Background
Phase III RCT (n=837) of treatment-naïve advanced hepatocellular carcinoma not amenable to curative or locoregional therapy, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A (cirrhosis ~60%; HBV/HCV ~30%). Excluded fibrolamellar, sarcomatoid, or combined HCC and HBV with viral load >500 IU/mL.
Interventions and follow up
Arm A: cabozantinib 40 mg/day + atezolizumab 1200 mg IV q3wk until progression or unacceptable toxicity
Arm B: cabozantinib 60 mg/day monotherapy
Arm C (control): sorafenib 400 mg PO BID
Primary endpoint: PFS (arm A vs C) and OS (arm A vs C) per ITT
Median follow up: 15.8 months
Arm B: cabozantinib 60 mg/day monotherapy
Arm C (control): sorafenib 400 mg PO BID
Primary endpoint: PFS (arm A vs C) and OS (arm A vs C) per ITT
Median follow up: 15.8 months
Results
mPFS (A vs C): 6.8 vs 4.2 months; HR 0.63, 99% CI 0.44–0.91; P=.0012
mOS (A vs C): 15.4 vs 15.5 months; HR 0.90, 96% CI 0.69–1.18; P=.44
mPFS (B vs C): 5.8 vs 4.3 months; HR 0.71, 99% CI 0.51–1.01; P=.011
mOS (A vs C): 15.4 vs 15.5 months; HR 0.90, 96% CI 0.69–1.18; P=.44
mPFS (B vs C): 5.8 vs 4.3 months; HR 0.71, 99% CI 0.51–1.01; P=.011
Adverse events
Grade 3–4 events: 64% vs 60% vs 46%, arm A vs B vs C
Subsequent systemic therapy: received by 20%, 29%, and 37% of patients in arms A, B, and C respectively
Subsequent systemic therapy: received by 20%, 29%, and 37% of patients in arms A, B, and C respectively
Conclusions
Cabozantinib plus atezolizumab significantly improved PFS over sorafenib in untreated advanced HCC, but did not improve overall survival, so the combination did not meet its dual primary endpoint.
Key Limitations
PFS benefit did not translate into an OS benefit; more grade 3–4 toxicity and less subsequent therapy in experimental arms may have contributed. OS analysis was at an early interim. Sorafenib comparator is now outdated given atezolizumab-bevacizumab as first-line standard.
Clinical Context
The negative OS result meant cabozantinib-atezolizumab was not adopted as first-line HCC therapy. First-line standards remain atezolizumab-bevacizumab (IMbrave150) and durvalumab-tremelimumab (HIMALAYA) per ASCO/ESMO guidance.