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Multicenter Study
. 2026 Feb;46(2):e70493.
doi: 10.1111/liv.70493.

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

Jung Sun Kim  1   2 , Jeffrey Wong  3 , San-Chi Chen  4   5 , David Tai  6 , Hannah Yang  1   2 , Youngun Kim  2 , Beodeul Kang  1   2 , Ilhwan Kim  7 , Hyeyeong Kim  8 , Chansik An  9 , Su Jin Jang  10 , Masatoshi Kudo  11 , Ho Yeong Lim  1   2 , Chan Kim  1   2 , Thomas Yau  3 , Hong Jae Chon  1   2
Affiliations
Multicenter Study

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

Jung Sun Kim et al. Liver Int. 2026 Feb.

Abstract

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.

Keywords: hepatocellular carcinoma; immunotherapy; ipilimumab; nivolumab.

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Conflict of interest statement

Hong Jae Chon consults for Eisai, Roche, Bayer, ONO, MSD, BMS, Sanofi, Servier, AstraZeneca, SillaJen, Menarini and GreenCross Cell; and has research grants from Roche, Dong‐A ST and Boryung Pharmaceuticals. Chan Kim consults for Roche, ONO, MSD, BMS, Oncocross and Virocure and receives research funding from Boryung Pharmaceuticals, Oncocross, SillaJen and Virocure. Masatoshi Kudo consults for ONO, Chugai, Roche, Eisai and AstraZeneca; and received a lecture fee from Chugai, Eisai, AstraZeneca; and has a research grant from ONO, Chugai, Roche, Eisai, AstraZeneca.

Figures

FIGURE 1
FIGURE 1
CONSORT diagram. HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; n, number.
FIGURE 2
FIGURE 2
Survival outcomes. (A) Progression‐free survival (PFS) in all patients. (B) PFS according to prior Atezolizumab/Bevacizumab (Ate/Bev) experience. (C) PFS of Nivolumab/Ipilimumab (Nivo/Ipi) responders according to prior Ate/Bev experience. (D) Overall survival (OS) in all patients. (E) OS according to prior Ate/Bev experience. (F) OS of Nivo/Ipi responders according to prior Ate/Bev experience. CI, confidence interval; m, months; NR, not reached.
FIGURE 3
FIGURE 3
Survival outcomes according to the occurrence of immune‐related adverse events (irAEs). (A) Overall survival. (B) Progression‐free survival. *The following irAEs of any grades were included for this analysis: adrenal insufficiency, hypothyroidism, pneumonitis, diabetes mellitus and hyperthyroidism.
FIGURE 4
FIGURE 4
Disease courses and clinicogenetic summary of Nivo/Ipi responders after failure of prior Ate/Bev. CP–A, Child‐Pugh class A; CR, complete response; PD, progressive disease; PR, partial response.
See this image and copyright information in PMC

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