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Effects on survival of the adverse event of atezolizumab plus bevacizumab for hepatocellular carcinoma: a multicenter study by the Japan Red Cross Liver Study Group

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Summary

This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04–6.58, P = 0.042) and 2.85 (95% CI: 1.37–5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22–13.84, P < 0.001) and 3.54 (95% CI: 1.83–6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23–0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25–0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223–13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS.

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Data availability

The data presented in this study are available upon request from the corresponding author.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  PubMed  Google Scholar 

  2. Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R (2022) Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab 34:969-977.e2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kudo M (2020) Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update. Liver Cancer 9:640–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M et al (2020) Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894–1905

    Article  CAS  PubMed  Google Scholar 

  5. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 391:1163–1173

    Article  CAS  PubMed  Google Scholar 

  6. Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS et al (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III sorafenib Asia-Pacific trial. Eur J Cancer 48:1452–1465

    Article  CAS  PubMed  Google Scholar 

  7. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M et al (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:56–66

    Article  CAS  PubMed  Google Scholar 

  8. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I et al (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E et al (2019) Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:282–296

    Article  CAS  PubMed  Google Scholar 

  10. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY et al (2022) Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 76:862–873

  11. Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, Kudo M et al (2021) Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): An open-label, randomised, phase 3 trial. Lancet Oncol 22:991–1001

    Article  CAS  PubMed  Google Scholar 

  12. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX et al (2018) AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67:358–380

    Article  PubMed  Google Scholar 

  13. European Association for the Study of the Liver (2018) Electronic address: easloffice.eu, EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 69:182–236

  14. Kokudo N, Takemura N, Hasegawa K, Takayama T, Kubo S, Shimada M, Nagano H et al (2019) Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res 49:1109–1113

    Article  PubMed  Google Scholar 

  15. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H et al (2021) Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer 10:181–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B (2021) Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 75:960–974

    Article  CAS  PubMed  Google Scholar 

  17. Chuma M, Uojima H, Hattori N, Arase Y, Fukushima T, Hirose S, Kobayashi S et al (2022) Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis. Hepatol Res 52:269–280

    Article  CAS  PubMed  Google Scholar 

  18. Ochi H, Kurosaki M, Joko K, Mashiba T, Tamaki N, Tsuchiya K, Marusawa H et al (2022) Usefulness of neutrophil-to-lymphocyte ratio in predicting progression and survival outcomes after atezolizumab-bevacizumab treatment for hepatocellular carcinoma. Hepatol Res 53:61–71

    Article  PubMed  Google Scholar 

  19. Shimose S, Iwamoto H, Tanaka M, Niizeki T, Kajiwara M, Itano S, Moriyama E et al (2022) Association between adverse events and prognosis in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab: A multicenter retrospective study. Cancers (Basel) 14:4284

    Article  CAS  PubMed  Google Scholar 

  20. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458

    Article  CAS  PubMed  Google Scholar 

  21. Hayakawa Y, Tsuchiya K, Kurosaki M, Yasui Y, Kaneko S, Tanaka Y, Ishido S et al (2022) Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice. Invest New Drugs 40:392–402

    Article  CAS  PubMed  Google Scholar 

  22. Tanaka T, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M et al (2022) Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice. Hepatol Res 52:773–783

    Article  CAS  PubMed  Google Scholar 

  23. Tada T, Kumada T, Hiraoka A, Hirooka M, Kariyama K, Tani J, Atsukawa M et al (2022) Safety and efficacy of atezolizumab plus bevacizumab in elderly patients with hepatocellular carcinoma: A multicenter analysis. Cancer Med 11:3796–3808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ando Y, Kawaoka T, Kosaka M, Shirane Y, Johira Y, Miura R, Murakami S et al (2021) Early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Cancers (Basel) 13:3958

    Article  CAS  PubMed  Google Scholar 

  25. Chan SL, Yip TC, Wong VW, Tse YK, Yuen BW, Luk HW, Lui RN et al (2020) Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. Cancer Med 9:7052–7061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yokohama K, Asai A, Matsui M, Okamoto N, Yasuoka H, Nishikawa T, Ohama H et al (2020) Liver dysfunction is associated with poor prognosis in patients after immune checkpoint inhibitor therapy. Sci Rep 10:14470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yamamoto T, Ito T, Hase T, Ishigami M, Mizuno K, Yamamoto K, Imai N et al (2022) Immune-related liver injury is a poor prognostic factor in patients with nonsmall cell lung cancer treated with immune checkpoint Inhibitors. Cancer Investig 40:189–198

    Article  CAS  Google Scholar 

  28. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  29. Karachaliou N, Saloustros E, Vamvakas L, Mavroudis D, Georgoulias V (2010) Proteinuria and favourable clinical response in a patient receiving paclitaxel + bevacizumab for metastatic breast cancer. Ann Oncol 21:1729–1730

    Article  CAS  PubMed  Google Scholar 

  30. Khoja L, Kumaran G, Zee YK, Murukesh N, Swindell R, Saunders MP, Clamp AR et al (2014) Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer. J Clin Gastroenterol 48:430–434

    Article  CAS  PubMed  Google Scholar 

  31. Carvalho B, Lopes RG, Linhares P, Costa A, Caeiro C, Fernandes AC, Tavares N et al (2020) Hypertension and proteinuria as clinical biomarkers of response to bevacizumab in glioblastoma patients. J Neurooncol 147:109–116

    Article  CAS  PubMed  Google Scholar 

  32. Iwasa S, Nakajima TE, Nagashima K, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y (2013) Lack of association of proteinuria and clinical outcome in patients treated with bevacizumab for metastatic colorectal cancer. Anticancer Res 33:309–316

    CAS  PubMed  Google Scholar 

  33. Uysal M, Bozcuk H, Sezgin Göksu S, Murat Tatli A, Arslan D, Gündüz S, Senol Coskun H et al (2014) Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother 68:409–412

    Article  CAS  PubMed  Google Scholar 

  34. Ando Y, Kawaoka T, Kosaka M, Shirane Y,Johira Y, Miura R et al (2022) Risk factors for early onset of proteinuria in patients receiving atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Liver Cancer. https://doi.org/10.1159/000528145

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Funding

This work was supported by a Grant-in-Aid from the Japan Agency for Medical Research and Development (JP20fk0210067h0001 and JP23fk0210123h0001).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan

    Shintaro Takaki, Nami Mori & Keiji Tsuji

  2. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

    Masayuki Kurosaki, Nobuharu Tamaki, Yutaka Yasui, Kaoru Tsuchiya & Namiki Izumi

  3. Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Ehime, Japan

    Hironori Ochi

  4. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan

    Hiroyuki Marusawa

  5. Department of Internal medicine, Himeji Red Cross Hospital, Hyogo, Japan

    Shinichiro Nakamura & Toshifumi Tada

  6. Department of Gastroenterology, Oita Red Cross Hospital, Oita, Japan

    Ryoichi Narita

  7. Department of Gastroenterology, Matsue Red Cross Hospital, Shimane, Japan

    Yasushi Uchida

  8. Department of Gastroenterology, Ishinomaki Red Cross Hospital, Miyagi, Japan

    Takehiro Akahane

  9. Department of Gastroenterology, Otsu Red Cross Hospital, Shiga, Japan

    Masahiko Kondo

  10. Department of Gastroenterology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Aichi, Japan

    Atsunori Kusakabe

  11. Department of Gastroenterology, Masuda Red Cross Hospital, Shimane, Japan

    Koichiro Furuta

  12. Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Okayama, Japan

    Haruhiko Kobashi

  13. Department of Gastroenterology, Maebashi Red Cross Hospital, Gunma, Japan

    Hirotaka Arai

  14. Department of Gastroenterology, Tokushima Red Cross Hospital, Tokushima, Japan

    Michiko Nonogi

  15. Department of Gastroenterology, Takatsuki Red Cross Hospital, Osaka, Japan

    Takashi Tamada

  16. Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Hokkaido, Japan

    Chitomi Hasebe

  17. Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Kagawa, Japan

    Chikara Ogawa

  18. Department of Gastroenterology, Nasu Red Cross Hospital, Tochigi, Japan

    Takashi Sato

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  1. Shintaro Takaki
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Contributions

Shintaro Takaki and Masayuki Kurosaki provided analysis and writing the main manuscript, Hironori Ochi,Toshifumi Tada and Kaoru Tsuchiya reviewed and corrected the main manuscript. Shintaro Takaki, Masayuki Kurosaki, Nami Mori, Keiji Tsuji, Hironori Ochi, Hiroyuki Marusawa, Shinichiro Nakamura, Toshifumi Tada, Narita Ryoichi, Yasushi Uchida, Takehiro Akahane, Masahiko Kondo, Atsunori Kusakabe, Koichiro Furuta, Haruhiko Kobashi, Hirotaka Arai, Riko Nonogi, Takashi Tamada, Chitomi Hasebe, Chikara Ogawa, Takashi Sato, Nobuharu Tamaki, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi treated the patients, collected the data and reviewed the final manuscript.

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Correspondence to Masayuki Kurosaki.

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Competing interests

Masayuki Kurosaki, Namiki Izumi and Kaoru Tsuchiya received lecture fees from Chugai. The other authors have no conficts of interest to declare.

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Takaki, S., Kurosaki, M., Mori, N. et al. Effects on survival of the adverse event of atezolizumab plus bevacizumab for hepatocellular carcinoma: a multicenter study by the Japan Red Cross Liver Study Group. Invest New Drugs 41, 340–349 (2023). https://doi.org/10.1007/s10637-023-01349-4

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