Background
CheckMate 040: open-label, non-comparative phase 1/2 dose-escalation and dose-expansion trial in 262 patients with advanced hepatocellular carcinoma, with or without hepatitis B/C, Child-Pugh A or B7. Cohorts included sorafenib-naive/intolerant, sorafenib-progressors, and HBV- and HCV-infected patients.
Interventions and follow up
Treatment: Nivolumab IV every 2 weeks (dose-escalation 0.1-10 mg/kg; dose-expansion 3 mg/kg)
Primary endpoint: Safety and tolerability (escalation); objective response rate (expansion)
mFollow up: 12.9 months
Primary endpoint: Safety and tolerability (escalation); objective response rate (expansion)
mFollow up: 12.9 months
Results
Dose-escalation ORR: 15%
Dose-escalation mDOR: 17mo
Dose-escalation mPFS: 3.4mo; mOS 15mo
Dose-expansion ORR: 20%
Dose-expansion mDOR: 9.9mo; mPFS 4.1mo
Dose-expansion 6-mo / 9-mo OS: 83% / 74%
Dose-escalation mDOR: 17mo
Dose-escalation mPFS: 3.4mo; mOS 15mo
Dose-expansion ORR: 20%
Dose-expansion mDOR: 9.9mo; mPFS 4.1mo
Dose-expansion 6-mo / 9-mo OS: 83% / 74%
Adverse events
Dose-escalation: Grade 3-4 events 25%; common any-grade rash 23%, increased AST 21%, increased ALT 21%; grade 3-4 adrenal insufficiency, diarrhea and hepatitis in 1 patient each
Dose-expansion: Grade 3-4 treatment-related events 19%
Dose-expansion: Grade 3-4 treatment-related events 19%
Conclusions
Nivolumab produced durable objective responses with a manageable safety profile across etiologies in advanced hepatocellular carcinoma.
Key Limitations
Single-arm, non-comparative phase 1/2 design; heterogeneous cohorts; no randomized control. The confirmatory phase 3 CheckMate 459 (nivolumab vs sorafenib) later missed its OS primary endpoint.
Clinical Context
CheckMate 040 supported FDA accelerated approval of nivolumab for sorafenib-treated HCC (2017); this indication was later voluntarily withdrawn after CheckMate 459 failed to confirm OS benefit. ASCO/ESMO no longer recommend single-agent nivolumab in this setting.