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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

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Abstract
PURPOSE 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: ). PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.
Author(s)
강윤구Alejandra NegroAnn-Lii ChengAntonio GasbarriniBruno SangroDavid W.-M. TaiGhassan K. Abou-AlHo Yeong LimJohanna BendelJordi BruixMallory MakowskyMasafumi IkedaMasatoshi KudoMitesh BoradNathan StandiferPhilip HeRobin Kate KelleyShukui QinSilvia DamianTae-You KimTakuji Okusak
Issued Date
2021
Type
Article
DOI
10.1200/JCO.20.03555
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8405
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2555112253&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Safety,%20Efficacy,%20and%20Pharmacodynamics%20of%20Tremelimumab%20Plus%20Durvalumab%20for%20Patients%20With%20Unresectable%20Hepatocellular%20Carcinoma:%20Randomized%20Expansion%20of%20a%20Phase%20I%2FII%20Study&offset=0&pcAvailability=true
Publisher
JOURNAL OF CLINICAL ONCOLOGY
Location
미국
Language
영어
ISSN
0732-183X
Citation Volume
39
Citation Number
27
Citation Start Page
2991
Citation End Page
2991
Appears in Collections:
Medicine > Medicine
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