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Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study

Journal of clinical oncology, 2021-09, Vol.39 (27), p.2991-3001 [Peer Reviewed Journal]

2021 by American Society of Clinical Oncology 2021 American Society of Clinical Oncology ;ISSN: 0732-183X ;EISSN: 1527-7755 ;DOI: 10.1200/JCO.20.03555 ;PMID: 34292792

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  • Title:
    Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study
  • Author: Kelley, Robin Kate ; Sangro, Bruno ; Harris, William ; Ikeda, Masafumi ; Okusaka, Takuji ; Kang, Yoon-Koo ; Qin, Shukui ; Tai, David W-M ; Lim, Ho Yeong ; Yau, Thomas ; Yong, Wei-Peng ; Cheng, Ann-Lii ; Gasbarrini, Antonio ; Damian, Silvia ; Bruix, Jordi ; Borad, Mitesh ; Bendell, Johanna ; Kim, Tae-You ; Standifer, Nathan ; He, Philip ; Makowsky, Mallory ; Negro, Alejandra ; Kudo, Masatoshi ; Abou-Alfa, Ghassan K
  • Subjects: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Carcinoma, Hepatocellular - drug therapy ; Female ; Humans ; Liver Neoplasms - drug therapy ; Male ; Middle Aged ; ORIGINAL REPORTS
  • Is Part Of: Journal of clinical oncology, 2021-09, Vol.39 (27), p.2991-3001
  • Description: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348). Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
  • Publisher: United States: Wolters Kluwer Health
  • Language: English
  • Identifier: ISSN: 0732-183X
    EISSN: 1527-7755
    DOI: 10.1200/JCO.20.03555
    PMID: 34292792
  • Source: GFMER Free Medical Journals
    MEDLINE
    Alma/SFX Local Collection
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