Citations 1
Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study
Kelley, Robin Kate , Harris, William Proctor , Ikeda, Masafumi , Okusaka, Takuji , Kang, Yoon‐Koo , Qin, Shukui , Tai, David , Lim, Ho Yeong , Yong, Wei Peng , Cheng, Ann‐Lii , Gasbarrini, Antonio , Damian, Silvia , Bruix, Jordi , Bendell, Johanna C. , Kim, Tae‐You , He, Philip , Makowsky, Mallory, Negro, Alejandra , Gasbarrini, Antonio , Ikeda, Masafumi , Okusaka, Takuji , Kang, Yoon-Koo , Qin, Shukui , Tai, David W-M , Lim, Ho Yeong , Yong, Wei-Peng , Cheng, Ann-Lii , Damian, Silvia , Borad, Mitesh J , He, Philip , Kudo, Masatoshi , Abou-Alfa, Ghassan K , Bruix, Jordi , Sangro, Bruno , Yau, Thomas , Borad, Mitesh J. , Standifer, Nathan E. , Kudo, Masatoshi , Abou‐Alfa, Ghassan K.
Journal of Clinical Oncology | July 22, 2021 | Volume: 39 | Issue: 27 | Pages: 2991-3001
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: NCT02519348 ). 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.