Carcinoma, Hepatocellular
Conditions
Brief summary
This study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab compared with active surveillance in participants with completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence.
Interventions
DRUGAtezolizumab
Atezolizumab 1200 mg will be administered by IV infusion 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
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with a first diagnosis of HCC who have undergone either a curative resection or ablation (radiofrequency ablation \[RFA\] or microwave ablation \[MVA\] only) within 4-12 weeks prior to randomization * Documented diagnosis of HCC that has been completely resected or ablated (RFA or MVA only) * Absence of major macrovascular invasion (except Vp1/Vp2) and extrahepatic spread * Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following curative procedure * Full recovery from surgical resection or ablation within 4 weeks prior to randomization * High risk for HCC recurrence after resection or ablation * For patients who received post-operative transarterial chemoembolization: full recovery from the procedure within 4 weeks prior to randomization * For patients with resected HCC, availability of a representative baseline tumor tissue sample * ECOG Performance Status of 0 or 1 * Child-Pugh Class A status * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm
Exclusion criteria
* Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC * Evidence of residual, recurrent, or metastatic disease at randomization * Clinically significant ascites * History of hepatic encephalopathy * Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization * Have received more than 1 cycle of adjuvant TACE following surgical resection * 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 CT scan * Significant cardiovascular disease within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina * 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 * Active tuberculosis * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications * Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to Day 1 of Cycle 1. * Co-infection with HBV and HCV * Co-infection with HBV and hepatitis D viral infection * Clinical significant uncontrolled or symptomatic hypercalcemia * Any treatment for HCC prior to resection or ablation, including systemic therapy and locoregional therapy such as TACE * Treatment with systemic immunostimulatory or immunosuppressive agents * Inadequately controlled arterial hypertension * History of hypertensive crisis or hypertensive encephalopathy * Significant vascular disease * Evidence of bleeding diathesis or significant coagulopathy * Current or recent use of aspirin or full-dose oral or parenteral anticoagulants * Core biopsy within 3 days of Day 1 of Cycle 1 * History of GI fistula, GI perforation, or intra-abdominal abscess * Serious non-healing or dehiscing wound * Major surgical procedure within four weeks * Chronic daily treatment with a non-steroidal anti-inflammatory drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-Free Survival (RFS), as Determined by IRF | Baseline up to approximately 33 months | RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an IRF, or death from any cause (whichever occurs first). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline up to approximately 91 months | OS is defined as the time from randomization to death from any cause. |
| RFS as Determined by the Investigator | Baseline up to approximately 91 months | RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an investigator, or death from any cause (whichever occurs first). |
| Time to Recurrence (TTR) | Baseline up to approximately 91 months | TTR defined as the time from randomization to first documented occurrence of intrahepatic or extrahepatic HCC, as determined by the investigator and by an IRF. |
| RFS Rate at 24 and 36 Months, as Assessed by the IRF | Randomization up to 24 months and up to 36 months | — |
| RFS Rate at 24 and 36 Months, as Assessed by the Investigator | Randomization up to 24 months and up to 36 months | — |
| OS Rate at 24 and 36 Months | Baseline to 24 and 36 months | OS rate defined as the proportion of patients who have not experienced death from any cause at 24 and 36 months after randomization. |
| Time to Extrahepatic Spread (EHS) or Macrovascular Invasion | Baseline up to approximately 91 months | Time to EHS or macrovascular invasion after randomization, defined as the time from randomization to the first appearance of EHS or macrovascular invasion, as determined by the investigator. |
| RFS in Pd-L1-High Subgroup | Baseline up to approximately 91 months | RFS after randomization as determined by the investigator and by an IRF, among patients in the PD-L1-high subgroup. |
| Percentage of Participants With Adverse Events | Baseline up to approximately 91 months | — |
| Serum Concentration of Atezolizumab | Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and 30 minutes after end of atezolizumab infusion on Day 1 of Cycle 1 (each cycle is 21 days) | Serum concentration of atezolizumab. |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Prior to any drug administration up to approximately 33 month | Number of participants with anti-drug antibodies to atezolizumab. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Costa Rica, Czechia, France, Germany, Hong Kong, Italy, Japan, Mexico, Netherlands, New Zealand, Peru, Poland, Russia, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
This study was conducted at 134 centers in 26 countries/regions.
Pre-assignment details
A total of 668 participants were randomized to the Atezo+Bev arm or the Active Surveillance (AS) arm (334 participants in each arm). Participants randomized to the Active Surveillance arm were offered the option to cross over to the Atezo+Bev arm after disease recurrence. 81 participants from the Active Surveillance arm crossed over to receive treatment with Atezo+Bev.
Participants by arm
| Arm | Count |
|---|---|
| Arm B (Active Surveillance) Active surveillance of participants. | 334 |
| Arm A (Atezolizumab Plus Bevacizumab) Participants received Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity. | 334 |
| Total | 668 |
Baseline characteristics
| Characteristic | Arm A (Atezolizumab Plus Bevacizumab) | Total | Arm B (Active Surveillance) |
|---|---|---|---|
| Age, Continuous | 59.0 Years STANDARD_DEVIATION 12.1 | 59.0 Years STANDARD_DEVIATION 12.3 | 58.9 Years STANDARD_DEVIATION 12.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 276 Participants | 545 Participants | 269 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 37 Participants | 21 Participants |
| Race (NIH/OMB) White | 35 Participants | 76 Participants | 41 Participants |
| Sex: Female, Male Female | 57 Participants | 113 Participants | 56 Participants |
| Sex: Female, Male Male | 277 Participants | 555 Participants | 278 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 334 | 27 / 334 | 11 / 81 |
| other Total, other adverse events | 111 / 330 | 296 / 332 | 63 / 81 |
| serious Total, serious adverse events | 34 / 330 | 80 / 332 | 10 / 81 |
Outcome results
Primary
Recurrence-Free Survival (RFS), as Determined by IRF
RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an IRF, or death from any cause (whichever occurs first).
Time frame: Baseline up to approximately 33 months
Population: The ITT population is defined as all randomized patients, whether or not the patient has received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B (Active Surveillance) | Recurrence-Free Survival (RFS), as Determined by IRF | NA Months |
| Arm A (Atezolizumab Plus Bevacizumab) | Recurrence-Free Survival (RFS), as Determined by IRF | NA Months |
Comparison: Stratification factors include geographic region (Asia Pacific excluding Japan vs. rest of world) and High risk features/curative procedure (Ablation vs. Resection with 1 high risk feature vs. Resection with 2 or more high risk features).p-value: 0.01295% CI: [0.56, 0.93]Log Rank
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
Number of participants with anti-drug antibodies to atezolizumab.
Time frame: Prior to any drug administration up to approximately 33 month
Population: The immunogenicity analysis population consisted of all participants who received any amount of study drug and had at least one measurable anti-drug antibody (ADA) result post-dose available at the clinical data cutoff for the clinical study report.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm B (Active Surveillance) | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Baseline evaluable participants | 8 Participants |
| Arm B (Active Surveillance) | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Post-baseline evaluable participants | 75 Participants |
Secondary
OS Rate at 24 and 36 Months
OS rate defined as the proportion of patients who have not experienced death from any cause at 24 and 36 months after randomization.
Time frame: Baseline to 24 and 36 months
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death from any cause.
Time frame: Baseline up to approximately 91 months
Secondary
Percentage of Participants With Adverse Events
Time frame: Baseline up to approximately 91 months
Secondary
RFS as Determined by the Investigator
RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an investigator, or death from any cause (whichever occurs first).
Time frame: Baseline up to approximately 91 months
Secondary
RFS in Pd-L1-High Subgroup
RFS after randomization as determined by the investigator and by an IRF, among patients in the PD-L1-high subgroup.
Time frame: Baseline up to approximately 91 months
Secondary
RFS Rate at 24 and 36 Months, as Assessed by the Investigator
Time frame: Randomization up to 24 months and up to 36 months
Secondary
RFS Rate at 24 and 36 Months, as Assessed by the IRF
Time frame: Randomization up to 24 months and up to 36 months
Secondary
Serum Concentration of Atezolizumab
Serum concentration of atezolizumab.
Time frame: Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and 30 minutes after end of atezolizumab infusion on Day 1 of Cycle 1 (each cycle is 21 days)
Population: The pharmacokinetic (PK) analysis population will consist of all patients whom had received any amount of study drug and had at least one measurable serum concentration result post-dose available at the clinical data cutoff for the clinical study report.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 1 Day 1 | NA μg/ mL | — |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 1 Day 1, 30 Min After End of Atezo | 440 μg/ mL | Standard Deviation 132 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 2 Day 1 | 88.7 μg/ mL | Standard Deviation 30.4 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 3 Day 1 | 137 μg/ mL | Standard Deviation 53 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 4 Day 1 | 159 μg/ mL | Standard Deviation 58.5 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 8 Day 1 | 196 μg/ mL | Standard Deviation 86.2 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 12 Day 1 | 202 μg/ mL | Standard Deviation 90.1 |
| Arm B (Active Surveillance) | Serum Concentration of Atezolizumab | Cycle 16 Day 1 | 204 μg/ mL | Standard Deviation 89.2 |
Secondary
Time to Extrahepatic Spread (EHS) or Macrovascular Invasion
Time to EHS or macrovascular invasion after randomization, defined as the time from randomization to the first appearance of EHS or macrovascular invasion, as determined by the investigator.
Time frame: Baseline up to approximately 91 months
Secondary
Time to Recurrence (TTR)
TTR defined as the time from randomization to first documented occurrence of intrahepatic or extrahepatic HCC, as determined by the investigator and by an IRF.
Time frame: Baseline up to approximately 91 months