Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor JPN)

Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.

Area under the curve from the time of dosing extrapolated to infinity was calculated by the linear trapezoidal summation and extrapolated to infinity using Clast/Lambda z after the first intravenous infusion. "Clast" was the last quantifiable concentration and "Lambda z" was terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Cmax was obtained directly from the concentration versus time curve.

Tmax was time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.

t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Terminal elimination rate constant was determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Participant wise data was reported for this outcome measure.

Percentage of PD-L1 receptors occupied by avelumab on human lymphocytes (CD3+ cells) was assessed by flow cytometry on peripheral blood mononuclear cell (PBMC) samples. Greater than or equal to [>=] 85 percent [%] of cell viability was required for reliable receptor occupancy assessment.

Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.

Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

Participants not having positive HAHA prior to treatment with Avelumab and with at least one positive post-baseline result in the HAHA assay were termed as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive. Participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result greater than or equal to [>=] 16 weeks apart or a positive evaluation at the most recent visit. Number of participants with treatment-emergent positive HAHA were reported.

An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. 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. TEAEs included both serious TEAEs and non-serious TEAEs.

AUC0-336hour was defined as area under the serum concentration-time curve from the time of dosing to the end of dose interval (336 hr). It was calculated by linear trapezoidal summation.

Ctrough was defined as the trough or minimum serum concentration.

The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay.

Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.

Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

Confirmed BOR was defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.

BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported.

PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates.

irPFS was defined as the time from the first dose of study treatment to the date of first documentation of immune-related progressive disease [irPD] (which was subsequently confirmed) or death due to any cause, whichever occurred first. irPD was defined as the sum of the longest diameters of target and new measurable lesions increases greater than or equal to [>=] 20 percent (%), confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented.

The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates.

An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. 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. TEAEs included both serious TEAEs and non-serious TEAEs.

Number of participants with positive HAHA were reported. Participants not having positive HAHA prior to treatment with avelumab and with at least one positive post-baseline result in the HAHA assay were characterized as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result >=16 weeks apart or a positive evaluation at the most recent visit.