Carcinoma, Hepatocellular
Conditions
Brief summary
This is a Phase IIIb, one arm, multicenter, open-label study primarily designed to evaluate the safety of atezolizumab + bevacizumab in participants with unresectable or unsuitable for locoregional treatments for metastatic HCC not previously treated with systemic therapy. As part of its secondary objectives, this study is also designed to evaluate the efficacy of atezolizumab and bevacizumab in these participants.
Interventions
DRUGAtezolizumab
Atezolizumab will be administered intravenously at a dose of 1200 mg on Day 1 of each 21-day cycle.
DRUGBevacizumab
Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology or radiologically, following the AASLD criteria * Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies * No prior systemic therapy (including systemic investigational agents) for HCC * At least one measurable (per RECIST 1.1) untreated lesion detected by CT scan * Patients who received prior local therapy such as radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization (excluding transarterial radioembolization.) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1
Exclusion criteria
* 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 (CT) scan * Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC * Co-infection of HBV and HCV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Atezolizumab and/or Bevacizumab Due to Adverse Events (AE) of Grade ≥ 3 | From Cycle 1 Day 1 up to 30 days after the final dose of the study drug or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 32 months) | AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of AEs was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) with the following grades: Grade 1 = asymptomatic or mild symptoms; Grade 2 = minimal, local, or non-invasive intervention indicated; Grade 3 = severe or medically significant, but not immediately life-threatening; Grade 4 = life-threatening consequences or urgent intervention indicated and Grade 5 = death related to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 35 months | OS was defined as the time from initiation of study treatment to death from any cause. OS was analyzed using Kaplan-Meier (K-M) methods and Greenwood's formula. Any participant who did not die during the study was censored at the last known date to be alive. |
| Time to Progression (TTP) | Up to 35 months | TTP was defined as the time from initiation of study treatment to the first occurrence of PD, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, SOD must also demonstrate an absolute increase of ≥ 5 mm. TTP was analyzed using K-M methods and Greenwood's formula. Any participant who had no disease progression was censored at the last known date without disease progression. |
| Progression-free Survival (PFS) | Up to 35 months | PFS was defined as the time from initiation of study treatment to the first occurrence of disease progression (PD) or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm). PFS was analyzed using K-M methods and Greenwood's formula. Any participant who did not experience disease progression or death during the study and were censored at the last known date to be alive or without disease progression. |
| Objective Response Rate (ORR) | Up to 35 months | ORR = percentage of participants with a complete or partial response (CR or PR), on 2 consecutive investigator assessments ≥ 4 weeks apart in participants with measurable disease at baseline as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants without a post-baseline tumor assessment were considered non-responders. 95% confidence interval (CI) was derived using Wilson score intervals. Percentages have been rounded off. |
| Percentage of Participants With Ascites and/or Hepatic Encephalopathy | Up to approximately 32 months | Deterioration of hepatic function was monitored by presence of ascites and/or hepatic encephalopathy. |
| Percentage of Participants Who Started Second-line Treatment | Up to 35 months | Participants who started second-line of treatment were assessed. Percentages have been rounded off. |
| Change From Baseline in International Normalized Ratio (INR) | Baseline up to Cycle 42 (1 cycle = 21 days) | The INR is a standardized measure of the prothrombin time. Blood samples were collected from participants to evaluate coagulation parameters. |
| Change From Baseline in Albumin-Bilirubin (ALBI) Score | Baseline up to Cycle 42 (1 cycle = 21 days) | Blood samples were collected from participants to evaluate of ALBI grades. ALBI assessment grades of 1 to 3 was based on ALBI score calculation. ALBI score= log10 bilirubin (micromole per liter) \[μmol/L\] × 0.66 + albumin (grams per liter) \[g/L\] × -0.0852. ALBI score ≤ -2.60 = ALBI grade 1; -2.60 \< ALBI score ≤ -1.39 = ALBI grade 2 and -1.39 \< ALBI score = ALBI grade 3. |
| Duration of Response (DOR) | Up to 35 months | DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. DOR was analyzed using K-M methods and Greenwood's formula. Any participant who did not experience disease progression or death during the study was censored at the last known date to be alive or without disease progression. |
Countries
Spain
Participant flow
Recruitment details
A total of 100 participants took part in the study in Spain from 04 May 2021 to 26 April 2024.
Pre-assignment details
Participants with unresectable hepatocellular carcinoma (HCC) who received no prior systemic treatment and were considered unsuitable for locoregional therapy were enrolled in this study to receive a combination of atezolizumab plus bevacizumab until unacceptable toxicity or loss of clinical benefit.
Participants by arm
| Arm | Count |
|---|---|
| Atezolizumab + Bevacizumab Participants received atezolizumab, 1200 mg, IV, Q3W along with bevacizumab, 15 mg/kg, IV, Q3W on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit. | 100 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 51 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Non-compliance With Study Drug | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 2 |
| Overall Study | Study Terminated by Sponsor | 31 |
| Overall Study | Withdrawal by Subject | 10 |
Baseline characteristics
| Characteristic | Atezolizumab + Bevacizumab |
|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 99 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 51 / 100 |
| other Total, other adverse events | 98 / 100 |
| serious Total, serious adverse events | 46 / 100 |
Outcome results
Primary
Number of Participants Who Discontinued Atezolizumab and/or Bevacizumab Due to Adverse Events (AE) of Grade ≥ 3
AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of AEs was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) with the following grades: Grade 1 = asymptomatic or mild symptoms; Grade 2 = minimal, local, or non-invasive intervention indicated; Grade 3 = severe or medically significant, but not immediately life-threatening; Grade 4 = life-threatening consequences or urgent intervention indicated and Grade 5 = death related to AE.
Time frame: From Cycle 1 Day 1 up to 30 days after the final dose of the study drug or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 32 months)
Population: Safety population included all screened participants (participants who signed the informed consent) who received at least one full or partial dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atezolizumab + Bevacizumab | Number of Participants Who Discontinued Atezolizumab and/or Bevacizumab Due to Adverse Events (AE) of Grade ≥ 3 | 19 Participants |
Secondary
Change From Baseline in Albumin-Bilirubin (ALBI) Score
Blood samples were collected from participants to evaluate of ALBI grades. ALBI assessment grades of 1 to 3 was based on ALBI score calculation. ALBI score= log10 bilirubin (micromole per liter) \[μmol/L\] × 0.66 + albumin (grams per liter) \[g/L\] × -0.0852. ALBI score ≤ -2.60 = ALBI grade 1; -2.60 \< ALBI score ≤ -1.39 = ALBI grade 2 and -1.39 \< ALBI score = ALBI grade 3.
Time frame: Baseline up to Cycle 42 (1 cycle = 21 days)
Population: Safety population included all screened participants (participants who signed the informed consent) who received at least one full or partial dose of study treatment. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atezolizumab + Bevacizumab | Change From Baseline in Albumin-Bilirubin (ALBI) Score | Baseline | -2.7 score | Standard Deviation 0.4 |
| Atezolizumab + Bevacizumab | Change From Baseline in Albumin-Bilirubin (ALBI) Score | Cycle 42 | 0.4 score | Standard Deviation 0.4 |
Secondary
Change From Baseline in International Normalized Ratio (INR)
The INR is a standardized measure of the prothrombin time. Blood samples were collected from participants to evaluate coagulation parameters.
Time frame: Baseline up to Cycle 42 (1 cycle = 21 days)
Population: Safety population included all screened participants (participants who signed the informed consent) who received at least one full or partial dose of study treatment. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atezolizumab + Bevacizumab | Change From Baseline in International Normalized Ratio (INR) | Baseline | 1.1 INR of prothrombin time | Standard Deviation 0.1 |
| Atezolizumab + Bevacizumab | Change From Baseline in International Normalized Ratio (INR) | Cycle 42 | 0.1 INR of prothrombin time | Standard Deviation 0 |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. DOR was analyzed using K-M methods and Greenwood's formula. Any participant who did not experience disease progression or death during the study was censored at the last known date to be alive or without disease progression.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study. Overall number analyzed is the number of participants with an overall response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Duration of Response (DOR) | 15.9 months |
Secondary
Objective Response Rate (ORR)
ORR = percentage of participants with a complete or partial response (CR or PR), on 2 consecutive investigator assessments ≥ 4 weeks apart in participants with measurable disease at baseline as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants without a post-baseline tumor assessment were considered non-responders. 95% confidence interval (CI) was derived using Wilson score intervals. Percentages have been rounded off.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Bevacizumab | Objective Response Rate (ORR) | 24.2 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from initiation of study treatment to death from any cause. OS was analyzed using Kaplan-Meier (K-M) methods and Greenwood's formula. Any participant who did not die during the study was censored at the last known date to be alive.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Overall Survival (OS) | 24.8 months |
Secondary
Percentage of Participants Who Started Second-line Treatment
Participants who started second-line of treatment were assessed. Percentages have been rounded off.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Bevacizumab | Percentage of Participants Who Started Second-line Treatment | 24.2 percentage of participants |
Secondary
Percentage of Participants With Ascites and/or Hepatic Encephalopathy
Deterioration of hepatic function was monitored by presence of ascites and/or hepatic encephalopathy.
Time frame: Up to approximately 32 months
Population: Safety population included all screened participants (participants who signed the informed consent) who received at least one full or partial dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Bevacizumab | Percentage of Participants With Ascites and/or Hepatic Encephalopathy | 17 percentage of participants |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from initiation of study treatment to the first occurrence of disease progression (PD) or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm). PFS was analyzed using K-M methods and Greenwood's formula. Any participant who did not experience disease progression or death during the study and were censored at the last known date to be alive or without disease progression.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Progression-free Survival (PFS) | 9.3 months |
Secondary
Time to Progression (TTP)
TTP was defined as the time from initiation of study treatment to the first occurrence of PD, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, SOD must also demonstrate an absolute increase of ≥ 5 mm. TTP was analyzed using K-M methods and Greenwood's formula. Any participant who had no disease progression was censored at the last known date without disease progression.
Time frame: Up to 35 months
Population: ITT population included all screened participants (participants who signed the informed consent) who were eligible for the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Time to Progression (TTP) | 11.2 months |