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Multicenter Study
. 2025 Jun;61(11):1755-1766.
doi: 10.1111/apt.70090. Epub 2025 Apr 4.

Therapeutic Sequences of Systemic Therapy After Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma: Real-World Analysis of the IMMUreal Cohort

Najib Ben Khaled  1 , Valentina Zarka  2 , Bernard Hobeika  1 , Julia Schneider  1 , Monika Rau  2 , Alexander Weich  3 , Hans Benno Leicht  2 , Liangtao Ye  1   4 , Ignazio Piseddu  1 , Michael T Dill  5   6   7 , Arne Kandulski  8 , Matthias Pinter  9 , Ursula Ehmer  10 , Peter Schirmacher  11 , Jens U Marquardt  12 , Julia Mayerle  1 , Enrico N De Toni  1 , Andreas Geier  2 , Florian P Reiter  2
Affiliations
Multicenter Study

Therapeutic Sequences of Systemic Therapy After Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma: Real-World Analysis of the IMMUreal Cohort

Najib Ben Khaled et al. Aliment Pharmacol Ther. 2025 Jun.

Abstract

Background: The introduction of several new systemic therapies in recent years has significantly altered the treatment landscape for advanced hepatocellular carcinoma. However, while the approval of the combination of atezolizumab and bevacizumab as the preferred first-line therapy over sorafenib represents progress, it has also raised uncertainties regarding optimal treatment sequencing for advanced disease.

Aims: This study evaluates the sequential treatment of hepatocellular carcinoma following therapy with atezolizumab and bevacizumab, providing evidence from a prospective real-world cohort.

Methods: Data were derived from the ongoing IMMUreal cohort, which investigates immunotherapy in hepatocellular carcinoma across two tertiary centres in Bavaria. A total of 124 patients treated with atezolizumab and bevacizumab as first-line therapy between June 2020 and December 2023 were analysed. Feasibility, treatment patterns, and outcomes of sequential therapy were assessed, with a focus on defined prognostic subgroups.

Results: The median overall survival under real-world conditions was 19.8 months. Less than half of the patients (41.2%) proceeded to second-line therapy, and only 19.2% were eligible for third-line treatment. This decline in treatment eligibility corresponded to a marked reduction in therapy duration and progressive deterioration in liver function, as indicated by Albumin-Bilirubin and Child-Pugh scores. While patients with worse baseline liver function, such as patients with Child-Pugh B or ALBI > 1, had a significantly lower probability of transitioning to 2nd line therapy, no significant association was found between the number of treatment lines and factors such as liver cirrhosis, poor physical condition, extrahepatic disease, or macrovascular invasion.

Conclusions: Sequential therapy following atezolizumab and bevacizumab is feasible only for selected patients. However, preserving liver function seems crucial to optimising multi-line therapy and improving outcomes in advanced hepatocellular carcinoma.

Keywords: hepatocellular carcinoma; immunotherapy; tyrosine kinase inhibition.

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Conflict of interest statement

N.B.K. has received reimbursement of meeting attendance fees and travel expenses from EISAI, lecture honoraria from the Falk Foundation and AstraZeneca, and served as an advisory board member for AstraZeneca, Roche, and Ipsen. U.E. has received honoraria for lectures from AstraZeneca, the Falk Foundation, IPSEN, and Novartis, and travel support from AstraZeneca and Biotest. She has served as an advisory board or steering committee member to AstraZeneca, Bayer, EISAI, and MSD. I.P. reports reimbursement of travel expenses from Roche and received third‐party funding for scientific research from Novartis. M.T.D. served as a speaker and/or advisory board member for AstraZeneca, Eisai, and Roche, and has received travel support from AstraZeneca and the Falk Foundation. A.K. has received lecture honoraria from Roche Pharma A.G., Eisai GmbH, Abbvie Germany A.G., Janssen‐Cilag GmbH, MSD Sharp & Dohme GmbH, Boston Scientific Corp., Fujifilm Germany, Micro‐Tech Germany, and Bayer Pharma A.G. Germany. M.P. served as a speaker and/or consultant and/or advisory board member for AstraZeneca, Bayer, Bristol‐Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer, Bristol‐Myers Squibb, Ipsen, and Roche. U.E. has received honoraria for lectures from AstraZeneca, the Falk Foundation, IPSEN and Novartis, and travel support from AstraZeneca and Biotest. She has served as an advisory board or steering committee member to AstraZeneca, Bayer, EISAI, MSD, and Roche. P.S. has served as an advisory board committee member to BMS, MSD, Eisai, and Incyte. He has received lecture honoraria from BMS, Eisai, Incyte and Janssen. He has received grants from BMS, Incyte, Falk and Chugai. J.U.M. has received honoraria for lectures, consulting activities and travel support from Roche, Eisai, AbbVie, Merz, Novo Nordisk, Ipsen, AstraZeneca, Janssen, and MSD. E.N.D.T. has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSEN, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS and the Falk Foundation. He has received third‐party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. A.G. is an advisory board or steering committee member to AbbVie, Alexion, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi‐Aventis, Sequana and speaker for Advanz. F.P.R. has received honoraria for lectures, consulting activities and travel support from the Falk Foundation, AbbVie, Gilead, Ipsen, AstraZeneca, Roche, and Novartis. All other authors have nothing to declare.

Figures

FIGURE 1
FIGURE 1
Study flow chart.
FIGURE 2
FIGURE 2
Therapeutic pathways of sequential systemic therapy in advanced HCC following atezo/bev. The Sankey diagram illustrates the therapeutic sequences subsequent to atezo/bev in first‐line therapy (n = 124). (This diagram was created using an open‐source program, available at https://sankeymatic.com).
FIGURE 3
FIGURE 3
Duration of Therapy. The duration of each therapeutic line up to the 3rd line is illustrated (n = 11 to 87; ***p < 0.001; *p < 0.05; ANOVA).
FIGURE 4
FIGURE 4
Development of liver function under sequential systemic therapy for HCC. The figure illustrates the development of liver function from the start of systemic therapy to the end of each therapeutic line. The Child‐Pugh score is indicated as Child A = 1, Child B = 2, and Child C = 3. For this analysis, patients who had ongoing therapy or received best supportive care were excluded (n = 10 to 108; **** p < 0.0001; **p < 0.01; ANOVA).
FIGURE 5
FIGURE 5
Number of therapeutic lines in different prognostic subgroups. The figure illustrates the number of applied therapeutic lines in patients with liver cirrhosis, reduced performance status, evidence of extrahepatic spread, or presence of macrovascular invasion (n = 3 to 93; ANOVA or Mann–Whitney U test).
See this image and copyright information in PMC

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