Efficacy of atezolizumab plus bevacizumab for unresectable HCC: Systematic review and meta-analysis of real-world evidence

Giulia Francesca Manfredi^{1

2}, Claudia Angela Maria Fulgenzi², Ciro Celsa^{2

3}, Bernardo Stefanini^{2

4}, Antonio D'Alessio², Matthias Pinter⁵, Bernhard Scheiner⁵, Nichola Awosika², Leonardo Brunetti², Pasquale Lombardi^{2

6}, Charles Latchford², Pei-Chang Lee^{7

8}, Yi-Hsiang Huang^{7

8

9}, Chun-Yen Lin^{10

11}, Andrea Dalbeni¹², Arndt Vogel^{13

14}, Peter R Galle¹⁵, Masatoshi Kudo¹⁶, Lorenza Rimassa^{17

18}, Hong Jae Chon¹⁹, Giuseppe Cabibbo³, Fabio Piscaglia^{4

20}, Calogero Cammà³, Anjana Pillai²¹, Mario Pirisi^{1

22}, Amit G Singal²³, David J Pinato^{1

2

24}

Affiliations

¹ Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
² Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
³ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
⁴ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁶ Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
⁷ Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
¹¹ College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹² General Medicine C & Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy.
¹³ Toronto General Hospital, UHN and Princess Margaret Cancer Centre, Toronto, ONT, Canada.
¹⁴ Hannover Medical School, Hannover, Germany.
¹⁵ University Medical Center Mainz, I. Department of Internal Medicine, Mainz, Germany.
¹⁶ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
¹⁷ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
¹⁸ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁹ Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
²⁰ Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
²¹ Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA.
²² Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy.
²³ Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
²⁴ Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

PMID: 40677696
PMCID: PMC12269603
DOI: 10.1016/j.jhepr.2025.101431

Efficacy of atezolizumab plus bevacizumab for unresectable HCC: Systematic review and meta-analysis of real-world evidence

Giulia Francesca Manfredi et al. JHEP Rep. 2025.

. 2025 Apr 22;7(8):101431.

doi: 10.1016/j.jhepr.2025.101431. eCollection 2025 Aug.

Authors

Affiliations

¹ Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
² Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
³ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
⁴ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁶ Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
⁷ Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
¹¹ College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹² General Medicine C & Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy.
¹³ Toronto General Hospital, UHN and Princess Margaret Cancer Centre, Toronto, ONT, Canada.
¹⁴ Hannover Medical School, Hannover, Germany.
¹⁵ University Medical Center Mainz, I. Department of Internal Medicine, Mainz, Germany.
¹⁶ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
¹⁷ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
¹⁸ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁹ Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
²⁰ Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
²¹ Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA.
²² Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy.
²³ Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
²⁴ Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

PMID: 40677696
PMCID: PMC12269603
DOI: 10.1016/j.jhepr.2025.101431

Abstract

Background & aims: Atezolizumab plus bevacizumab (A+B) is a standard-of-care treatment in unresectable hepatocellular carcinoma (uHCC). Verification of its effectiveness outside clinical trials is an area of unmet need, especially in estimating long-term survival outcomes.

Methods: We conducted a systematic review and meta-analysis of the MEDLINE, Embase, and Cochrane libraries to evaluate therapy outcomes in patients treated with frontline A+B for uHCC outside trials. Pooled estimates of overall survival (OS) and progression-free survival (PFS) at 6 and 12 months were calculated from individual patient-level data using random-effects analysis.

Results: Of 2,179 patients selected from 12 cohorts, 80.5% were male, median age was 66 years (IQR 61.6-73.0), 61.6% had advanced-stage hepatocellular carcinoma (HCC), and 83.6% were Child-Pugh (CP) class A. Pooled 6- and 12-month OS was 82% (95% CI: 76-86%; I ² = 80%) and 65% (95% CI: 60-70%; I ² = 66%). Median OS of patients with CP-A liver function was 20.9 months (95% CI: 15.7-20.9), consistent with IMbrave150 estimates (19.2 months, 95% CI: 17.0-23.7, p = 0.58). Pooled PFS at 6 and 12 months was 57% (95% CI: 53-61%; I ² = 49%) and 35% (95% CI: 31-39%, I ² = 60%). Among patients with longer follow-up, the OS (n = 1,783) and PFS (n = 959) rates were 52% (95% CI: 46-58; I ² = 90%) and 26% (95% CI: 17-37; I ² = 91%) at 18 months, respectively. At 24 months, OS (n = 1,556) rate was 39% (95% CI: 31-49; I ² = 90%) and PFS (n = 732) rate was 25% (95% CI: 12-45; I ² = 95%).

Conclusions: The effectiveness of A+B after registration mirrors its efficacy estimates from clinical trial datasets. Long-term survival at 24 months can be achieved in up to 39% of patients with uHCC treated with A+B in routine clinical practice.

Impact and implications: This study provides real-world evidence supporting the long-term efficacy of atezolizumab plus bevacizumab (A+B) for unresectable hepatocellular carcinoma, showing survival outcomes similar to those achieved in clinical trials. These findings are important for clinicians in supporting A+B as a frontline treatment, particularly for patients with Child-Pugh class A liver function. They also offer valuable insights for policymakers and researchers for optimising treatment strategies for unresectable hepatocellular carcinoma. However, results should be interpreted with caution because of potential variability in patient populations.

Keywords: Child–Pugh; HCC; Immunotherapy; RWE; Survival.

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Conflict of interest statement

GFM received travel support from Roche. CC received speaker fees and advisory board honoraria from AstraZeneca, Eisai, Merck Sharp & Dohme, and Ipsen, and travel support from Roche. AntD received educational support for congress attendance from Roche, and consultancy fees from Roche, AstraZeneca, and Chugai. MatP received speaker honoraria from Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he is a consultant/advisory board member for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received grants from AstraZeneca, Bayer, BMS, Eisai, and Roche, and travel support from Bayer, BMS, Ipsen, and Roche. BS received grant support (to institution) from AstraZeneca and Eisai, travel support from AbbVie, AstraZeneca, Ipsen, Gilead, and Roche, as well as speaker honoraria from Eisai and AstraZeneca. YHH received honoraria from AstraZeneca, GSK, MSD, Eisai, Gilead, and BMS. AndD received honoraria from Astrazeneca, Eisai, and Roche. AV holds consulting and advisory roles with AbbVie, AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, EISAI, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, and Tahio. PG received honoraria from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, and Ipsen. LR reports consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Guerbet, Incyte, Ipsen, Roche, and Servier; travel expenses from AstraZeneca; and research grants (to institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, TransThera, and Zymeworks. HJC holds consulting or advisory roles with Eisai, Roche, Bayer, ONO, MSD, BMS, Celgene, Sanofi, Servier, AstraZeneca, SillaJen, Menarini, and GreenCross Cell, and has received research grants from Roche, Dong-A ST, and Boryung Pharmaceuticals. FP received honoraria from AstraZeneca, Bayer, Bracco, ESAOTE, EISAI, Exact Sciences, GE, Gilead, IPSEN, MSD, Nerviano, Roche, Samsung, and Siemens Healthineers. AP has served on medical advisory boards for Genentech, AstraZeneca, and Exelexis. AGS has served as a consultant or on advisory boards for Genentech, AstraZeneca, Eisai, Bayer, Elevar, Exelixis, Merck, Boston Scientific, Sirtex, HistoSonics, FujiFilm Medical Sciences, Exact Sciences, Roche, Abbott, Glycotest, Freenome, and GRAIL. DJP received lecture fees from ViiV Healthcare, EISAI, IPSEN, and Bayer Healthcare, and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, IPSEN, DaVolterra, Mursla, and Astra Zeneca; and research funding (to institution) from MSD and BMS. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

**Fig. 1**
Forest plots of the pooled OS rates at (A) 6, (B) 12, (C) 18, and (D) 24 months. Lines represent the 95% CI for the OS rate for each considered timeline for each study. Size of squares represents the weight of each study. Diamonds represent the pooled effect. OS, overall survival.

**Fig. 2**
Comparison of the (A) OS curves and (B) PFS curves from the CP-A observational cohort *vs.* the IMbrave150 cohort. The median OS of the IMbrave150 cohort was 19.2 months (95% CI: 17.0–23.7), whereas that reported in the real-world cohort was 20.9 months (95% CI: 15.7–20.9) with no significant differences reported between the two cohorts (log rank p = 0.58). The median PFS in the real-word cohort was 11.8 months (95% CI: 10.5–18.1), compared with 6.9 months in the IMbrave150 cohort (95% CI: 5.7–8.6; log rank p <0.0001). CP, Child–Pugh; OS, overall survival; PFS, progression-free survival.

**Fig. 3**
Forest plots of the pooled PFS rates at (A) 6, (B) 12, (C) 18, and (D) 24 months. Lines represent the 95% CI for the PFS rate for each considered timeline for each study. Size of squares represents the weight of each study. Diamonds represent the pooled effect. PFS, progression-free survival.

**Fig. 4**
Forest plots of the (A) pooled ORR and (B) pooled DCR according to RECIST v1.1. Lines represent the 95% CI for the (A) ORR or (B) DCR for each study. Size of squares represents the weight of each study. Diamonds represent the pooled effect. CP, Child–Pugh; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

See this image and copyright information in PMC

References

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Efficacy of atezolizumab plus bevacizumab for unresectable HCC: Systematic review and meta-analysis of real-world evidence

Affiliations

Efficacy of atezolizumab plus bevacizumab for unresectable HCC: Systematic review and meta-analysis of real-world evidence

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

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