. 2025 Mar 11;25(1):434.

doi: 10.1186/s12885-025-13648-5.

Protocol of the IMPACT study: randomized, multicenter, phase 3 study evaluating the efficacy of immunotherapy (Atezolizumab) plus anti-VEGF therapy (Bevacizumab) in combination with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Yoshihisa Kodama¹, Kazuomi Ueshima², Michihisa Moriguchi³, Yoshitaka Inaba⁴, Tatsuya Yamashita⁵, Hideki Iwamoto⁶, Makoto Ueno⁷, Sadahisa Ogasawara⁸, Teiji Kuzuya⁹, Takahiro Kodama¹⁰, Yozo Sato⁴, Toshifumi Tada¹¹, Kaoru Tsuchiya¹², Hideyuki Nishiofuku¹³, Koichiro Yamakado¹⁴, Miyuki Sone¹⁵, Masafumi Ikeda¹⁶, Tetsuo Takehara¹⁰, Tetsutaro Hamano¹⁷, Masatoshi Kudo¹⁸

Affiliations

¹ Department of Radiology, Teine Keijinkai Hospital, 1-12-1-40, Maeda, Teine-Ku, Sapporo, Hokkaido, 006-8555, Japan.
² Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
³ Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-Cho, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
⁴ Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan.
⁵ Department of Gastroenterology, Kanazawa University Hospital, 13-1, Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan.
⁶ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-Machi, Kurume, Fukuoka, 830-0011, Japan.
⁷ Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-Ku, Chiba, 260-8677, Japan.
⁹ Department of Gastroenterology and Hepatology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
¹¹ Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, 1-12-1, Shimoteno, Himeji, Hyogo, 670-8540, Japan.
¹² Department of Gastroenterology and Hepatology, Japanese Red Cross Musashino Hospital, 1-26-1, Kyonan-Cho, Musashino, Tokyo, 180-8610, Japan.
¹³ Department of Diagnostic and Interventional Radiology, Nara Medical University, 840, Shijo-Cho, Kashihara, Nara, 634-8522, Japan.
¹⁴ Department of Radiology, Hyogo Medical University, 1-1, Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan.
¹⁵ Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
¹⁶ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
¹⁷ Head office, P4 Statistics Co. Ltd., 5-11-14, Todoroki, Setagaya-Ku, Tokyo, 158-0082, Japan.
¹⁸ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. m-kudo@med.kindai.ac.jp.

PMID: 40069616
PMCID: PMC11895279
DOI: 10.1186/s12885-025-13648-5

Protocol of the IMPACT study: randomized, multicenter, phase 3 study evaluating the efficacy of immunotherapy (Atezolizumab) plus anti-VEGF therapy (Bevacizumab) in combination with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Yoshihisa Kodama et al. BMC Cancer. 2025.

. 2025 Mar 11;25(1):434.

doi: 10.1186/s12885-025-13648-5.

Authors

Affiliations

¹ Department of Radiology, Teine Keijinkai Hospital, 1-12-1-40, Maeda, Teine-Ku, Sapporo, Hokkaido, 006-8555, Japan.
² Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
³ Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-Cho, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
⁴ Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan.
⁵ Department of Gastroenterology, Kanazawa University Hospital, 13-1, Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan.
⁶ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-Machi, Kurume, Fukuoka, 830-0011, Japan.
⁷ Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-Ku, Chiba, 260-8677, Japan.
⁹ Department of Gastroenterology and Hepatology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
¹¹ Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, 1-12-1, Shimoteno, Himeji, Hyogo, 670-8540, Japan.
¹² Department of Gastroenterology and Hepatology, Japanese Red Cross Musashino Hospital, 1-26-1, Kyonan-Cho, Musashino, Tokyo, 180-8610, Japan.
¹³ Department of Diagnostic and Interventional Radiology, Nara Medical University, 840, Shijo-Cho, Kashihara, Nara, 634-8522, Japan.
¹⁴ Department of Radiology, Hyogo Medical University, 1-1, Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan.
¹⁵ Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
¹⁶ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
¹⁷ Head office, P4 Statistics Co. Ltd., 5-11-14, Todoroki, Setagaya-Ku, Tokyo, 158-0082, Japan.
¹⁸ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. m-kudo@med.kindai.ac.jp.

PMID: 40069616
PMCID: PMC11895279
DOI: 10.1186/s12885-025-13648-5

Abstract

Background: Atezolizumab plus bevacizumab is recommended as a first-line treatment for unresectable hepatocellular carcinoma (uHCC). A subgroup analysis of the IMbrave150 trial showed shorter overall survival (OS) in uHCC patients with stable disease (SD) than patients with complete response (CR) or partial response (PR) after atezolizumab plus bevacizumab. Improving OS in patients with SD is an unmet medical need. Transcatheter arterial chemoembolization (TACE) may enhance treatment efficacy by controlling intrahepatic lesions and activating anti-tumor immunity. The IMPACT study aims to evaluate whether combining atezolizumab plus bevacizumab with TACE improves OS in patients with SD.

Methods: IMPACT is a multicenter, phase 3 study being conducted in Japan, recruiting uHCC patients aged ≥ 18 years with Barcelona Clinic Liver Cancer stage A (single tumor ≥ 5 cm only, TACE unsuitable), stage B (TACE unsuitable) or stage C (excluding Vp3 or 4), Child-Pugh A liver function, and no prior systemic therapy. After 12 weeks of atezolizumab plus bevacizumab treatment as induction therapy, patients are being divided into two cohorts based on response: a randomized cohort for patients who achieve SD, or an atezolizumab plus bevacizumab followed by curative conversion (ABC-conversion) cohort for patients who achieve CR or PR. Patients in the randomized cohort are receiving atezolizumab plus bevacizumab and intrahepatic control TACE (Group A), or continuing atezolizumab plus bevacizumab (Group B). Patients in the ABC-conversion cohort are receiving atezolizumab plus bevacizumab. All cohorts can be considered for curative conversion therapies for residual tumors if these therapies are considered curative, in the patient's best interests, and deemed necessary by the investigator. The primary endpoint is OS for the randomized cohort and conversion rate for the ABC-conversion cohort. Secondary endpoints in both cohorts include progression-free survival, objective response rate, duration of response, time to CR, and safety. The study is expected to last 6.5 years from June 2023.

Discussion: IMPACT is evaluating the efficacy of combination therapy with atezolizumab plus bevacizumab and TACE, as well as exploring the efficacy of curative conversion therapy. The results should contribute to establishing a response-guided treatment strategy for uHCC by determining optimal treatment according to the therapeutic effect of atezolizumab plus bevacizumab.

Trial registration: Japan Registry of Clinical Trials (jRCT), identifier: jRCTs051230037. Registered 13 June 2023.

Protocol version: 8 May 2024; version 1.4.

Keywords: Atezolizumab; Bevacizumab; Conversion; Hepatocellular carcinoma; Multidisciplinary treatment; Protocol; Study design; Transcatheter arterial chemoembolization; Unresectable.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study protocol was reviewed and approved by the Nara Medical University Certified Review Board (ethics approval number nara0058). All patients provided written informed consent prior to inclusion in the study. Consent for publication: Not applicable. Competing interests: KU has received consulting fees from Chugai Pharmaceutical, Eisai; and research funding from Chugai Pharmaceutical; and lecture fees from Chugai Pharmaceutical, Eisai; Takeda Pharmaceutical, Lilly Japan, and AstraZeneca. MM has received consulting fees from Chugai Pharmaceutical, AstraZeneca, Bayer Yakuhin, Esai, Eli Lilly Japan, Takeda Pharmaceutical, and MSD; and participated in advisory boards for Chugai Pharmaceutical and AstraZeneca. YI has received research funding from Eisai, AstraZeneca, and Chugai Pharmaceutical. TY has received honoraria for speakers’ bureaus from AstraZeneca, Chugai Pharmaceutical, Eisai and Eli Lilly Japan; and participated in advisory boards for AstraZeneca and Eisai. MU has received honoraria from Taiho Pharmaceutical, AstraZeneca, Yakult Honsha, MSD, Nihon Servier, Ono Pharmaceutical, Incyte Biosciences Japan, Chugai Pharmaceutical, Boehringer Ingelheim, J-Pharma, Daiichi Sankyo, Eisai, Takeda Pharmaceutical, and Novartis Pharma; and research funding from Taiho Pharmaceutical, AstraZeneca, MSD, Nihon Servier, Ono Pharmaceutical, Incyte Biosciences Japan, Chugai Pharmaceutical, Boehringer Ingelheim, J-Pharma, Eisai, Novartis Pharma, Astellas Pharma, DFP (Delta Fly Pharma), Novocure, and Chiome Bioscience. SO has received grants for research from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, and Eisai; and lecture fees from Chugai Pharmaceutical, AstraZeneca, and Eisai. T Kuzuya has received lecture fees from Chugai Pharmaceutical, Takeda, Eisai, and AstraZeneca. T Kodama has received research funding from AstraZeneca; and lecture fees from Chugai Pharmaceutical, AstraZeneca, and Eisai. T Tada has received lecture fees from AbbVie GK, Eisai, and Chugai Pharmaceutical. KT has received lecture fees from Chugai Pharmaceutical, Eisai, Takeda Pharmaceutical, and AstraZeneca. KY has received research funding from Chugai Pharmaceutical, Eisai, GE Healthcare Japan, Guerbet Japan, Chugai Pharmaceutical, Terumo, Stryker Japan, and Japan Lifeline; consulting fees from Canon, Boston Scientific, Covidien Japan, and Century Medical; lecture fees from Covidien Japan, Guerbet Japan, Alfresa, Boston Scientific, Bayer Yakuhin, and Merit Medical Japan; payment for expert testimony from Boston Scientific; participated on advisory boards for Boston Scientific, and Covidien; and is the president of the Japanese Society of Interventional Radiology and the Asia–Pacific Society of Cardiovascular Interventional Radiology. MS has received grants for research from Canon Medical Systems Corporation and Dream Medical Partners; consulting fees from Boston Scientific Japan, Astellas Pharma, Guerbet Japan and Cardinal Health; honoraria for speakers’ bureaus from Covidien Japan, Canon Medical Systems, Global Embolization Oncology Symposium and Technologies, The Japanese Society For Neuroendovascular Therapy, Cardinal Health, Boston Scientific Japan, Society of Advanced Medical Imaging, Chugai Pharmaceutical, Bayer Yakuhin, Terumo, Japanese College of Angiology, AstraZeneca, The Japan Society of Gynecologic Oncology, GE Healthcare Japan, Guerbet Europe, Guerbet Japan, Tokyo Association of Radiological Technologists, Japan Radiological Society, Japanese Society of Nephrology, LaForce Group, Japanese Society of Medical Oncology, Hikari Pharmaceutical, Chinese College of Interventionalists, and Iwate Medical University; lecture fees from Covidien Japan, Boston Scientific Japan, Guerbet Japan, and PIOLAX MEDICAL DEVICES; payment for expert testimony from the Pharmaceuticals and Medical Devices Agency and travel support from Global Embolization Oncology Symposium and Technologies. MI has received research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, MSD, Ono Pharmaceutical, Merck Serono, and Novartis; consulting fees from AbbVie, AstraZeneca, Bayer, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, MSD, and Ono Pharmaceutical; and lecture fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Gilead, MSD, Sumitomo Dainippon, and Takeda Pharmaceutical. T Takehara has received grants for research and lecture fees from Chugai Pharmaceutical. TH has received consulting fees from Chugai Pharmaceutical; and lecture fees from Kyorin Pharmaceutical and Meiji Seika Pharma. MK has received grants for research from Otsuka Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, GE Healthcare Japan, Eisai, and AbbVie; consulting fees from Chugai Pharmaceutical, F. Hoffmann-La Roche, Eisai, and AstraZeneca; and lecture fees from Chugai Pharmaceutical, Eisai, AstraZeneca, Eli Lilly Japan, and Takeda Pharmaceutical. YK, HI, YS, and HN have no conflicts of interest.

Figures

**Fig. 1**
Study schema of the IMPACT study. PFS is defined as the shortest time to first disease progression (determined using RECIST v1.1 or mRECIST) or death from any cause from the date of randomization. ORR is defined as the proportion of patients in whom the best overall response is either CR or PR from the date of initiation of induction therapy to the date of discontinuation of protocol treatment or the date of first observed progression or death, whichever occurs first. DOR is defined as the time from the date of the first confirmed response (the date of first documented CR or PR status) to the date of the first confirmed disease progression or death, whichever occurs first, after transition to the randomized cohort. Time to CR is defined as the time from randomization to the first occurrence of CR (determined using RECIST v1.1). ABC-conversion, atezolizumab plus bevacizumab followed by curative conversion; Atezo, atezolizumab; Bev, bevacizumab; BCLC-A, Barcelona Clinic Liver Cancer stage A (early stage); BCLC-B, Barcelona Clinic Liver Cancer stage B (intermediate stage); BCLC-C, Barcelona Clinic Liver Cancer (advanced stage); CR, complete response; DOR, duration of response; EHS, extrahepatic spread; MVI, macroscopic vascular invasion; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; Q3W, every 3 weeks; R, randomization; (m)RECIST v1.1, (modified) Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease; TACE, transcatheter arterial chemoembolization; uHCC, unresectable hepatocellular carcinoma; Vp3-4, right, left, or main portal vein invasion

**Fig. 2**
Intrahepatic control transcatheter arterial chemoembolization (TACE), versus standard TACE. The purpose of intrahepatic control TACE is to reduce tumor burden, while preserving hepatic functional reserve. Further, the release of neoantigens may enhance the efficacy of atezolizumab plus bevacizumab

See this image and copyright information in PMC

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Protocol of the IMPACT study: randomized, multicenter, phase 3 study evaluating the efficacy of immunotherapy (Atezolizumab) plus anti-VEGF therapy (Bevacizumab) in combination with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Affiliations

Protocol of the IMPACT study: randomized, multicenter, phase 3 study evaluating the efficacy of immunotherapy (Atezolizumab) plus anti-VEGF therapy (Bevacizumab) in combination with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Authors

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Abstract

Conflict of interest statement

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