Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma

OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This primary outcome measure presents OS analysis of Treme 300mg x1 dose + Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).

Time frame: From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Number (%) of participants with a Best Objective Response (BoR) of CR, PR, or SD. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters. Stable disease (ie., SD) was defined as neither sufficient decrease in sum of diameters to qualify for PR nor sufficient increase to qualify for progression.

Time frame: From the date of randomization until objective tumor progression or date of death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Time from the date of first documented confirmed response (complete or partial response) until the first date of documented progression or death in the absence of disease progression. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.

Time frame: From the date of first documented response until the first date of documented progression or death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: A subset of FAS subjects who achieve confirmed CR or PR as determined per RECIST 1.1 using Investigator assessment. T75+D arm was closed during study.

European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30), which consists of 30 questions combined to produce a global health status/QoL scale. Higher scores indicate better health. A clinically meaningful deterioration is defined as a decrease in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.

Time frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.

Population: A subset of the FAS who had baseline scores of \>=10. T75+D arm was closed during study.

EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.

Time frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.

Population: A subset of the FAS who have a baseline symptom score \<= 90. T75+D arm was closed during study.

EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.

Time frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.

Population: A subset of the FAS who have a baseline symptom score \<= 90. T75+D arm was closed during study.

EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.

Time frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.

Population: A subset of the FAS who have a baseline symptom score \<= 90. T75+D arm was closed during study.

ORR (per RECIST 1.1 as assessed by the Investigator) was defined as the number (%) of participants with at least 1 confirmed visit response of CR or PR until progression, or the last evaluable assessment in the absence of progression. Participants who go off treatment without progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.

Time frame: From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Percentage of participants who were alive at fixed time points (18, 24, and 36 months) after randomization. The estimated percentage of survival along with the 95% confidence interval were calculated using Kaplan-Meier technique on the full analysis set.

Time frame: At 18, 24, and 36 months post-randomization. Assessed at the final analysis DCO (27Aug2021).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Overall survival by baseline PD-L1 expression levels (positive vs. negative). PD-L1 expression level is based on the Tumor and Immune Cell Positivity (TIP) score method as: PD-L1 Positive (TIP ≥ 1%) or PD-L1 Negative (TIP \< 1%).

Time frame: From the date of randomization until death due to any cause, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: A subset of FAS who had non-missing baseline PD-L1 status. T75+D arm was closed during study.

OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This secondary outcome measure presents OS analysis of Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).

Time frame: From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Number of participants with Anti-Drug Antibody (ADA) response to Durvalumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Durvalumab for each indicated category.

Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of durvalumab. Assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: The Durvalumab ADA evaluable set includes all participants who received at least 1 dose of Durvalumab and had non-missing baseline ADA and at least 1 non-missing post-baseline ADA results for Durvalumab. T75+D arm was closed during study.

Number of participants with Anti-Drug Antibody (ADA) response to Tremelimumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Tremelimumab for each indicated category.

Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of tremelimumab. Assessed up to approximately 46 months after the first randomization.

Population: The Tremelimumab ADA evaluable set includes all participants who received at least 1 dose of Tremelimumab and had non-missing baseline ADA and at least 1 non-missing post-baseline ADA results for Tremelimumab. T75+D arm was closed during study.

PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\] using Investigator assessments) was defined as the time from the date of randomization until the date of objective disease progression or death by any cause in the absence of progression, regardless of whether the patient withdrew from study treatment or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as a at least 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - 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 5 mm from nadir.

Time frame: Tumor scans performed at baseline, every 8 weeks for the first 48 weeks following randomization, and every 12 weeks thereafter until RECIST 1.1-defined progression. Assessed up to DCO (27Aug2021, to a maximum of approximately 46 months)

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.

Blood sample were collected at pre-specified timepoints and Durvalumab concentrations in serum (ug/mL) were reported over time.

Time frame: To evaluate the PK of Durvalumab, samples were collected pre-dose at week 4 and week 12 and post-dose at week 12. Assessed at the final analysis DCO (27Aug2021).

Population: PK analysis set includes all participants who received at least 1 dose Durvalumab per the study protocol for whom any PK post-dose data were available (ie, at least 1 non-missing post-dose PK result). T75+D arm was closed during study.

Blood sample were collected at pre-specified timepoints and Tremelimumab concentrations in serum (ug/mL) were reported over time.

Time frame: To evaluate the PK of Tremelimumab, samples were collected at week 0 (post-dose), week 4, and week 12. Assessed at the final analysis DCO (27Aug2021).

Population: PK analysis set includes all participants who received at least 1 dose of Tremelimumab per the study protocol for whom any PK post-dose data were available (ie, at least 1 non-missing post-dose PK result). T75+D arm was closed during study.

TTP was defined as the time from randomization until objective tumor progression in the absence of death. If participants died without tumor progression, they were censored at the time of death.

Time frame: From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Population: The FAS included all participants who were randomized. T75+D arm was closed during study.