A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150)

• ClinicalTrials.gov Identifier: NCT03434379
• Recruitment Status: Completed
• First Posted: February 15, 2018
• Results First Posted: November 5, 2021
• Last Update Posted: November 25, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 31, 2018
• First Posted Date: February 15, 2018
• Results First Submitted Date: August 16, 2021
• Results First Posted Date: November 5, 2021
• Last Update Posted Date: November 25, 2022
• Actual Study Start Date: March 15, 2018
• Actual Primary Completion Date: August 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 16, 2021)

• Overall Survival (OS) in the Global Population [ Time Frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months) ]
  OS was defined as the time from randomization to death from any cause.
• Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• Overall Survival (OS) in the China Population [ Time Frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months) ]
  OS was defined as the time from randomization to death from any cause.
• PFS-IRF Per RECIST v1.1 in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).

Original Primary Outcome Measures (submitted: February 9, 2018)

• Overall Survival (OS) [ Time Frame: Baseline to death from any cause, through the end of study (up to approximately 4 years) ]
• Objective Response (OR) defined as complete response or partial response as determined by the Investigator according to RECIST V1.1 [ Time Frame: Baseline until disease progression or death from any cause, whichever occurs first. Following initiation of study treatment, assessed at baseline, every 6 weeks for first 54 weeks, and every 9 weeks thereafter (up to approximately 4 years) ]

Current Secondary Outcome Measures (submitted: October 7, 2021)

• Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• PFS-IRF Per HCC mRECIST in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• TTP-IRF Per HCC mRECIST in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• Overall Survival by Baseline AFP in the Global Population [ Time Frame: From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  OS was defined as the time from randomization to death from any cause. Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed.
• PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed.
• PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed.
• Time to Deterioration (TTD) in the Global Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  TTD was defined as the time from randomization to the first deterioration (decrease from baseline of >/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks.
• Percentage of Participants With Adverse Events (AEs) in the Global Population [ Time Frame: Up to end of study (up to approximately 40 months) ]
  An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
• Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population [ Time Frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days) ]
• Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population [ Time Frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days) ]
• Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population [ Time Frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 months) ]
• Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
• Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population [ Time Frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• PFS-IRF Per HCC mRECIST in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• TTP-IRF Per HCC mRECIST in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
• Time to Deterioration (TTD) in the China Population [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) ]
  TTD was defined as the time from randomization to the first deterioration (decrease from baseline of >/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks.
• Percentage of Participants With Adverse Events (AEs) in the China Population [ Time Frame: Up to end of study (up to approximately 40 months) ]
  An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
• Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population [ Time Frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days) ]
• Trough Serum Concentration (Cmin) of Atezolizumab in the China Population [ Time Frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days) ]
• Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population [ Time Frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months) ]

Original Secondary Outcome Measures (submitted: February 9, 2018)

• Progression Free Survival (PFS) as Determined by the Investigator According to RECIST v1.1 [ Time Frame: Baseline until disease progression or death from any cause, whichever occurs first. Following initiation of study treatment, assessed at baseline, every 6 weeks for first 54 weeks, and every 9 weeks thereafter (up to approximately 4 years) ]
• Time to Progression (TTP) as Determined by the Investigator According to RECIST v1.1 [ Time Frame: Baseline to first occurance of disease progression. Following initiation of study treatment, assessed at baseline, every 6 weeks for first 54 weeks, and every 9 weeks thereafter (up to approximately 4 years) ]
• Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From first occurrence of a documented objective response to disease progression or death. Following initiation of study treatment, assessed at baseline, every 6 weeks for the first 54 weeks, and every 9 weeks thereafter (up to approximately 4 years) ]
• OR as Determined by an Independent Review Facility (IRF) According to Response Evaluation Criteria in Solid Tumors, v1.1 (RECIST v1.1) [ Time Frame: From the first occurrence of a documented objective response until confirmed disease progression or death from any cause (whichever occurs first), through the end of study (Approximately 4 years) ]
• PFS as Determined by an IRF According to RECIST v1.1 [ Time Frame: Baseline until confirmed disease progression or death from any cause (whichever occurs first), through the end of study (Approximately 4 years) ]
• TTP as Determined by an IRF According to RECIST v1.1 [ Time Frame: Baseline until confirmed disease progression or death from any cause (whichever occurs first), through the end of study (up to approximately 4 years) ]
• DOR as Determined by an IRF According to RECIST v1.1 [ Time Frame: From the first occurrence of a documented objective response until confirmed disease progression or death from any cause (whichever occurs first), through the end of study (up to approximately 4 years) ]
• OR as Determined by an IRF According to Hepatocellular Carcinoma Modified RECIST (HCC mRECIST) [ Time Frame: From the first occurrence of a documented objective response until confirmed disease progression or death from any cause (whichever occurs first), through the end of study (up to approximately 4 years) ]
• PFS Determined by an IRF According to HCC mRECIST [ Time Frame: Baseline to first occurrence of disease progression or death from any cause (whichever occurs first), through the end of study (up to approximately 4 years) ]
• TTP as Determined by an IRF According to HCC mRECIST [ Time Frame: Baseline to first occurrence of disease progression or death from any cause (whichever occurs first), through the end of study (up to approximately 4 years) ]
• DOR as Determined by an IRF According to HCC mRECIST [ Time Frame: Time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) through the end of study (up to approximately 4 years) ]
• Time to Deterioration (TTD) in Patient-Reported HRQoL/GHS, physical functioning, and role functioning, as determined by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30) Score [ Time Frame: Baseline to first deterioration maintained for two consecutive timepoints, or one timepoint followed by death (from any cause) within 3 weeks from any cause, through 1 year after treatment discontinuation ]
• OR as determined by the investigator according to RECIST v1.1 [ Time Frame: Baseline Serum Alpha-Fetoprotein (AFP) Level (< 400 ng/mL or >/=400 ng/mL) ]
• Serum Concentration of Atezolizumab [ Time Frame: Day 1 cycle 1, prior to infusion and 30 minutes post-infusion; Day 1 of cycles 2 and 4 prior to infusion; at treatment discontinuation, through end of study (Approximately 4 years) ]
• Change from Baseline in Anti-Drug Antibodies (ADAs) to Atezolizumab [ Time Frame: Baseline to first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 4 years) ]
• Percentage of Participants with Adverse Events [ Time Frame: Baseline to end of study (approximately 4 years) ]
• OR as Determined by an IRF According to RECIST v1.1 [ Time Frame: Baseline Serum AFP Level (< 400 ng/mL or >/=400 ng/mL) ]
• OS [ Time Frame: Baseline Serum AFP Level (< 400 ng/mL or >/= 400 ng/mL) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
• Official Title: A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
• Brief Summary: This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.
• Detailed Description: The participants will be randomized in a 2:1 ratio to one of the two treatment arms: Arm A (experimental arm): Atezolizumab +bevacizumab; Arm B (control arm): Sorafenib
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Drug: Atezolizumab
  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21 day cycle
• Drug: Bevacizumab
  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21 day cycle
• Drug: Sorafenib
  Sorafenib will be administered by mouth, 400 mg twice per day, on days 1-21 of each 21-day cycle

Study Arms

• Experimental: Atezolizumab + Bevacizumab
  Participants will receive Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator
  Interventions:

  • Drug: Atezolizumab
  • Drug: Bevacizumab
• Active Comparator: Sorafenib
  Participants will receive Sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator
  Intervention: Drug: Sorafenib

Publications *

• Kaseb AO, Guan Y, Gok Yavuz B, Abbas AR, Lu S, Hasanov E, Toh HC, Verret W, Wang Y. Serum IGF-1 Scores and Clinical Outcomes in the Phase III IMbrave150 Study of Atezolizumab Plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma. J Hepatocell Carcinoma. 2022 Oct 11;9:1065-1079. doi: 10.2147/JHC.S369951. eCollection 2022.
• Li Y, Liang X, Li H, Chen X. Atezolizumab plus bevacizumab versus nivolumab as first-line treatment for advanced or unresectable hepatocellular carcinoma: A cost-effectiveness analysis. Cancer. 2022 Nov 15;128(22):3995-4003. doi: 10.1002/cncr.34457. Epub 2022 Sep 16.
• Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. doi: 10.1016/j.jhep.2021.11.030. Epub 2021 Dec 11.
• Salem R, Li D, Sommer N, Hernandez S, Verret W, Ding B, Lencioni R. Characterization of response to atezolizumab + bevacizumab versus sorafenib for hepatocellular carcinoma: Results from the IMbrave150 trial. Cancer Med. 2021 Aug;10(16):5437-5447. doi: 10.1002/cam4.4090. Epub 2021 Jun 29.
• Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, Kudo M, Breder V, Merle P, Kaseb A, Li D, Mulla S, Verret W, Xu DZ, Hernandez S, Ding B, Liu J, Huang C, Lim HY, Cheng AL, Ducreux M. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):991-1001. doi: 10.1016/S1470-2045(21)00151-0. Epub 2021 May 27.
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• Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 26, 2021): 558
• Original Estimated Enrollment (submitted: February 9, 2018): 480
• Actual Study Completion Date: November 17, 2022
• Actual Primary Completion Date: August 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Locally advanced or metastatic and/or unresectable Hepatocellular Carcinoma (HCC)
• No prior systemic therapy for HCC. Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization.
• At least one measurable untreated lesion
• ECOG Performance Status of 0 or 1
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent
• For men: agreement to remain abstinent
• Child-Pugh class A

Exclusion Criteria:

• History of leptomeningeal disease
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
• Known active tuberculosis
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
• A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
• Moderate or severe ascites
• History of hepatic encephalopathy
• Co-infection of HBV and HCV
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Treatment with systemic immunostimulatory agents
• Inadequately controlled arterial hypertension
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Evidence of bleeding diathesis or significant coagulopathy
• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
• Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, China, Czechia, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03434379
• Other Study ID Numbers: YO40245; 2017-003691-31 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: November 2022