Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Durvalumab

Tremelimumab

Sorafenib

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Protein Kinase Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

Durvalumab in combination with tremelimumab (Regimen 1)

Durvalumab in combination with tremelimumab (Regimen 2)

Tremelimumab (Regimen 1)

Tremelimumab (Regimen 2)

Durvalumab (Regimen 1)

Durvalumab (Regimen 2)

This is a randomized, open-label, multi-center, global, Phase III study to assess the efficacy and safety of durvalumab plus tremelimumab combination therapy and durvalumab monotherapy versus sorafenib in the treatment of patients with no prior systemic therapy for unresectable HCC. The patients cannot be eligible for locoregional therapy

The study population includes patients 18 years of age or older with advanced HCC, Barcelona Clinic Liver Cancer stage B not eligible for locoregional therapy or stage C, and Child-Pugh A classification liver disease. Patients must not have received any prior systemic therapy for unresectable HCC.

Patients in all treatment arms may continue receiving their originally assigned treatment, at the Investigator's discretion, until progression

Patients in all arms with confirmed PD who, in the Investigator's opinion, continue to receive benefit from their assigned treatment and meet the criteria for treatment in the setting of PD may continue to receive their assigned treatment.

If a patient discontinues study drug(s) due to disease progression, the patient will enter survival follow-up. Patients who have discontinued treatment due to toxicity or symptomatic deterioration or who have commenced subsequent anticancer therapy, will have tumor assessments until confirmed PD and will be followed for survival

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

A Randomized, Open-label, Multi-center Phase III 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).

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).

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.

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.

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.

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.

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 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.

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%).

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.

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.

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.

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.

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

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

AstraZeneca

TEAE was defined as any AE that started after dosing or prior to dosing and worsens following treatment exposure. AE was observed up until 90 days following discontinuation of the last dose of study drug, or until the initiation of the first subsequent therapy following discontinuation of treatment. All-cause mortality was reported for all randomized participants. Adverse events were reported for participants who received at least 1 dose of study drug regardless of the randomized assignment.

Durva 1500 mg

Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W

Treme 300 mg x1 Dose + Durva 1500 mg

Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg Q4W

Treme 75 mg x4 Doses + Durva 1500 mg

Sora 400 mg

Total

Age, Continuous

>=65-<75

>=75

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

Asia (except Japan)

Rest of World (includes Japan)

Region group

The full analysis set (FAS) included all participants who were randomized.

Global Clinical Lead

The analysis was performed using stratified log-rank test adjusting for treatment, etiology of liver disease (HBV versus HCV versus others), ECOG (0 versus 1), and macro-vascular invasion (yes versus no). The values of the stratification factors were obtained from IVRS.

The analysis was performed using a Cox proportional hazards model adjusting for treatment, etiology of liver disease (HBV versus HCV versus others), ECOG (0 versus 1), and macro-vascular invasion (yes versus no). Values of the variables used for adjustment were obtained from IVRS.

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

Overall Survival (OS) - Treme 300 mg x1 Dose + Durva 1500 mg vs Sora 400 mg

Overall Survival (OS) - Durva 1500 mg vs Sora 400 mg

Survival rate at 18 months

Survival rate at 24 months

Survival rate at 36 months

Overall Survival (OS) at 18, 24, and 36 Months After Randomization

Progression Free Survival (PFS)

Time To Progression (TTP)

Objective Response Rate (ORR)

Disease Control Rate (DCR)

Duration of response from onset of response

Time to onset of response from randomization

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.

Duration of Objective Response (DoR)

PD-L1 expression positive (TIP>=1%)

PD-L1 expression negative (TIP<1%)

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

Overall Survival (OS) by PD-L1

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

EORTC QLQ-C30 Time to Global Health Status/QoL Deterioration

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

EORTC QLQ-HCC18 Time to Symptom (Abdominal Pain) Deterioration

EORTC QLQ-HCC18 Time to Symptom (Shoulder Pain) Deterioration

EORTC QLQ-HCC18 Time to Symptom (Abdominal Swelling) Deterioration

Treatment-emergent ADA positive (ADA Incidence)

Treatment-induced ADA (Positive Post-baseline only)

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.

Presence of ADA for Durvalumab

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.

Presence of ADA for Tremelimumab

Cycle 2 (Week 4) pre-dose, Geometric mean

Cycle 4 (Week 12) pre-dose, Geometric mean

Cycle 4 (Week 12) post-dose, Geometric mean

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.

Summary of Durvalumab Concentration Over Time

Cycle 1 (Week 0) post-dose, Geometric mean

Cycle 2 (Week 4), Geometric mean

Cycle 4 (Week 12), Geometric mean

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.

Spots Global Cancer Trial Database for durvalumab (regimen 2)