy or surgical procedure within 2 weeks (4 weeks for major surgery) of enrollment. * Patients with known symptomatic brain metastases requiring steroids. * Presence of hepatic encephalopathy (ie, Child Pugh score of 2 or 3) and/or clinically relevant ascites (ie, Child Pugh score of 3). * Presence of main portal vein invasion by HCC. * Any of the following within the 12 months prior to enrollment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack. * Active infection requiring systemic therapy except for hepatitis C virus (HCV) and hepatitis B virus (HBV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were graded by investigator according to NCI CTCAE v.4.03 as follows: Grade 1: mild AE, Grade 2: moderate AE, Grade 3: severe AE, Grade 4: life-threatening consequences and urgent intervention indicated, Grade 5: death related to AE. |
| Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) | As per NCI-CTCAE v 4.03, anemia Grade 1= Less than (\<) lower limit of normal (LLN) to 100 gram per liter (g/L),Grade 2= \<100 to 80 g/L; hemoglobin increased: Grade 1= increase of greater than (\>) 0 to 2 gram per deciliter(g/dL) above upper limit of normal \[ULN\]; lymphocyte count decreased: Grade 1= \<LLN to 0.8\*10\^9/L, Grade 2= \<0.8\*10\^9/L to 0.5\*10\^9/L, Grade 3= \<0.5\*10\^9/L to 0.2\*10\^9/L ; lymphocyte count increased: Grade 2= \>4\*10\^9/L to 20\*10\^9/L; neutrophil count decreased: Grade 1= \<LLN to 1.5\*10\^9/L ,Grade 2= \<1.5\*10\^9/L to 1.0\*10\^9/L; platelet count decreased: Grade 1= \<LLN to 75.0\*10\^9/L, Grade 2= \<75.0\*10\^9/L to 50.0\*10\^9/L; white blood cell decreased: Grade 1= \<LLN to 3\*10\^9/L, Grade 2= \<3\*10\^9/L to 2\*10\^9/L. |
| Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) | ALT,ALP,AST increased grades(g):g1\>ULN-3.0\*ULN,g2\>3.0-5.0\*ULN,g3\>5.0-20.0\*ULN; blood bilirubin increased:g1\>ULN-1.5\*ULN, g2\>1.5-3.0\*ULN, g3\>3.0-10.0\*ULN; \[cholesterol high:g1\>ULN-7.75, g2 \>7.75-10.34,g4 \>12.92\]millimoles per liter(mmol/L);creatine phosphokinase, gamma-glutamyl transferase(ggt) increased g1\>ULN-2.5\*ULN, g2\>2.5\*ULN-5\*ULN; Ggt increased g3 \>5.0-20.0\*ULN; Creatinine increased: g1\>ULN-1.5\*ULN; \[hypoalbuminemia:g1\<LLN-30,g2\<30-20\] grams per liter(g/L);\[hyperglycemia:g1\> ULN-8.9,g2\> 8.9-13.9,g3\> 13.9-27.8;hypermagnesemia:g1\>ULN-1.23;hypercalcemia:g1\>ULN -2.9;hyperkalemia:g1\>ULN-5.5,hypernatremia:g1\>ULN-150;hypertriglyceridemia g1:1.71-3.42,g2 \>3.42-5.7;hypocalcemia:g1\<LLN-2.0,hypoglycemia:g1\<LLN-3.0, g2\<3.0-2.2;hypokalemia:g2\<LLN-3.0,g4\<2.5,hypomagnesemia:g1\<LLN-0.5,hyponatremia:g1\<LLN-130, g3\<130-120,hypophosphatemia:g1\<LLN-0.8,g2\<0.8-0.6\]mmol/L;lipase increased:g1\>ULN-1.5\*ULN,g3 \>2.0-5.0\*ULN;serum amylase increased:g1\>ULN-1.5\*ULN, g2\>1.5-2.0\*ULN,g3\>2.0-5.0\*ULN. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Control (DC) | From first dose of study drug until first documentation of CR or PR or SD or till non-CR/non-PD (maximum up to 20 months) | Disease control as assessed by investigator according to RECIST v1.1, was defined as participants with CR, PR, stable disease (SD), or non-CR/non-PD. CR: disappearance of all target and non-target lesions and sustained for 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameters of target lesions taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm or appearance of \>=1 new lesions. Non-CR/non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limit at \>=8 weeks after date of first dose of study treatment. |
| Time to Tumor Response (TTR) | From first dose of study drug until first documentation of CR or PR (maximum up to 20 months) | TTR as assessed by investigator according to RECIST v1.1 was defined as the time (in months) from the date of first dose of study drug to the first documentation of objective response (CR or PR) that was subsequently confirmed. CR was defined as disappearance of all target and non-target lesions, 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: \>= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters. |
| Duration of Response (DR) | From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months) | DR as assessed by investigator according to RECIST v1.1, was defined as the time from date of first documentation of objective response (CR or PR) to date of PD or death due to any cause, or data censoring date, whichever occurred first. CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) reduced in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study treatment, with absolute increase of at least 5 mm or appearance of \>=1 new lesions. DR data was censored on the date of last adequate tumor assessment for participants without an event (CR, PR, PD or death), for participants who start new anti-cancer treatment prior to DR assessment, for participants with DR assessment after \>=2 missing tumor assessments. |
| Overall Survival (OS) | From first dose of study drug to date of death from any cause or data censoring date, whichever occurred first (maximum up to 21 months) | OS was defined as the time (in months) from the date of first dose of study drug to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at the date of last contact. OS was analyzed by Kaplan-Meier method. |
| Maximum Observed Serum Concentration of Avelumab | Pre-dose, at the end of avelumab infusion on Day 1 of Cycle 2, 3, 4 (Duration of each cycle=14 days) | — |
| Maximum Observed Plasma Concentration of Axitinib | Pre-dose, 2 hours post dose Axitinib administration on Day 1 of Cycle 2, 3 (Duration of each cycle=14 days) | — |
| Time to Disease Progression (TTP) | From first dose of study drug until first documentation of progressive disease or data censoring date, whichever occurred first (maximum up to 20 months) | TTP as assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was define as time (in months) from date of first dose of study drug to date of first documentation of progressive disease (PD) or data censoring date, whichever occurred first. PD was defined as greater than or equal to (\>=) 20 percent (%) increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment), with a minimum absolute increase of at least 5 millimeter (mm), or appearance of \>=1 new lesions. TTP was analyzed by Kaplan-Meier method. TTP data was censored on the date the last adequate tumor assessment for participants without PD, for participants who start new anti-cancer treatment prior to PD, for participants who died without PD, or for participants with PD after \>=2 missing tumor assessments. |
| Pre-dose Plasma Concentration of Axitinib | Pre-dose on Day 1 of Cycle 2 and 3 (Duration of each cycle=14 days) | — |
| Number of Participants With Their Target Programmed Death-Ligand 1 (PD-L1) Status | Baseline (Day 1) | PD-L1 status was defined as positive when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering \>= 1% of the tumor area. PD-L1 status was defined as negative when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering \< 1% of the tumor area. |
| Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells | From first dose of study drug up to end of treatment (maximum up to 20 months) | CD8+ cells are the type of T-lymphocytes. Invasive margin is defined as the region on each side of the border between tumor cells. Expression of CD8+ cells in invasive margin, center of tumor cells, total area of tumor cells has been reported as mean percentage of CD8+cells per unit area. Area was measured in millimeter square (mm\^2). |
| Summary of Cluster of Differentiation 8 (CD8+) Cells Expression: Total Area Covered by CD8+ Cells in Center of Tumor Cells | From first dose of study drug up to end of treatment (up to 20 months) | CD8+ cells are the type of T-lymphocytes. |
| Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Positive Neutralizing Antibodies (nAbs) | From first dose of study drug until 30 days after the last dose of study drug (maximum up to 21 months) | ADA positive was defined as presence of at least one positive ADA sample. nAb positive was defined as presence of at least one positive nAb sample. |
| Pre-dose Serum Concentration of Avelumab | Pre-dose on Day 1 of Cycle 2, 3, 4, 6, 8, 12, 16, 20, 24, 28 (Duration of each cycle=14 days) | — |
| Progression Free Survival (PFS) | From first dose of study drug until first documentation of PD or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months) | PFS as assessed by investigator per RECIST v1.1, was defined as time (in months) from date of first dose of study drug to date of first documentation of PD or death due to any cause or data censoring date, whichever occurred first. PD: \>= 20% increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment). The sum must also demonstrate absolute increase of \>=5 mm, or appearance of \>=1 new lesions. PFS was analyzed by Kaplan-Meier method. PFS data was censored on the date the last adequate tumor assessment for participants without an event (PD or death), for participants who started new anti-cancer treatment prior to PFS event, for participants with a PFS event after \>=2 missing tumor assessments. |
| Percentage of Participants With Objective Response (OR) | From first dose of study drug until disease progression or death due to any cause (maximum up to 20 months) | OR as assessed by investigator per RECIST v.1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR), were recorded from first dose of study drug until disease progression or death due to any cause. CR was defined as disappearance of all target and non-target lesions, 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 \>=30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
Japan
Participant flow
Recruitment details
Participants with advanced hepatocellular carcinoma (HCC) who did not receive any prior systemic therapy were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Avelumab + Axitinib Participants with advanced HCC were administered with Avelumab 10 mg/kg as 1-hour IV infusion, on Day 1 of each cycle along with Axitinib 5 mg oral tablets, twice daily on a continuous dosing schedule (without a break in dosing except in case of drug-related toxicity) until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the sponsor, whichever occurred first (up to maximum of 40 cycles). Duration of each cycle =14 days. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 12 |
| Overall Study | Terminated from study by sponsor | 10 |
Baseline characteristics
| Characteristic | Avelumab + Axitinib |
|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 14.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 8 / 22 |
Outcome results
Primary
Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03
ALT,ALP,AST increased grades(g):g1\>ULN-3.0\*ULN,g2\>3.0-5.0\*ULN,g3\>5.0-20.0\*ULN; blood bilirubin increased:g1\>ULN-1.5\*ULN, g2\>1.5-3.0\*ULN, g3\>3.0-10.0\*ULN; \[cholesterol high:g1\>ULN-7.75, g2 \>7.75-10.34,g4 \>12.92\]millimoles per liter(mmol/L);creatine phosphokinase, gamma-glutamyl transferase(ggt) increased g1\>ULN-2.5\*ULN, g2\>2.5\*ULN-5\*ULN; Ggt increased g3 \>5.0-20.0\*ULN; Creatinine increased: g1\>ULN-1.5\*ULN; \[hypoalbuminemia:g1\<LLN-30,g2\<30-20\] grams per liter(g/L);\[hyperglycemia:g1\> ULN-8.9,g2\> 8.9-13.9,g3\> 13.9-27.8;hypermagnesemia:g1\>ULN-1.23;hypercalcemia:g1\>ULN -2.9;hyperkalemia:g1\>ULN-5.5,hypernatremia:g1\>ULN-150;hypertriglyceridemia g1:1.71-3.42,g2 \>3.42-5.7;hypocalcemia:g1\<LLN-2.0,hypoglycemia:g1\<LLN-3.0, g2\<3.0-2.2;hypokalemia:g2\<LLN-3.0,g4\<2.5,hypomagnesemia:g1\<LLN-0.5,hyponatremia:g1\<LLN-130, g3\<130-120,hypophosphatemia:g1\<LLN-0.8,g2\<0.8-0.6\]mmol/L;lipase increased:g1\>ULN-1.5\*ULN,g3 \>2.0-5.0\*ULN;serum amylase increased:g1\>ULN-1.5\*ULN, g2\>1.5-2.0\*ULN,g3\>2.0-5.0\*ULN.
Time frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months)
Population: Safety analysis set included participants who received at least one dose of study drug. Categories with at least 1 participant with abnormality were reported in this outcome measure. One participant might have more than 1 abnormality.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | AST increased: Grade 3 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Cholesterol high: Grade 4 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Creatine phosphokinase increased: Grade 2 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Creatine phosphokinase increased: Grade 1 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Creatinine increased: Grade 1 | 21 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Gamma-glutamyl transferase(Ggt) increased: Grade 1 | 6 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypertriglyceridemia; Grade 1 | 9 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypertriglyceridemia; Grade 2 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypoalbuminemia: Grade 1 | 15 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypoalbuminemia: Grade 2 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypocalcemia: Grade 1 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypoglycemia: Grade 1 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypoglycemia: Grade 2 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypokalemia: Grade 2 | 7 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypokalemia: Grade 4 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypomagnesemia: Grade 1 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyponatremia: Grade 1 | 15 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyponatremia: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypophosphatemia: Grade 1 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypophosphatemia: Grade 2 | 8 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Lipase increased: Grade 1 | 8 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Lipase increased: Grade 3 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Serum amylase increased: Grade 1 | 5 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Serum amylase increased: Grade 2 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Serum amylase increased: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Ggt increased: Grade 2 | 5 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Ggt increased: Grade 3 | 7 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypercalcemia: Grade 1 | 10 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyperglycemia: Grade 1 | 11 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyperglycemia: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyperglycemia: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hyperkalemia: Grade 1 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypermagnesemia: Grade 1 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Hypernatremia: Grade 1 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Alanine aminotransferase (ALT) increased: Grade 1 | 15 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | ALT increased: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | ALT increased: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Alkaline phosphatase (ALP) increased: Grade 1 | 11 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | ALP increased: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | ALP increased: Grade 3 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Aspartate aminotransferase(AST) increased: Grade 1 | 15 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | AST increased: Grade 2 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Blood bilirubin increased: Grade 1 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Blood bilirubin increased: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Blood bilirubin increased: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Cholesterol high: Grade 1 | 5 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 | Cholesterol high: Grade 2 | 1 Participants |
Primary
Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03
As per NCI-CTCAE v 4.03, anemia Grade 1= Less than (\<) lower limit of normal (LLN) to 100 gram per liter (g/L),Grade 2= \<100 to 80 g/L; hemoglobin increased: Grade 1= increase of greater than (\>) 0 to 2 gram per deciliter(g/dL) above upper limit of normal \[ULN\]; lymphocyte count decreased: Grade 1= \<LLN to 0.8\*10\^9/L, Grade 2= \<0.8\*10\^9/L to 0.5\*10\^9/L, Grade 3= \<0.5\*10\^9/L to 0.2\*10\^9/L ; lymphocyte count increased: Grade 2= \>4\*10\^9/L to 20\*10\^9/L; neutrophil count decreased: Grade 1= \<LLN to 1.5\*10\^9/L ,Grade 2= \<1.5\*10\^9/L to 1.0\*10\^9/L; platelet count decreased: Grade 1= \<LLN to 75.0\*10\^9/L, Grade 2= \<75.0\*10\^9/L to 50.0\*10\^9/L; white blood cell decreased: Grade 1= \<LLN to 3\*10\^9/L, Grade 2= \<3\*10\^9/L to 2\*10\^9/L.
Time frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months)
Population: Safety analysis set included participants who received at least one dose of study drug. Categories with at least 1 participant with abnormality were reported in this outcome measure. One participant might have more than 1 abnormality.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Platelet count decreased: Grade 1 | 14 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Platelet count decreased: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | White blood cell decreased: Grade 1 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | White blood cell decreased: Grade 2 | 4 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Anemia: Grade 1 | 13 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Anemia: Grade 2 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Hemoglobin increased: Grade 1 | 5 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Lymphocyte count decreased: Grade 1 | 11 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Lymphocyte count decreased: Grade 2 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Lymphocyte count decreased: Grade 3 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Lymphocyte count increased: Grade 2 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Neutrophil count decreased: Grade 1 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 | Neutrophil count decreased: Grade 2 | 5 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were graded by investigator according to NCI CTCAE v.4.03 as follows: Grade 1: mild AE, Grade 2: moderate AE, Grade 3: severe AE, Grade 4: life-threatening consequences and urgent intervention indicated, Grade 5: death related to AE.
Time frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months)
Population: Safety analysis set included participants who received at least one dose of study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Axitinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | Grade 1 | 2 Participants |
| Avelumab + Axitinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | Grade 2 | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | Grade 3 | 16 Participants |
| Avelumab + Axitinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | Grade 4 | 1 Participants |
| Avelumab + Axitinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 | Grade 5 | 0 Participants |
Secondary
Duration of Response (DR)
DR as assessed by investigator according to RECIST v1.1, was defined as the time from date of first documentation of objective response (CR or PR) to date of PD or death due to any cause, or data censoring date, whichever occurred first. CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) reduced in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study treatment, with absolute increase of at least 5 mm or appearance of \>=1 new lesions. DR data was censored on the date of last adequate tumor assessment for participants without an event (CR, PR, PD or death), for participants who start new anti-cancer treatment prior to DR assessment, for participants with DR assessment after \>=2 missing tumor assessments.
Time frame: From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Axitinib | Duration of Response (DR) | 7.29 Months |
Secondary
Maximum Observed Plasma Concentration of Axitinib
Time frame: Pre-dose, 2 hours post dose Axitinib administration on Day 1 of Cycle 2, 3 (Duration of each cycle=14 days)
Population: PK analysis set included all participants who had received at least one dose of study drug and who had at least one of the PK parameters of interest for axitinib. Here, number analyzed signifies participants evaluable for specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Axitinib | Maximum Observed Plasma Concentration of Axitinib | Cycle 2 Day 1 | 89.70 Nanograms per milliliter | Geometric Coefficient of Variation 23.015 |
| Avelumab + Axitinib | Maximum Observed Plasma Concentration of Axitinib | Cycle 3 Day 1 | 109.00 Nanograms per milliliter | Geometric Coefficient of Variation 17.275 |
Secondary
Maximum Observed Serum Concentration of Avelumab
Time frame: Pre-dose, at the end of avelumab infusion on Day 1 of Cycle 2, 3, 4 (Duration of each cycle=14 days)
Population: Pharmacokinetic (PK) analysis set included all participants who had received at least one dose of study drug and who had at least one of the PK parameters of interest for avelumab. Here, number analyzed signifies participants evaluable for specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Axitinib | Maximum Observed Serum Concentration of Avelumab | Cycle 2 Day 1 | 231.06 Microgram per milliliter | Geometric Coefficient of Variation 24 |
| Avelumab + Axitinib | Maximum Observed Serum Concentration of Avelumab | Cycle 3 Day 1 | 228.48 Microgram per milliliter | Geometric Coefficient of Variation 25 |
| Avelumab + Axitinib | Maximum Observed Serum Concentration of Avelumab | Cycle 4 Day 1 | 245.66 Microgram per milliliter | Geometric Coefficient of Variation 26 |
Secondary
Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells
CD8+ cells are the type of T-lymphocytes. Invasive margin is defined as the region on each side of the border between tumor cells. Expression of CD8+ cells in invasive margin, center of tumor cells, total area of tumor cells has been reported as mean percentage of CD8+cells per unit area. Area was measured in millimeter square (mm\^2).
Time frame: From first dose of study drug up to end of treatment (maximum up to 20 months)
Population: CD8+ biomarker analysis set included participants who had received at least one dose of study drug and who had at least one screening biomarker assessment for CD8+ cells. Here, number analyzed signifies participants evaluable for specific rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Axitinib | Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells | CD8+ Cells in Invasive Margin | 2.12 Percentage of CD8+cells per mm^2 | Standard Deviation 1.76 |
| Avelumab + Axitinib | Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells | CD8+ Cells in Center of Tumor Cells | 0.91 Percentage of CD8+cells per mm^2 | Standard Deviation 1.328 |
| Avelumab + Axitinib | Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells | CD8+ Cells in Total Area of Tumor Cells | 1.02 Percentage of CD8+cells per mm^2 | Standard Deviation 1.353 |
Secondary
Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Positive Neutralizing Antibodies (nAbs)
ADA positive was defined as presence of at least one positive ADA sample. nAb positive was defined as presence of at least one positive nAb sample.
Time frame: From first dose of study drug until 30 days after the last dose of study drug (maximum up to 21 months)
Population: The immunogenicity analysis set included participants who have received at least one dose of study drug and who had at least one ADA or nAb sample collected for avelumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Axitinib | Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Positive Neutralizing Antibodies (nAbs) | ADA positive | 3 Participants |
| Avelumab + Axitinib | Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Positive Neutralizing Antibodies (nAbs) | nAb positive | 3 Participants |
Secondary
Number of Participants With Their Target Programmed Death-Ligand 1 (PD-L1) Status
PD-L1 status was defined as positive when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering \>= 1% of the tumor area. PD-L1 status was defined as negative when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering \< 1% of the tumor area.
Time frame: Baseline (Day 1)
Population: PD-L1 biomarker analysis set included participants who had received at least one dose of study drug and who had at least one screening biomarker assessment for PD-L1.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab + Axitinib | Number of Participants With Their Target Programmed Death-Ligand 1 (PD-L1) Status | PD-L1: Positive | 17 Participants |
| Avelumab + Axitinib | Number of Participants With Their Target Programmed Death-Ligand 1 (PD-L1) Status | PD-L1: Negative | 3 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time (in months) from the date of first dose of study drug to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at the date of last contact. OS was analyzed by Kaplan-Meier method.
Time frame: From first dose of study drug to date of death from any cause or data censoring date, whichever occurred first (maximum up to 21 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Axitinib | Overall Survival (OS) | 14.05 Months |
Secondary
Percentage of Participants With Disease Control (DC)
Disease control as assessed by investigator according to RECIST v1.1, was defined as participants with CR, PR, stable disease (SD), or non-CR/non-PD. CR: disappearance of all target and non-target lesions and sustained for 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameters of target lesions taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm or appearance of \>=1 new lesions. Non-CR/non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limit at \>=8 weeks after date of first dose of study treatment.
Time frame: From first dose of study drug until first documentation of CR or PR or SD or till non-CR/non-PD (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Axitinib | Percentage of Participants With Disease Control (DC) | 68.2 Percentage of participants |
Secondary
Percentage of Participants With Objective Response (OR)
OR as assessed by investigator per RECIST v.1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR), were recorded from first dose of study drug until disease progression or death due to any cause. CR was defined as disappearance of all target and non-target lesions, 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 \>=30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study drug until disease progression or death due to any cause (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab + Axitinib | Percentage of Participants With Objective Response (OR) | 13.6 Percentage of participants |
Secondary
Pre-dose Plasma Concentration of Axitinib
Time frame: Pre-dose on Day 1 of Cycle 2 and 3 (Duration of each cycle=14 days)
Population: PK analysis set included all participants who had received at least one dose of study drug and who had at least one of the PK parameters of interest for axitinib. Here, number analyzed signifies participants evaluable for specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Axitinib | Pre-dose Plasma Concentration of Axitinib | Cycle 2 Day 1 | 11.6439 Nanograms per milliliter | Geometric Coefficient of Variation 123 |
| Avelumab + Axitinib | Pre-dose Plasma Concentration of Axitinib | Cycle 3 Day 1 | 9.2226 Nanograms per milliliter | Geometric Coefficient of Variation 164 |
Secondary
Pre-dose Serum Concentration of Avelumab
Time frame: Pre-dose on Day 1 of Cycle 2, 3, 4, 6, 8, 12, 16, 20, 24, 28 (Duration of each cycle=14 days)
Population: PK analysis set included all participants who had received at least one dose of study drug and who had at least one of the PK parameters of interest for avelumab. Here, number analyzed signifies participants evaluable at specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 2 Day 1 | 33.80 Microgram per milliliter | Geometric Coefficient of Variation 17.722 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 3 Day 1 | 19.419 Microgram per milliliter | Geometric Coefficient of Variation 64 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 4 Day 1 | 19.220 Microgram per milliliter | Geometric Coefficient of Variation 118 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 6 Day 1 | 23.922 Microgram per milliliter | Geometric Coefficient of Variation 68 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 8 Day 1 | 24.814 Microgram per milliliter | Geometric Coefficient of Variation 39 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 12 Day 1 | 29.832 Microgram per milliliter | Geometric Coefficient of Variation 37 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 16 Day 1 | 35.388 Microgram per milliliter | Geometric Coefficient of Variation 35 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 20 Day 1 | 31.211 Microgram per milliliter | Geometric Coefficient of Variation 36 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 24 Day 1 | 30.070 Microgram per milliliter | Geometric Coefficient of Variation 43 |
| Avelumab + Axitinib | Pre-dose Serum Concentration of Avelumab | Cycle 28 Day 1 | 35.578 Microgram per milliliter | Geometric Coefficient of Variation 19 |
Secondary
Progression Free Survival (PFS)
PFS as assessed by investigator per RECIST v1.1, was defined as time (in months) from date of first dose of study drug to date of first documentation of PD or death due to any cause or data censoring date, whichever occurred first. PD: \>= 20% increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment). The sum must also demonstrate absolute increase of \>=5 mm, or appearance of \>=1 new lesions. PFS was analyzed by Kaplan-Meier method. PFS data was censored on the date the last adequate tumor assessment for participants without an event (PD or death), for participants who started new anti-cancer treatment prior to PFS event, for participants with a PFS event after \>=2 missing tumor assessments.
Time frame: From first dose of study drug until first documentation of PD or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Axitinib | Progression Free Survival (PFS) | 5.52 Months |
Secondary
Summary of Cluster of Differentiation 8 (CD8+) Cells Expression: Total Area Covered by CD8+ Cells in Center of Tumor Cells
CD8+ cells are the type of T-lymphocytes.
Time frame: From first dose of study drug up to end of treatment (up to 20 months)
Population: CD8+ biomarker analysis set included participants who had received at least one dose of study drug and who had at least one screening biomarker assessment for CD8+ cells. Here, Overall Number of Participants Analyzed signifies the number of participants evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Avelumab + Axitinib | Summary of Cluster of Differentiation 8 (CD8+) Cells Expression: Total Area Covered by CD8+ Cells in Center of Tumor Cells | 53.88 mm^2 | Standard Deviation 48.832 |
Secondary
Time to Disease Progression (TTP)
TTP as assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was define as time (in months) from date of first dose of study drug to date of first documentation of progressive disease (PD) or data censoring date, whichever occurred first. PD was defined as greater than or equal to (\>=) 20 percent (%) increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment), with a minimum absolute increase of at least 5 millimeter (mm), or appearance of \>=1 new lesions. TTP was analyzed by Kaplan-Meier method. TTP data was censored on the date the last adequate tumor assessment for participants without PD, for participants who start new anti-cancer treatment prior to PD, for participants who died without PD, or for participants with PD after \>=2 missing tumor assessments.
Time frame: From first dose of study drug until first documentation of progressive disease or data censoring date, whichever occurred first (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Axitinib | Time to Disease Progression (TTP) | 5.52 Months |
Secondary
Time to Tumor Response (TTR)
TTR as assessed by investigator according to RECIST v1.1 was defined as the time (in months) from the date of first dose of study drug to the first documentation of objective response (CR or PR) that was subsequently confirmed. CR was defined as disappearance of all target and non-target lesions, 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: \>= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters.
Time frame: From first dose of study drug until first documentation of CR or PR (maximum up to 20 months)
Population: Full analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab + Axitinib | Time to Tumor Response (TTR) | 1.91 Months |