Background
Phase III RCT of 743 patients with advanced hepatocellular carcinoma not eligible for, or progressing after, surgery or locoregional treatment, with no prior systemic therapy. Child-Pugh A.
Interventions and follow up
Arm A: Nivolumab 240 mg IV Q2W
Arm B: Sorafenib 400 mg PO BID
Primary endpoint: Overall survival (intention-to-treat)
mFollow up: Minimum 22.8 mo
Arm B: Sorafenib 400 mg PO BID
Primary endpoint: Overall survival (intention-to-treat)
mFollow up: Minimum 22.8 mo
Results
mOS: 16.4 mo (nivolumab) vs 14.7 mo (sorafenib); HR 0.85, 95% CI 0.72–1.02; P=.075 (did not meet prespecified threshold P=.0419)
ORR: 15% vs 7%
mPFS: 3.7 mo vs 3.8 mo; HR 0.93
ORR: 15% vs 7%
mPFS: 3.7 mo vs 3.8 mo; HR 0.93
Adverse events
Dermatologic/vascular (grade 3-4, A vs B): Palmar-plantar erythrodysaesthesia <1% vs 14%; hypertension 0 vs 7%
Hepatic (grade 3-4, A vs B): AST elevation 6% vs 4%
Serious/discontinuation: Discontinuation 27 vs 42 patients; treatment-related deaths 4 (Arm A) vs 1 (Arm B)
Hepatic (grade 3-4, A vs B): AST elevation 6% vs 4%
Serious/discontinuation: Discontinuation 27 vs 42 patients; treatment-related deaths 4 (Arm A) vs 1 (Arm B)
Conclusions
First-line nivolumab did not significantly improve OS versus sorafenib. However, given comparable clinical activity and a favorable safety profile, nivolumab may be an option for patients unable to tolerate TKIs or antiangiogenic agents.
Key Limitations
Primary endpoint not met; open-label design; subsequent therapies (including immunotherapy) may have diluted the OS signal; predates combination IO regimens now standard in 1L.
Clinical Context
CheckMate 459 did not support single-agent nivolumab as 1L standard; the FDA later withdrew the accelerated approval for nivolumab monotherapy in HCC. First-line standards are now combination regimens (atezolizumab/bevacizumab per IMbrave150; durvalumab/tremelimumab per HIMALAYA). ESMO guidelines favor these IO-based combinations.