An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer

Number of participants who died during the study.

Time frame: From first dose of study medication until study closure (Up to approximately 144 months)

Population: All treated participants

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants

Participants with abnormalities in liver function tests related to potential drug-induced liver injury. Blood samples were collected and analyzed for liver function parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abnormalities were assessed relative to the upper limit of normal (ULN) for each parameter. Abbreviations: ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; ULN = Upper Limit of Normal.

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants

Number of participants with thyroid-related laboratory abnormalities during the study. Blood samples were collected and analyzed for thyroid function markers (FT3, FT4). Abnormalities were assessed against LLN and ULN for each parameter. Abbreviations: FT3 = Free T3; FT4 = Free T4; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal; TSH = Thyroid Stimulating Hormone

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants with at least one on-treatment thyroid stimulating hormone (TSH) measurement.

Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants

Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Population: All treated participants for Cohort 2 only. Pre-specified to be reported for Cohort 2 only.

Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Population: All treated participants for Cohorts 05, and all randomized participants for Cohorts 03, 04 and 06 only. Pre-specified to be reported for Cohorts 3 through 6.

AI\_AUC is accumulation index ratio of AUC at steady state to that after the first dose

Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval.

Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

The percentage of participants whose best overall response (BOR) is CR, PR or SD in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Failure to meet criteria for complete or partial response, in the absence of progressive disease. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

DOR is defined as the time from the first documented objective response (either complete or partial response) until the date of disease progression or death from any cause, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From first documented response to first documented progression or death, whichever occurs first (Up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6 whose best overall response (BOR) is either complete response (CR) or partial response (PR). Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

Effective half-life is defined as the time it takes for the amount of a drug in the body to decrease by half.

Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Cmax is the maximum observed serum concentration.

Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Baseline ADA Positive: Participant with baseline ADA-positive sample ADA Positive: Participant with at least one ADA-positive sample relative to baseline Persistent Positive (PP): ADA-positive sample at 2 or more consecutive timepoints Not PP-Last Sample Positive: Not persistent but with ADA-positive sample at the last sampling timepoint Other Positive: Not persistent but some ADA-positive samples with the last sample being negative ADA Negative: Participant with no ADA-positive sample after initiation of treatment

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Population: All treated participants in Cohort 1 and 2 with baseline and at least 1 post-baseline assessment. Pre-specified to be reported for Cohort 1 and 2 only.

The number of participants whose best overall response (BOR) is CR in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to approximately 144 months after first dose

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Population: All treated participants in Cohort 1; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

OS is defined as the time from randomization date or first dosing date of study medication to the date of death (due to any cause). Participants who were alive were censored at the last known alive dates.

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of death or date last known alive (up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

OS rate is defined as the percentage of participants who are still alive at certain time points during the study.

Time frame: At 6, 12, 24, 48 and 60 months

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

PFS is defined as the time from randomization date or first dosing date of study medication to the date of the first objectively documented tumor progression or death due to any cause. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to documented disease progression or death, whichever occurs first (up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

AI\_Cmax is ratio of an exposure measure at steady state to that after the first dose (exposure measure includes Cmax)

Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Ctrough is the lowest observed serum concentration.

Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Serum Concentration Achieved at the End of the Infusion (Ceoinf) refers to the amount of drug present in the blood (serum) immediately after the completion of an infusion. It represents the concentration measured at the exact time the infusion ends, before any significant elimination or distribution occurs.

Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Tmax is the time taken to reach the maximum observed serum concentration (Cmax).

Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)

Population: All treated participants in Cohort 1 with baseline and at least 1 post-baseline assessment; uninfected HCC, HCV-infected, and HBV-infected participants reported together as pre-specified.

Time to Progression (TTP) is defined from the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of the first objectively documented disease progression. Participants who have not progressed as assessed by radiography will be censored at the last tumor assessment date prior to subsequent anti-cancer therapy. Participants who have no on-study tumor assessments were censored at the date of randomization. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

TTP rate is defined as the percentage of participants without disease progression at select time points (milestones) during the study. Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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 the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Time frame: At 6 and 12 months

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6. Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.

Time to Response (TTR) defined as the time from randomization to the date of the first confirmed CR or PR for Cohort 3, 4 and 6, and from the first dosing date of study medication to the date of the first confirmed CR or PR for cohort 1, 2 and 5. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of attainment of complete response (CR) or partial response (PR) (up to approximately 144 months)

Population: All treated participants for Cohort 1, 2, and 5, and all randomized participants for Cohort 3, 4 and 6 whose best overall response (BOR) is either complete response (CR) or partial response (PR). Uninfected HCC, HCV-infected, and HBV-infected participants were pre-specified to be reported together for Cohort 1.