1. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study
- Author
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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, and Abou-Alfa, Ghassan K
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,HIV/AIDS ,Orphan Drug ,Rare Diseases ,Cancer ,Biotechnology ,Clinical Research ,Digestive Diseases ,Clinical Trials and Supportive Activities ,Liver Cancer ,Patient Safety ,Liver Disease ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Carcinoma ,Hepatocellular ,Female ,Humans ,Liver Neoplasms ,Male ,Middle Aged ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeThis 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 and methodsPatients 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.ResultsA 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.ConclusionAll 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.
- Published
- 2021