Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real‑world practice

Shimose,Shigeo; Saeki,Issei; Tomonari,Tetsu; Ito,Takanori; Tani,Joji; Takeuchi,Yasuto; Yoshioka,Naoki; Naito,Takehito; Takeuchi,Mamiko; Kakizaki,Satoru; Hatanaka,Takeshi; Sasaki,Kyo; Yasunaka,Tetsuya; Sakata,Masahiro; Iwamoto,Hideki; Itano,Satoshi; Shirono,Tomotake; Tanabe,Norikazu; Yamamoto,Takafumi; Naganuma,Atsushi; Nishina,Soji; Otsuka,Motoyuki; Kawashima,Hiroki; Takayama,Tetsuji; Takami,Taro; Kawaguchi,Takumi

doi:10.3892/ol.2024.14530

Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real‑world practice

Authors:
- Shigeo Shimose
- Issei Saeki
- Tetsu Tomonari
- Takanori Ito
- Joji Tani
- Yasuto Takeuchi
- Naoki Yoshioka
- Takehito Naito
- Mamiko Takeuchi
- Satoru Kakizaki
- Takeshi Hatanaka
- Kyo Sasaki
- Tetsuya Yasunaka
- Masahiro Sakata
- Hideki Iwamoto
- Satoshi Itano
- Tomotake Shirono
- Norikazu Tanabe
- Takafumi Yamamoto
- Atsushi Naganuma
- Soji Nishina
- Motoyuki Otsuka
- Hiroki Kawashima
- Tetsuji Takayama
- Taro Takami
- Takumi Kawaguchi
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Affiliations: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830‑0011, Japan, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755‑8505, Japan, Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima 770‑8504, Japan, Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8560, Japan, Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Takamatsu, Kagawa 761‑0793, Japan, Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Gastroenterology and Hepatology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi 453‑8511, Japan, Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Aichi 441‑8570, Japan, Department of Gastroenterology, Anjo Kosei Hospital, Anjo, Aichi 446‑8602, Japan, Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma 370‑0829, Japan, Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Gunma 371‑0821, Japan, Department of Gastroenterology, Kawasaki Medical School, Kurashiki, Okayama 701‑0192, Japan, Department of Gastroenterology, Fukuyama City Hospital, Fukuyama, Okayama 721‑8511, Japan, Department of Gastroenterology, Fukuyama Medical Center, Fukuyama, Okayama 720‑8520, Japan, Department of Gastroenterology and Hepatology, Kurume Central Hospital, Kurume, Fukuoka 830‑0001, Japan, Division of Laboratory, Yamaguchi University Hospital, Ube, Yamaguchi 755‑8505, Japan, Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma 370‑0829, Japan, Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama 700‑8558, Japan
Published online on: June 25, 2024 https://doi.org/10.3892/ol.2024.14530
Article Number: 397
Copyright: © Shimose et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first‑line therapy for patients with unresectable hepatocellular carcinoma (u‑HCC), its outcomes in real‑world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u‑HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression‑free survival (PFS), therapeutic response and adverse events (AEs) were assessed. The objective response rate (ORR) and disease control rates (DCR) were 15.8 and 53.3%, respectively. The median PFS was 3.9 months. The incidence rates of AEs of any grade and those grade 3 or higher were 83.3 and 36.7%, respectively. Liver injury was the most frequent AE of any grade and grade 3 or higher. Although there was no significant difference in ORR and PFS between the first and later line groups (ORR 15.8 vs. 15.7%, P=0.986; PFS 4.5 vs. 3.6 months, P=0.213), there was a significant difference in DCR between the two groups (65.8 vs. 45.9%, P=0.034). No significant differences were noted between the first‑ and later‑line treatment groups regarding the incidence rate of AEs. Decision tree analysis revealed that poor liver function and advanced age were significant variables for discontinuation owing to AEs. In conclusion, Dur/Tre as first‑line therapy had better disease control responses compared with later‑line therapy; however, this regimen should be carefully administered to patients with deteriorating hepatic function or advanced ag9

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1	Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, Laversanne M, McGlynn KA and Soerjomataram I: Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 77:1598–1606. 2022. View Article : Google Scholar : PubMed/NCBI
2	Vogel A, Meyer T, Sapisochin G, Salem R and Saborowski A: Hepatocellular carcinoma. Lancet. 400:1345–1362. 2022. View Article : Google Scholar : PubMed/NCBI
3	Villanueva A: Hepatocellular carcinoma. N Engl J Med. 380:1450–1462. 2019. View Article : Google Scholar : PubMed/NCBI
4	Kudo M: Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update. Liver Cancer. 9:640–662. 2020. View Article : Google Scholar : PubMed/NCBI
5	Rimassa L, Finn RS and Sangro B: Combination immunotherapy for hepatocellular carcinoma. J Hepatol. 79:506–515. 2023. View Article : Google Scholar : PubMed/NCBI
6	Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, et al: AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 78:1922–1965. 2023. View Article : Google Scholar : PubMed/NCBI
7	Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, et al: Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1:EVIDoa21000702022. View Article : Google Scholar : PubMed/NCBI
8	Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, et al: BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 76:681–693. 2022. View Article : Google Scholar : PubMed/NCBI
9	Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Dao TV, De Toni EN, et al: Plain language summary of the HIMALAYA study: Tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer). Future Oncol. 19:2505–2516. 2023. View Article : Google Scholar : PubMed/NCBI
10	Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, Kim SW, Ursol G, Hussein M, Lim FL, et al: Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: The phase III POSEIDON study. J Clin Oncol. 41:1213–1227. 2023. View Article : Google Scholar : PubMed/NCBI
11	Psyrri A, Fayette J, Harrington K, Gillison M, Ahn MJ, Takahashi S, Weiss J, Machiels JP, Baxi S, Vasilyev A, et al: Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study. Ann Oncol. 34:262–274. 2023. View Article : Google Scholar : PubMed/NCBI
12	Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D'Angelo SP, Woo KM, et al: Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol. 33:3193–3198. 2015. View Article : Google Scholar : PubMed/NCBI
13	Postow MA, Sidlow R and Hellmann MD: Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 378:158–168. 2018. View Article : Google Scholar : PubMed/NCBI
14	Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D and Burroughs AK: Systematic review: The model for end-stage liver disease-should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 22:1079–1089. 2005. View Article : Google Scholar : PubMed/NCBI
15	Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O'Beirne J, Fox R, Skowronska A, Palmer D, et al: Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach-the ALBI grade. J Clin Oncol. 33:550–558. 2015. View Article : Google Scholar : PubMed/NCBI
16	Hatanaka T, Kakizaki S, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, et al: Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach. Cancer Med. 12:21680–21693. 2023. View Article : Google Scholar : PubMed/NCBI
17	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
18	Hayakawa Y, Tsuchiya K, Kurosaki M, Yasui Y, Kaneko S, Tanaka Y, Ishido S, Inada K, Kirino S, Yamashita K, et al: Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice. Invest New Drugs. 40:392–402. 2022. View Article : Google Scholar : PubMed/NCBI
19	Yang Y, Zhang Y, Iwamoto H, Hosaka K, Seki T, Andersson P, Lim S, Fischer C, Nakamura M, Abe M, et al: Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun. 7:126802016. View Article : Google Scholar : PubMed/NCBI
20	Sangro B, Chan SL, Kelly RK, Lau G, Kudo M, Sukeepaisarnjaroen W, Yarchoan M, De Toni EN, Furuse J, Kang YK, et al: Four-year overall survival update from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 35:448–457. 2024. View Article : Google Scholar : PubMed/NCBI
21	Tanabe N, Saeki I, Aibe Y, Matsuda T, Hanazono T, Nishi M, Hidaka I, Kuwashiro S, Shiratsuki S, Matsuura K, et al: Early prediction of response focused on tumor markers in atezolizumab plus bevacizumab therapy for hepatocellular carcinoma. Cancers (Basel). 15:29272023. View Article : Google Scholar : PubMed/NCBI
22	Waterhouse D, Lam J, Betts KA, Yin L, Gao S, Yuan Y, Hartman J, Rao S, Lubinga S and Stenehjem D: Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small cell lung cancer. Lung Cancer. 156:41–49. 2021. View Article : Google Scholar : PubMed/NCBI
23	Buchbinder EI and Desai A: CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol. 39:98–106. 2016. View Article : Google Scholar : PubMed/NCBI
24	Robert L, Tsoi J, Wang X, Emerson R, Homet B, Chodon T, Mok S, Huang RR, Cochran AJ, Comin-Anduix B, et al: CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res. 20:2424–2432. 2014. View Article : Google Scholar : PubMed/NCBI
25	Shimose S, Hiraoka A, Tanaka M, Iwamoto H, Tanaka T, Noguchi K, Aino H, Yamaguchi T, Itano S, Suga H, et al: Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma. Sci Rep. 12:170182022. View Article : Google Scholar : PubMed/NCBI
26	Delire B, De Martin E, Meunier L, Larrey D and Horsmans Y: Immunotherapy and gene therapy: New challenges in the diagnosis and management of drug-induced liver injury. Front Pharmacol. 12:7861742021. View Article : Google Scholar : PubMed/NCBI
27	Ito T, Ishigami M, Yamamoto T, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Yasuda S, et al: Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies. Hepatol Int. 15:1278–1287. 2021. View Article : Google Scholar : PubMed/NCBI
28	Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M, Hartmann D, Hüser N, Meiser P, Bayerl F, et al: Auto-aggressive CXCR6⁺ CD8 T cells cause liver immune pathology in NASH. Nature. 592:444–449. 2021. View Article : Google Scholar : PubMed/NCBI
29	Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, Gupta R, Qiu M, Deczkowska A, Weiner A, et al: NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 592:450–456. 2021. View Article : Google Scholar : PubMed/NCBI
30	Tani J, Senoh T, Moriya A, Ogawa C, Deguchi A, Sakamoto T, Takuma K, Nakahara M, Oura K, Tadokoro T, et al: Long-term outcomes and evaluation of hepatocellular carcinoma recurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All kagawa liver disease group (AKLDG) study. Cancers (Basel). 13:22572021. View Article : Google Scholar : PubMed/NCBI
31	Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa J, et al: Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients. Eur J Cancer. 189:1129332023. View Article : Google Scholar : PubMed/NCBI
32	Takeuchi Y, Nouso K, Fujioka SI, Kariyama K, Kobashi H, Uematsu S, Moriya A, Hagihara H, Takabatake H, Nakamura S, et al: The prediction of early progressive disease in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab. Cancer Med. 12:17559–17568. 2023. View Article : Google Scholar : PubMed/NCBI
33	Tomonari T, Tani J, Sato Y, Tanaka H, Tanaka T, Taniguchi T, Asahiro M, Okamoto K, Sogabe M, Miyamoto H, et al: Initial therapeutic results of atezolizumab plus bevacizumab for unresectable advanced hepatocellular carcinoma and the importance of hepatic functional reserve. Cancer Med. 12:2646–2657. 2023. View Article : Google Scholar : PubMed/NCBI
34	Hatanaka T, Kakizaki S, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, et al: Comparative analysis of the therapeutic outcomes of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma patients aged 80 years and older: Multicenter study. Hepatol Res. 54:382–391. 2023. View Article : Google Scholar : PubMed/NCBI
35	Iavarone M, Cabibbo G, Biolato M, Corte CD, Maida M, Barbara M, Basso M, Vavassori S, Craxì A, Grieco A, et al: Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology. 62:784–791. 2015. View Article : Google Scholar : PubMed/NCBI
36	Shimose S, Iwamoto H, Niizeki T, Shirono T, Noda Y, Kamachi N, Okamura S, Nakano M, Suga H, Kuromatsu R, et al: Clinical significance of adverse events for patients with unresectable hepatocellular carcinoma treated with lenvatinib: A multicenter retrospective study. Cancers (Basel). 12:18672020. View Article : Google Scholar : PubMed/NCBI
37	Dale W, Mohile SG, Eldadah BA, Trimble EL, Schilsky RL, Cohen HJ, Muss HB, Schmader KE, Ferrell B, Extermann M, et al: Biological, clinical, and psychosocial correlates at the interface of cancer and aging research. J Natl Cancer Inst. 104:581–589. 2012. View Article : Google Scholar : PubMed/NCBI