Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable HCC: HIMALAYA phase III randomized clinical trial

doi:10.1097/HEP.0000000000001385

. 2025 May 16.

doi: 10.1097/HEP.0000000000001385. Online ahead of print.

Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable HCC: HIMALAYA phase III randomized clinical trial

George Lau¹, Bruno Sangro², Ann-Lii Cheng³, Masatoshi Kudo⁴, Robin Kate Kelley⁵, Won Young Tak⁶, Antonio Gasbarrini⁷, Maria Reig⁸, Ho Yeong Lim⁹, David Tougeron¹⁰, Enrico N De Toni¹¹, Vincent C Tam¹², Kabir Mody¹³, Jun Gong¹⁴, Oxana V Crysler¹⁵, Wattana Sukeepaisarnjaroen¹⁶, Oleg Lipatov¹⁷, Manabu Morimoto¹⁸, Isabelle Archambeaud¹⁹, Valentina Burgio²⁰, Le Thi Tuyet Phuong²¹, Yee Chao²², Jean-Marie Peron²³, Marie-Luise Berres^{24

25}, Yoo-Joung Ko²⁶, Di Ran²⁷, Mallory Makowsky^{27

28}, Alejandra Negro²⁷, Ghassan K Abou-Alfa^{29

30

31}

Affiliations

¹ Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong Special Administrative Region, China.
² Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain.
³ Department of Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
⁵ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
⁶ Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
⁷ Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
⁸ Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
⁹ Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
¹⁰ Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France.
¹¹ Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.
¹² Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
¹³ Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁴ Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
¹⁶ Department of Medicine, Faculty of Medicine, Khon Kaen University, Srinagarind Hospital, Khon Kaen, Thailand.
¹⁷ Department of Oncology, Republican Clinical Oncology Dispensary, Ufa, Russia.
¹⁸ Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
¹⁹ Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Institut des Maladies de l'Appareil Digestif (IMAD), Nantes Université, CHU Nantes, Nantes, France.
²⁰ Department of Medical Oncology, Vita-Salute University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²¹ People's Hospital 115, Ho Chi Minh City, Vietnam.
²² Department of Oncology, Division of Medical Oncology, Center for Immuno-oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
²³ Hepatology Unit, Rangueil University Hospital, Toulouse, France.
²⁴ Clinic of Gastroenterology, Metabolic Diseases and Internal Medicine Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
²⁵ Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.
²⁶ St Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
²⁷ AstraZeneca, Gaithersburg, Maryland, USA.
²⁸ Department of Clinical Development, Erasca, Inc., San Diego, California, USA.
²⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁰ Weill Medical College, Cornell University, New York, New York, USA.
³¹ Trinity College Dublin, Dublin, Ireland.

PMID: 40384092
DOI: 10.1097/HEP.0000000000001385

Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable HCC: HIMALAYA phase III randomized clinical trial

George Lau et al. Hepatology. 2025.

. 2025 May 16.

doi: 10.1097/HEP.0000000000001385. Online ahead of print.

Authors

Affiliations

¹ Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong Special Administrative Region, China.
² Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain.
³ Department of Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
⁵ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
⁶ Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
⁷ Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
⁸ Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
⁹ Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
¹⁰ Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France.
¹¹ Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.
¹² Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
¹³ Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁴ Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
¹⁶ Department of Medicine, Faculty of Medicine, Khon Kaen University, Srinagarind Hospital, Khon Kaen, Thailand.
¹⁷ Department of Oncology, Republican Clinical Oncology Dispensary, Ufa, Russia.
¹⁸ Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
¹⁹ Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Institut des Maladies de l'Appareil Digestif (IMAD), Nantes Université, CHU Nantes, Nantes, France.
²⁰ Department of Medical Oncology, Vita-Salute University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²¹ People's Hospital 115, Ho Chi Minh City, Vietnam.
²² Department of Oncology, Division of Medical Oncology, Center for Immuno-oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
²³ Hepatology Unit, Rangueil University Hospital, Toulouse, France.
²⁴ Clinic of Gastroenterology, Metabolic Diseases and Internal Medicine Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
²⁵ Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.
²⁶ St Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
²⁷ AstraZeneca, Gaithersburg, Maryland, USA.
²⁸ Department of Clinical Development, Erasca, Inc., San Diego, California, USA.
²⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁰ Weill Medical College, Cornell University, New York, New York, USA.
³¹ Trinity College Dublin, Dublin, Ireland.

PMID: 40384092
DOI: 10.1097/HEP.0000000000001385

Abstract

Background and aims: In the global phase III HIMALAYA study in unresectable HCC, STRIDE significantly improved overall survival (OS) versus sorafenib; durvalumab was noninferior to sorafenib. Immune checkpoint inhibitor studies have shown an association between the occurrence of immune-mediated adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA.

Approach and results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS HRs (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56-0.95) for STRIDE and 1.14 (0.82-1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1-46.7) and 27.7% (22.4-34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation.

Conclusions: Participants who experienced imAEs with STRIDE had a numerical improvement in OS versus those who did not, which was not observed for durvalumab. Long-term OS with STRIDE was observed regardless of imAEs. Most imAEs were low grade, manageable, and occurred in the first 3 months after treatment initiation. Results continue to support the benefits of STRIDE in a diverse population that reflects unresectable HCC globally.

Keywords: anti-cytotoxic T-lymphocyte–associated antigen 4; anti–programmed cell death ligand-1; immune checkpoint inhibitors; safety; survival.

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References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263.
1. Park J-W, Chen M, Colombo M, Roberts LR, Schwartz M, Chen P-J, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 2015;35:2155–2166.
1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.
1. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173.
1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–1905.

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[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263.

[2] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263.

[3] Park J-W, Chen M, Colombo M, Roberts LR, Schwartz M, Chen P-J, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 2015;35:2155–2166.

[4] Park J-W, Chen M, Colombo M, Roberts LR, Schwartz M, Chen P-J, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 2015;35:2155–2166.

[5] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.

[6] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.

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

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

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

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

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Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable HCC: HIMALAYA phase III randomized clinical trial

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Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable HCC: HIMALAYA phase III randomized clinical trial

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