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| Name | Class |
|---|---|
| Hoffmann-La Roche | INDUSTRY |
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Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths globally and in Korea. Many patients diagnosed at advanced stage, and systemic therapy is mainstay of treatment in patients with advanced HCC.
However, immune-checkpoint inhibitor (ICI) monotherapy did not significantly improve overall survival in phase III studies. According to previous retrospective analyses, ICI treatment in advanced HCC showed different organ-specific responses. The intrahepatic HCC was the least responsive organ to ICI treatment. The failure of phase III trials of ICI monotherapy may have been attributed to different organ-specific response pattern of ICIs.
Combination of atezolizumab plus bevacizumab is expected to overcome the immunosuppressive microenvironment of liver and may enhance intrahepatic response of ICI.
In a previous retrospective analysis of pembrolizumab treated patients with advanced melanoma and NSCLC, patients with liver metastases showed poorer PFS compared with those without liver metastases with reduced ORR. Similar observations have also been reported in metastatic of triple-negative breast cancer patients, there were no responses in patients with liver metastases. Taken together the results of previous studies, hepatic metastases had reduced response to ICI compared with metastases at other organs, regardless of cancer types.
In addition, ICI treatment in advanced HCC showed different organ-specific responses. The poorer response rate in liver to ICI might be affected by liver-specific immunosuppressive microenvironment (TME). To overcome the unfavorable immunosuppressive TME of the liver, combination strategies are needed to achieve enhanced anti-tumor immune responses or alleviated tumor-associated immunosuppression.
Since the cause of death in most HCC patients was hepatic failure due to intrahepatic HCC or underlying liver cirrhosis, the response rate to ICI of intrahepatic tumor lesions is a crucial factor in determining the overall prognosis of advanced HCC.
Therefore, we hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly.
Objectives We hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Atezolizumab plus bevacizumab | Patients received combination therapy with atezolizumab and bevacizumab as first-line systemic treatment for advanced HCC. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atezolizumab plus bevacizumab | Drug | Patients received combination therapy with atezolizumab (Tecentriq) and bevacizumab (Avastin) as first-line systemic treatment for advanced hepatocellular carcinoma. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Lesions With Organ-specific Response | Organ-specific response will be assessed at the lesion level according to RECIST 1.1 criteria. Up to two target lesions per organ (maximum of five total lesions per patient) will be selected and measured unidimensionally. Complete response (CR) is defined as disappearance of the lesion or lymph node short axis diameter <1.0 cm. Partial response (PR) is defined as ≥30% reduction in lesion size. Progressive disease (PD) is defined as ≥20% increase in lesion size. Stable disease (SD) is defined as neither CR, PR, nor PD. New lesions are recorded in addition to original target lesions to determine the total tumor burden. | From treatment initiation until last follow-up (median 10.1 months) |
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Inclusion Criteria:
Exclusion Criteria:
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Patients enrollment was performed in the CHA Bundang Medical Center, Ulsan University Hospital and Chinese University of Hong Kong
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| Name | Affiliation | Role |
|---|---|---|
| Hong Jae Chon, MD, PhD | CHA University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cha Medical Center | Seongnam-si | Gyeonggi-do | 13496 | South Korea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30061739 | Background | Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018 Oct;15(10):599-616. doi: 10.1038/s41571-018-0073-4. | |
| 28279062 | Background | Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH; Community of Population-Based Regional Cancer Registries. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2014. Cancer Res Treat. 2017 Apr;49(2):292-305. doi: 10.4143/crt.2017.118. Epub 2017 Mar 9. |
| Label | URL |
|---|---|
| Lee M, Ryoo BY, Hsu CH, et al: Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Annals of Oncology 30:v875, 2019 | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Atezolizumab Plus Bevacizumab | Atezolizumab plus bevacizumab Atezolizumab plus bevacizumab: Atezolizumab plus bevacizumab |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
We enrolled patients who received first-line Ate/Bev treatment for aHCC. Eligible patients included those with Child-Pugh A liver function, measurable tumor lesions, and serial image studies available for response evaluation.
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| ID | Title | Description |
|---|---|---|
| BG000 | Atezolizumab Plus Bevacizumab | Atezolizumab plus bevacizumab Atezolizumab plus bevacizumab: Atezolizumab plus bevacizumab |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Lesions With Organ-specific Response | Organ-specific response will be assessed at the lesion level according to RECIST 1.1 criteria. Up to two target lesions per organ (maximum of five total lesions per patient) will be selected and measured unidimensionally. Complete response (CR) is defined as disappearance of the lesion or lymph node short axis diameter <1.0 cm. Partial response (PR) is defined as ≥30% reduction in lesion size. Progressive disease (PD) is defined as ≥20% increase in lesion size. Stable disease (SD) is defined as neither CR, PR, nor PD. New lesions are recorded in addition to original target lesions to determine the total tumor burden. | Organ-specific responses were assessed for 260 individual tumor lesions from 131 participants who received atezolizumab plus bevacizumab: 152 liver lesions, 42 lymph node lesions, 24 lung lesions, and 42 other metastatic lesions were evaluated. | Posted | Number | Percentage of Units (lesions) | From treatment initiation until last follow-up (median 10.1 months) | lesion | lesion |
|
From treatment initiation until last follow-up (median 10.1 months)
Adverse events were collected from the start of treatment until last follow-up, and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atezolizumab Plus Bevacizumab | Atezolizumab plus bevacizumab Atezolizumab plus bevacizumab: Atezolizumab plus bevacizumab |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal bleeding (Grade ≥3) | Gastrointestinal disorders | CTCAE v5.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | CTCAE v5.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Hong Jae Chon | CHA Bundang Medical Center | 82-31-780-3928 | minidoctor@cha.ac.kr |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 27, 2023 | Sep 17, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006528 | Carcinoma, Hepatocellular |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C000594389 | atezolizumab |
| D000068258 | Bevacizumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| 29628281 | Background | European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019. Epub 2018 Apr 5. No abstract available. |
| 29307467 | Background | Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5. |
| 28434648 | Background | El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20. |
| 31790344 | Background | Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020 Jan 20;38(3):193-202. doi: 10.1200/JCO.19.01307. Epub 2019 Dec 2. |
| 31799205 | Background | Lu LC, Hsu C, Shao YY, Chao Y, Yen CJ, Shih IL, Hung YP, Chang CJ, Shen YC, Guo JC, Liu TH, Hsu CH, Cheng AL. Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Liver Cancer. 2019 Nov;8(6):480-490. doi: 10.1159/000501275. Epub 2019 Aug 6. |
| 25601652 | Background | Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19. |
| 24793239 | Background | Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014 Jun;20(6):607-15. doi: 10.1038/nm.3541. Epub 2014 May 4. |
| 29229461 | Background | Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018 Oct;52(Pt 2):117-124. doi: 10.1016/j.semcancer.2017.12.002. Epub 2017 Dec 8. |
| 32402160 | Background | Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. |
| 29545369 | Background | Pao W, Ooi CH, Birzele F, Ruefli-Brasse A, Cannarile MA, Reis B, Scharf SH, Schubert DA, Hatje K, Pelletier N, Spleiss O, Reed JC. Tissue-Specific Immunoregulation: A Call for Better Understanding of the "Immunostat" in the Context of Cancer. Cancer Discov. 2018 Apr;8(4):395-402. doi: 10.1158/2159-8290.CD-17-1320. Epub 2018 Mar 15. |
| 29875066 | Background | Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3. |
| 28411193 | Background | Tumeh PC, Hellmann MD, Hamid O, Tsai KK, Loo KL, Gubens MA, Rosenblum M, Harview CL, Taube JM, Handley N, Khurana N, Nosrati A, Krummel MF, Tucker A, Sosa EV, Sanchez PJ, Banayan N, Osorio JC, Nguyen-Kim DL, Chang J, Shintaku IP, Boasberg PD, Taylor EJ, Munster PN, Algazi AP, Chmielowski B, Dummer R, Grogan TR, Elashoff D, Hwang J, Goldinger SM, Garon EB, Pierce RH, Daud A. Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol Res. 2017 May;5(5):417-424. doi: 10.1158/2326-6066.CIR-16-0325. Epub 2017 Apr 14. |
| 30475950 | Background | Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, Hui R, Curigliano G, Toppmeyer D, O'Shaughnessy J, Loi S, Paluch-Shimon S, Tan AR, Card D, Zhao J, Karantza V, Cortes J. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019 Mar 1;30(3):397-404. doi: 10.1093/annonc/mdy517. |
| 17577038 | Background | Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007 Jun 20;25(18):2586-93. doi: 10.1200/JCO.2006.09.4565. |
| 28167218 | Background | Eggert T, Greten TF. Tumor regulation of the tissue environment in the liver. Pharmacol Ther. 2017 May;173:47-57. doi: 10.1016/j.pharmthera.2017.02.005. Epub 2017 Feb 4. |
| 18485901 | Background | Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008 Jul;135(1):234-43. doi: 10.1053/j.gastro.2008.03.020. Epub 2008 Mar 21. |
| 25833323 | Background | Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H, Ye Q, Lee JS, Kim JH, Greten TF, Wang XW. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology. 2015 Aug;62(2):481-95. doi: 10.1002/hep.27822. Epub 2015 Apr 28. |
| 17039564 | Background | Berg M, Wingender G, Djandji D, Hegenbarth S, Momburg F, Hammerling G, Limmer A, Knolle P. Cross-presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor-specific CD8+ T cell tolerance. Eur J Immunol. 2006 Nov;36(11):2960-70. doi: 10.1002/eji.200636033. |
| 23225218 | Background | Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, Li XF, Zheng L. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013 Mar;57(3):1107-16. doi: 10.1002/hep.26192. Epub 2013 Jan 18. |
| 22505239 | Background | Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012 Oct;56(4):1342-51. doi: 10.1002/hep.25777. |
| 17230611 | Background | Uka K, Aikata H, Takaki S, Shirakawa H, Jeong SC, Yamashina K, Hiramatsu A, Kodama H, Takahashi S, Chayama K. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol. 2007 Jan 21;13(3):414-20. doi: 10.3748/wjg.v13.i3.414. |
| 38618972 | Background | Cheon J, Jung S, Kim JS, Kang B, Kim H, Chan LL, Becker L, Gaillard VE, Chan SL, Kim C, Chon HJ. Organ-specific responses to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma: A multicentre, retrospective study. Liver Int. 2024 Aug;44(8):1961-1970. doi: 10.1111/liv.15935. Epub 2024 Apr 15. |
| T. Yau, J.W. Park, R.S. Finn, et al: LBA38\_PR - CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). | View source |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Race and Ethnicity data were not collected in this study (South Korea, Hong Kong). | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 |
| Atezolizumab Plus Bevacizumab |
Atezolizumab plus bevacizumab Atezolizumab plus bevacizumab: Atezolizumab plus bevacizumab |
|
|
| 57 |
| 131 |
| 16 |
| 131 |
| 108 |
| 131 |
| Proteinuria (Grade ≥3) | Renal and urinary disorders | CTCAE v5.0 | Systematic Assessment |
|
| Hypertension (Grade ≥3) | Vascular disorders | CTCAE v5.0 | Systematic Assessment |
|
| Other treatment-related SAEs | General disorders | CTCAE v5.0 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | CTCAE v5.0 | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE v5.0 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | CTCAE v5.0 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE v5.0 | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | CTCAE v5.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | CTCAE v5.0 | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D008113 | Liver Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |