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. 2025 Aug 5.
doi: 10.1159/000547792. Online ahead of print.

Conversion Ability of Immunotherapy in Hepatocellular Carcinoma: Insights from the International Converse Study

Alessandro Vitale  1 , Jung Sun Kim  2 , Giuseppe Cabibbo  3 , Andrea Casadei-Gardini  4 , Massimo Iavarone  5   6 , Lorenza Rimassa  7   8 , Francesca Romana Ponziani  9   10 , Francesco Tovoli  11   12 , Hong Jae Chon  2 , Beodeul Kang  2 , Chan Kim  2 , Hiroshi Imaoka  13 , Masafumi Ikeda  13 , Masatoshi Kudo  14 , Tomoko Aoki  14 , Raffaella Tortora  15 , Marco Guarracino  15 , Bernardo Stefanini  11 , Mariarosaria Marseglia  12 , Alba Sparacino  3 , Ciro Celsa  3 , Mariangela Bruccoleri  5 , Eleonora Alimenti  5 , Fabio Marra  16 , Claudia Campani  16 , Sherrie Bhoori  17 , Vincenzo Mazzaferro  17   18 , Rodolfo Sacco  19 , Antonio Facciorusso  19 , Andrea Martini  20 , Leonardo Stella  9 , Lucia Cerrito  9 , Hidenori Toyoda  21 , Satoshi Yasuda  21 , Federico Rossari  4 , Margherita Rimini  4 , Goki Suda  22 , Takuya Sho  22 , Gianluca Masi  23 , Caterina Vivaldi  23 , Tiziana Pressiani  8 , Satoru Kakizaki  24 , Atsushi Naganuma  25 , Antonio Avallone  26 , Anna Nappi  26 , Gianpaolo Vidili  27 , Caterina Soldà  28 , Francesca Bergamo  28 , David J Pinato  29   30 , Filippo Pelizzaro  1 , Francesco Giuseppe Foschi  31 , Alice Secomandi  31 , Francesco Verderame  32 , Enrico Bronte  32 , Erika Martinelli  33 , Donatella Marino  34 , Sara Grasselli  35 , Andrea Olivani  35 , Maurizia Rossana Brunetto  36 , Francesco Damone  36 , Andrea Mega  37 , Luca Marzi  37 , Emiliano Tamburini  38 , Matteo Ramundo  38 , Piera Federico  39 , Bruno Daniele  39 , Edoardo G Giannini  40   41 , Andrea Pasta  40   41 , Filomena Morisco  42 , Maria Guarino  42 , Celine Hoyek  43 , Sara Boninsegna  44 , Ajay Gupta  45 , David Sacerdoti  46 , Andrea Dalbeni  47 , Irina Calvo Ramos  48 , Jorge Adeva  49 , Carlo Saitta  50 , Concetta Pitrone  50 , Maria Luisa Lentini Graziano  51 , Nunzia Farella  51 , Maria Rendina  52 , Teresa Grassi  53 , Maria Grazia Rodriquenz  54 , Evaristo Maiello  54 , José Presa  55 , Inês Pinho  55 , Yoichi Hiasa  56 , Masashi Hirooka  56 , Jocelin Chen  57 , Gianluca Arrichiello  58 , Carlo Aschele  59 , Alessandro Furlanetto  1 , Umberto Cillo  1
Affiliations

Conversion Ability of Immunotherapy in Hepatocellular Carcinoma: Insights from the International Converse Study

Alessandro Vitale et al. Liver Cancer. .

Abstract

Introduction: The potential for curative conversion with immunotherapy-based systemic treatment used with noncurative intent in patients with hepatocellular carcinoma (HCC) remains debated. This study aimed to provide a reliable epidemiological snapshot of response patterns to atezolizumab plus bevacizumab (AB) therapy, with a focus on curative conversion rates.

Methods: Patients with HCC undergoing first-line noncurative AB or lenvatinib (LENV, used as reference) from 2019 to 2023 were included, using centre-level aggregate data from a broad international consortium. The primary endpoint was the curative conversion rate, differentiating potential conversion (PC) - when objective response (OR) resulted in a consistent decrease in tumour burden and alpha-fetoprotein levels - from actual conversion (AC), when OR led to curative treatment. Secondary endpoints included OR, under-conversion (UC; [PC - AC]/OR) rates, and crude survival rates of AC patients. A meta-analytic approach was employed to analyse aggregate data.

Results: Forty-eight international centres treating 2,379 patients with HCC with a noncurative intent (1,401 with AB and 978 with LENV) were included. A significant discrepancy was observed between PC (16% and 13% for AB and LENV, p = 0.03) and AC rates (3% for both AB and LENV, p = 0.14). UC rates remained similarly high (40% and 36% for AB and LENV, p = 0.93), despite differing OR rates (29% and 24% for AB and LENV, p = 0.01). Subgroup and meta-regression analyses did not identify any clear treatment, centre, or patient patterns that explained the high UC rate. The 3-year survival rate for the 72 patients who underwent a curative conversion after AB was 93%.

Conclusions: Although patients treated with AB achieved higher OR and PC rates than those treated with LENV, AC remained similarly low, highlighting a potentially worrisome UC phenomenon in real life, also with novel immunotherapy-based combinations.

Keywords: Conversion; Hepatocellular carcinoma; Immunotherapy; Surgery.

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Conflict of interest statement

Alessandro Vitale, Massimo Iavarone, Lorenza Rimassa, Masafumi Ikeda, Masatoshi Kudo, and Edoardo G. Giannini were members of the journal’s Editorial Board at the time of submission. Hong Jae Chon received consulting or advisory roles with Eisai, Roche, ONO, MSD, BMS, BeiGene, Sanofi, Servier, AstraZeneca, Menarini, and GreenCross Cell, and research grants from Roche, Dong-A ST, and Boryung Pharmaceuticals. Hiroshi Imaoka received research funding from Ono Pharmaceutical. Masafumi Ikeda has received consulting fees from AbbVie, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly Japan, MSD, and Ono Pharmaceutical; honoraria from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, Gilead, MSD, Sumitomo Dainippon, and Takeda; and research funding from AstraZeneca, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, MSD, Ono Pharmaceutical, Merck-Serono, and Novartis. Francesco Tovoli reports being consultant for Eisai, Roche, and AstraZeneca Giuseppe Cabibbo participated in advisory boards and received speaker fees for Bayer, Eisai, Ipsen, AstraZeneca, MSD, Roche, and Gilead. Massimo Iavarone received support from Roche, AstraZeneca, Bayer, Roche Diagnostics, Gilead, MSD, EISAI, and IPSEN. Fabio Marra reports being consultant for Roche, AstraZeneca, MSD/EISAI, and Ipsen. Claudia Campani received speaking fees from Roche, AstraZeneca, Travel fees Roche, and AstraZeneca. Hidenori Toyoda, M.D., Ph.D., received lecturer’s fee from Gilead Sciences, AbbVie, Eisai, Fujifilm WAKO, Terumo, Takeda, Chugai, Kowa, and Bayer but do not receive fee or funding regarding this study. Andrea Casadei-Gardini reports consulting fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, and Servier; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Roche, and Servier; travel expenses from AstraZeneca; and research grants (to Institution) from AstraZeneca and Eisai. Lorenza Rimassa reports consulting/advisory role for AbbVie, AstraZeneca, Basilea, Bayer, BMS, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; received honoraria/lecture fees from AstraZeneca, Bayer, BMS, Guerbet, Incyte, Ipsen, Roche, and Servier; received travel expenses from AstraZeneca; received research funding to their institution from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, and Zymeworks. Antonio Avallone reports receipt of honoraria or consultation fees for speaker, consultancy, and advisory roles from Amgen, Bayer, Eisai, Merck-Serono, MSD, Bristol-Meyers, and Takeda. Caterina Soldà reports advisory role for AstraZeneca. Filippo Pelizzaro reports advisory role for MSD and received travel and accommodation expenses from MSD. Erika Martinelli reports the following: Merck-Serono – invited speaker; Pierre Fabre – writing engagement, advisory board, invited speaker, and travel grant; Servier – writing engagement, advisory board, and invited speaker; BAYER – invited speaker; Roche – writing engagement, advisory board, and invited speaker; AstraZeneca – writing engagement and travel grant; Merck S.p.A. – invited speaker; ESMO – invited speaker; MSD – writing engagement and advisory board; and Takeda – advisory board and invited speaker. Donatella Marino received advisory board fees from F. Hoffmann-La Roche AG, MSD, Merck & Co, Inc., AstraZeneca, and travel expenses from Pierre Fabre and Amgen Inc. Jorge Adeva Alfonso reports consulting or advisory role for MSD Oncology, Basilea Pharmaceutical, Servier, Incyte, AstraZeneca, and received travel and accommodations expenses from Servier and Roche. Maria Grazia Rodriquenz reports consultancy for Roche and honoraria from AstraZeneca. José Presa, MD, reports support from Eisai, Roche, and AstraZeneca. Other authors have no conflict of interest to declare.

Figures

Fig. 1.
Fig. 1.
Forest plots of the proportions of ORs (a), ACs (b), PCs (c), and UCs (d) in AB-treated patients (n = 1,401) of the included international centres (n = 45). OR, objective response; AC, actual conversion; PC, potential conversion; UC, under-conversion.
Fig. 2.
Fig. 2.
Forest plots of the proportions of ORs (a), ACs (b), PCs (c), and UCs (d) in LENV-treated patients (n = 978) of the included international centres (n = 40). OR, objective response; AC, actual conversion; PC, potential conversion; UC, under-conversion.
See this image and copyright information in PMC

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