Hepatocellular Carcinoma
Conditions
Keywords
liver, cancer, hepatocellular, carcinoma
Brief summary
This Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with atezolizumab versus the standard of care sorafenib in adults with advanced hepatocellular carcinoma (HCC) who have not received previous systemic anticancer therapy. A single-agent cabozantinib arm will be enrolled in which participants receive single agent cabozantinib in order to determine its contribution to the overall safety and efficacy of the combination with atezolizumab.
Detailed description
This is a multicenter, randomized, open-label, controlled Phase 3 trial of cabozantinib in combination with atezolizumab versus sorafenib in adults with advanced HCC who have not received previous systemic anticancer therapy in the advanced HCC setting. The primary objective of this study is to evaluate the effect of cabozantinib in combination with atezolizumab on the duration of progression-free survival (PFS) and duration of overall survival (OS) versus sorafenib. The secondary objective is to evaluate the activity of single-agent cabozantinib compared with sorafenib in this patient population.
Interventions
DRUGCabozantinib
Supplied as 20-mg tablets; administered orally daily at 40 mg
DRUGSorafenib
Supplied as 200-mg tablets; administered orally twice daily at 400 mg
DRUGAtezolizumab
Supplied as 1200 mg/20 mL (60 mg/mL) in sing-dose vials; administered as an intravenous (IV) infusion q3w
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
At least 740 eligible participants with advanced HCC will be randomized in a 2:1:1 ratio. Experimental arm (at least 370 participants) will receive cabozantinib plus atezolizumab. Control arm (at least 185 participants) will receive sorafenib. Single-agent cabozantinib arm (at least185 participants) will receive single-agent cabozantinib
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients by Computed Tomography (CT) or Computed Tomography (MRI) per the American Association for the Study of Liver Diseases (AASLD) 2018 or European Association for the Study of the Liver (EASL) 2018 guidelines. * The participant has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, ablation therapy) or locoregional therapy (eg, TACE). * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the Investigator. * Barcelona Clinic Liver Cancer (BCLC) stage Category B or C. * Child-Pugh Score of A. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Key
Exclusion criteria
* Known fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma. * Prior systemic anticancer therapy for advanced HCC including but not limited to chemotherapy, small molecule kinase inhibitors, and immune checkpoint inhibitors (ICIs). Participants who have received local intratumoral or arterial chemotherapy are eligible; local anticancer therapy within ≥ 28 days before randomization * Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 8 weeks prior to randomization. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 8 weeks prior to randomization. * Concomitant anticoagulation with oral anticoagulants Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population | From the date of first participant randomization up to 28 months | PFS was defined as the time from randomization to the earlier of either the date of radiographic progression defined as a 20% increase in the sum of the longest diameters of target lesions, or the unequivocal appearance of new lesions, or progression of non-target disease per Blinded Independent Radiology Committee (BIRC) or the date of death due to any cause per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. |
| Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population | From the date of first participant randomization up to 36 months | OS was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population | From the date of first participant randomization up to 28 months | PFS was defined as the time from randomization to the earlier of either the date of radiographic progression per BIRC or the date of death due to any cause per RECIST version 1.1. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Colombia, Czechia, France, Georgia, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Mexico, Netherlands, New Zealand, Philippines, Poland, Romania, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm: Cabozantinib + Atezolizumab Participants received 40 mg cabozantinib oral tablets once daily + 1200 mg IV infusion of atezolizumab once every 3 weeks for up to 38 months. | 432 |
| Single-Agent Cabozantinib Participants received 60 mg cabozantinib oral tablets once daily for up to 38 months. | 188 |
| Control Arm: Sorafenib Participants received 400 mg sorafenib oral tablets twice daily for up to 38 months. | 217 |
| Total | 837 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 140 | 60 | 51 |
| Overall Study | Did not receive any study treatment | 3 | 0 | 10 |
| Overall Study | Lack of Efficacy | 12 | 6 | 6 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
| Overall Study | Other than specified | 5 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 |
| Overall Study | Radiographic progression | 204 | 92 | 115 |
| Overall Study | Sponsor decision, | 41 | 5 | 7 |
| Overall Study | Withdrawal by Subject | 26 | 23 | 24 |
Baseline characteristics
| Characteristic | Control Arm: Sorafenib | Total | Single-Agent Cabozantinib | Experimental Arm: Cabozantinib + Atezolizumab |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 105 Participants | 394 Participants | 91 Participants | 198 Participants |
| Age, Categorical Between 18 and 65 years | 112 Participants | 443 Participants | 97 Participants | 234 Participants |
| Race/Ethnicity, Customized Asian | 72 Participants | 263 Participants | 64 Participants | 127 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants | 14 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 15 Participants | 78 Participants | 21 Participants | 42 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 183 Participants | 693 Participants | 158 Participants | 352 Participants |
| Race/Ethnicity, Customized Not Reported | 19 Participants | 66 Participants | 9 Participants | 38 Participants |
| Race/Ethnicity, Customized Other than specified | 33 Participants | 137 Participants | 24 Participants | 80 Participants |
| Race/Ethnicity, Customized White | 111 Participants | 423 Participants | 95 Participants | 217 Participants |
| Sex: Female, Male Female | 31 Participants | 133 Participants | 30 Participants | 72 Participants |
| Sex: Female, Male Male | 186 Participants | 704 Participants | 158 Participants | 360 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 307 / 429 | 135 / 188 | 141 / 207 |
| other Total, other adverse events | 414 / 429 | 182 / 188 | 202 / 207 |
| serious Total, serious adverse events | 226 / 429 | 88 / 188 | 85 / 207 |
Outcome results
Primary
Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population
OS was defined as the time from randomization to death due to any cause.
Time frame: From the date of first participant randomization up to 36 months
Population: ITT population included all participants randomized to the experimental (cabozantinib + atezolizumab) arm and control (sorafenib) arm.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Experimental Arm: Cabozantinib + Atezolizumab | Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population | 16.46 months |
| Control Arm: Sorafenib | Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population | 15.51 months |
p-value: 0.905696% CI: [0.78, 1.24]Log Rank
Primary
Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population
PFS was defined as the time from randomization to the earlier of either the date of radiographic progression defined as a 20% increase in the sum of the longest diameters of target lesions, or the unequivocal appearance of new lesions, or progression of non-target disease per Blinded Independent Radiology Committee (BIRC) or the date of death due to any cause per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: From the date of first participant randomization up to 28 months
Population: PITT population included the first 372 participants randomized to the experimental (cabozantinib + atezolizumab) arm and control (sorafenib) arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm: Cabozantinib + Atezolizumab | Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population | 6.80 months |
| Control Arm: Sorafenib | Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population | 4.21 months |
p-value: 0.001299% CI: [0.44, 0.91]Log Rank
Secondary
PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population
PFS was defined as the time from randomization to the earlier of either the date of radiographic progression per BIRC or the date of death due to any cause per RECIST version 1.1.
Time frame: From the date of first participant randomization up to 28 months
Population: ITT population included all participants randomized to the single agent cabozantinib arm and control (sorafenib) arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm: Cabozantinib + Atezolizumab | PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population | 5.82 months |
| Control Arm: Sorafenib | PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population | 4.27 months |