Outcomes of Nivolumab Plus Ipilimumab After Atezolizumab Plus Bevacizumab in Advanced <scp>HCC</scp> : An International Multicentre Study

BACKGROUND/AIMS: Immune checkpoint inhibitors (ICIs) have transformed advanced HCC treatment. The benefit of sequential immunotherapy after prior ICI failure remains unclear. Given the expanded use of atezolizumab plus bevacizumab (Ate/Bev) over the past 5 years, we explored the real-world outcomes of nivolumab plus ipilimumab (Nivo/Ipi) in patients with advanced HCC, with more focus on those previously exposed to Ate/Bev. METHODS: Patients treated with Nivo/Ipi for advanced HCC from six referral hospitals in Korea, Hong Kong, Taiwan and Singapore were included. Patients with prior non-Ate/Bev ICI or Child-Pugh B-C were excluded. Outcomes were compared between the ICI-naïve and Ate/Bev-experienced groups. RESULTS: Among 116 patients with advanced HCC treated with Nivo/Ipi, 57 were ICI-naïve and 59 had prior Ate/Bev exposure. Overall objective response rate was 31.2%, higher in the ICI-naïve group (42.6% vs. 20.0%, p = 0.01). However, the median duration of response was comparable between groups (24.8 vs. 23.7 months; p = 0.71), suggesting durable benefits regardless of prior Ate/Bev therapy. Median progression-free survival (PFS) and overall survival (OS) were 2.5 and 11.3 months, respectively, with longer PFS (5.3 vs. 1.6 months; p < 0.01) and OS (16.2 vs. 7.8 months; p = 0.06) in the ICI-naïve. Immune-related adverse events (irAEs), especially thyroid dysfunction, were associated with longer PFS and OS. Notably, most Nivo/Ipi responders post-Ate/Bev (8/11) had irAEs during Nivo/Ipi treatment, whereas no irAEs occurred during prior Ate/Bev. Nivo/Ipi responders post-Ate/Bev revealed a high tumour mutational burden (5.71-12.75 mutations/Mb). CONCLUSION: Nivo/Ipi demonstrated meaningful clinical activity in patients with advanced HCC, even after Ate/Bev failure.