Checkmate 040 - Update

Background

CheckMate 040 nivolumab-plus-ipilimumab cohort: randomized phase 1/2 study in 148 patients with advanced hepatocellular carcinoma previously treated with sorafenib, allocated 1:1:1 to three dosing regimens.

Interventions and follow up

Arm A: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (4 doses), then nivolumab 240 mg every 2 weeks
Arm B: Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks (4 doses), then nivolumab 240 mg every 2 weeks
Arm C: Nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks
Primary endpoint: Safety/tolerability, ORR, and duration of response
mFollow up: ≥28 months

Results

ORR: 32% vs 27% vs 29% (Arm A vs B vs C)
Median duration of response: not reached vs 15.2mo vs 21.7mo (Arm A vs B vs C)
mOS: 22.8mo vs 12.5mo vs 12.7mo (Arm A vs B vs C)

Adverse events

Any treatment-related events: 94% vs 71% vs 79% (Arm A vs B vs C)
Events leading to discontinuation: 18% vs 6% vs 2% (Arm A vs B vs C)

Conclusions

Nivolumab plus ipilimumab produced durable responses with a manageable safety profile in sorafenib-treated advanced hepatocellular carcinoma, with Arm A showing the highest response and OS.

Key Limitations

Small subgroups (~50/arm); non-comparative design without a control; not powered for between-arm survival comparisons; higher toxicity in the nivolumab 1 / ipilimumab 3 regimen.

Clinical Context

This cohort supported FDA accelerated approval of nivolumab plus ipilimumab for sorafenib-treated HCC (2020); the accelerated approval was later withdrawn. The combination was subsequently validated first-line in the phase 3 CheckMate 9DW trial. ASCO/ESMO address immunotherapy combinations in their HCC guidance.

References

Yau T et al, JAMA Oncology, 2020, PMID: 33001113
El-Khoueiry AB et al, Lancet, 2017 (CheckMate 040), PMID: 28434648