This phase III trial compares the effect of immunotherapy (IO) with stereotactic body radiation therapy (SBRT) to IO alone in treating patients with liver cancer (hepatocellular cancer) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). The usual approach is treatment with IO-based drug combinations, such as atezolizumab and bevacizumab, durvalumab and tremelimumab, or ipilimumab and nivolumab. IO with monoclonal antibodies, such as durvalumab, tremelimumab, atezolizumab, nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Giving IO with SBRT may be more effective than IO alone in helping patients with advanced hepatocellular cancer live longer.
Pathologically (histologically or cytologically) proven diagnosis of HCC (strongly recommended)
Radiographically proven (American Association for the Study of Liver Diseases [AASLD] criteria) diagnosis of HCC by multiphasic MRI and/or CT scan is allowed.
For patients with a prior or concurrent malignancy, pathologic confirmation of hepatocellular cancer is required.
HCC macrovascular invasion, defined as enhancing vascular thrombosis demonstrating arterial enhancement and venous or delayed venous washout on multiphasic MRI and/or CT is required.
None
Parallel
Atezolizumab
Biological/VaccineGiven IV
Bevacizumab
Biological/VaccineGiven IV
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT and PET/CT
Durvalumab
Biological/VaccineGiven IV
Ipilimumab
Biological/VaccineGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Nivolumab
Biological/VaccineGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Questionnaire Administration
Other interventionAncillary studies
Stereotactic Body Radiation Therapy
RadiationUndergo liver SBRT
Tremelimumab
Biological/VaccineGiven IV
Overall survival (OS)
Will be estimated by the Kaplan-Meier method (Kaplan 1958). The distributions of the OS estimates between the two arms will be compared using a log-rank test. The Cox regression model will be used to analyze the effects of factors, in addition to treatment, including, but not limited to stratification factors, which may be associated with OS. The primary analysis will happen after at least 150 OS events (deaths) have occurred and will be tested with a 1-sided significance level of 0.022 (level based on not having stopped at either of the 2 planned interim analyses).
Progression-free survival (PFS)
Defined as local progression, distant failure, or death due to any cause. PFS will be estimated by the Kaplan-Meier method (Kaplan 1958) and estimates between treatment arms will be compared using the log-rank test (Mantel 1966). The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS (Cox 1972).
Objective response rate (ORR)
Defined as having a complete or partial response. ORR will be compared between treatment arms using a chi-squared test. Duration of response will also be reported.
Vascular recanalization (VR)
Defined as having a complete or partial vascular thrombosis response. The VR proportion for each treatment arm will be determined and compared between treatment arms using a chi-squared test. Time to best VR response before progression and duration of VR response will be reported, but no statistical testing will be done.
Short-term toxicity
Defined as grade ≥ 4 adverse events (AEs). Will be compared between the treatment arms using a Z-test.
Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) mean total score at 6 Months
Mean FACT-Hep total score will be compared between treatment arms using a t-test, if normality is met, or Wilcoxon rank-sum test if not. Regression modeling will be used to analyze the effects of factors (e.g. stratification factors and other relevant baseline factors), in addition to treatment, that may be associated with 6-month mean FACT-Hep total score. No statistical testing will be done for subscales.
FACT-Hep total score over time
A mixed effects model will be used to assess changes over time. Fixed effects will include baseline scores, treatment arm, stratification factors, as well as the interaction between time and treatment. If the interaction between time and treatment is significant at the 0.05 level, t-tests assessing the between arm difference at each timepoint, within the context of the model, will be conducted.
Quality-adjusted survival
If the primary endpoint supports the primary hypothesis and/or the European Quality of Life Five Dimension (EQ-5D) significantly differs between treatment arms, the quality-adjusted survival of each treatment will be evaluated and compared using the EQ-5D scale. The EQ-5D is a 2-part self-assessment questionnaire. To examine trade-offs between the survival time and QOL, they will be combined for each patient into a single measurement: quality-adjusted life years (QALY). QALY is defined by the weighted sum of different time episodes added up to a total quality-adjusted survival time. QALY will be analyzed using the EQ-5D, using a 2-sided alpha=0.025 to adjust for multiple comparisons.
OS by sex
Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals (CIs) by sex will be provided.
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