Nivolumab plus ipilimumab induces a long-term survival benefit in patients with advanced HCC after sorafenib treatment: 5-year update from CheckMate 040

Previously, the CheckMate 040 study showed promising outcomes with the combination of nivolumab (NIVO) + ipilimumab (IPI), followed by NIVO in the treatment of patients with sorafenib-pretreated advanced hepatocellular carcinoma (HCC). The 5-year updated results of this trial showed that NIVO + IPI regimen provides long-term survival benefits, supporting  the use of this regimen as second-line treatment for patients with advanced HCC pretreated with sorafenib.

Previously, the CheckMate 040 study showed that the combination of nivolumab (NIVO) + ipilimumab (IPI), followed by NIVO,  results in an objective response rate (ORR) of 32% and  a median overall survival (OS) of 22.8 months in sorafenib-treated advanced HCC patients. These outcomes led to accelerated approval of this treatment regimen for this population in the United States. During the ESMO WGCI 2022, updated results of this trial were presented with 5 years of follow up.

Study design

The aim of this study was to evaluate the efficacy of nivolumab + ipilimumab for the treatment of patients with advanced HCC and a child Pugh index of ≤6, who previously received sorafenib. In total, 148 patients were randomized (1:1:1) to NIVO 1 mg/kg + IPI 3 mg/kg Q3W (four doses) (arm A), NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses) (arm B), or NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (arm C). In arms A and B the initial treatment was followed by NIVO 240 mg Q2W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included overall response rate (ORR), duration of response (DoR), and OS. Safety and tolerability and the association of biomarkers with survival were also evaluated.

Results

At a minimum follow-up of 60 months, the ORR was reported at 34% in arm A, 27% in arm B, and 29% in arm C. Durable responses were achieved across all three treatment arms, with a median DoR of 51.2 months in arm A, 15.2 months in arm B, and 21.7 months in arm C. The median OS was confirmed at 22.2 months in arm A, whole this was 12.5 months in arm B, and 12.7 months in arm C. At 36-months, this translated into OS rates of 42%, 26%, and 30%, respectively. At the 60-months landmark OS rates were 29%, 19%, and 21%.

No new treatment-related adverse events (TRAEs) were reported with longer follow-up. There was one additional discontinuation due to TRAE in arm B, but no new discontinuations due to immune-mediated adverse events (IMAEs) were reported since the primary analysis. IMAEs were more frequently reported in arm A than in arms B or C. Most IMAEs resolved when treated using established algorithms, with median time to resolution between 0.1 and 39.1 weeks across organ categories and treatment arms.

Conclusions

At a minimum follow-up of 60 months, the combination NIVO + IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in advanced HCC patients who previously received sorafenib. Durable responses were achieved across all treatment arms. The safety profile was manageable with longer follow-up, and no new safety signals were identified.  These results further support the use of NIVO1+IPI3 as second-line treatment for patients with advanced HCC who have previously received sorafenib.

Reference

Melero I, Yau T, Kang Y-K et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (aHCC): 5-year results from CheckMate 040. Presented at ESMO WGCI; Abstract SO-12.