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Войти в исследования Hepatology (Baltimore, Md.) · 2025
A multicenter dose-defining/expansion phase 1b study of first-line regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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El-Khoueiry Anthony B, Kim Richard D, Harris William P, Sung Max W, Waldschmidt Dirk, Cabrera Roniel, Garosi Vittorio L, Ploeger Bart A, Zebger-Gong Hong, Brennan Barbara J, Wang Ying A, Mueller Udo, Weispfenning Anke, Seidel Henrik, Coppieters Sabine, Ishida Tatiane C, Galle Peter R
Аннотация
BACKGROUND AND AIMS: Combinations including an immune checkpoint inhibitor are preferred first-line treatments for advanced HCC. We investigated the safety of regorafenib plus pembrolizumab as first-line systemic therapy for advanced HCC.
APPROACH AND RESULTS: This was a dose-defining/expansion phase 1b study in adults with advanced HCC without prior systemic treatment. Patients received regorafenib 80 or 120 mg/day for 3 weeks plus pembrolizumab 200 mg every 3 weeks in 4-week cycles (rego-80/pembro or rego-120/pembro): rego-80/pembro in the dose-defining phase; rego-80/pembro or rego-120/pembro in 2 dose-expansion cohorts. The primary objective was to assess safety; antitumor activity was a secondary objective. The MTD of regorafenib was 120 mg/day plus pembrolizumab; 4/19 patients receiving rego-120/pembro experienced dose-limiting toxicities [grade 3 increased AST with grade 1/2 increased bilirubin (n=2), and grade 3 rash (n=2)]. The most common treatment-emergent adverse events (TEAEs) in the overall safety cohort (n=57) were diarrhea (53%) and fatigue (51%). The most common grade ≥3 TEAEs were increased AST (18%) and hypertension (16%). Dose modifications due to study drug-related adverse events were less frequent with rego-80/pembro than with rego-120/pembro. The objective response rate (ORR) in 54 response-evaluable patients was 31% and the disease control rate (DCR) was 89%. Exploratory analyses suggested an association between lower angiogenesis and transforming growth factor-β signaling before treatment and response.
CONCLUSIONS: Treatment with rego/pembro is feasible in patients with advanced HCC with a manageable safety profile. ORR and DCR are promising and consistent with other immunotherapy combinations in this setting.
APPROACH AND RESULTS: This was a dose-defining/expansion phase 1b study in adults with advanced HCC without prior systemic treatment. Patients received regorafenib 80 or 120 mg/day for 3 weeks plus pembrolizumab 200 mg every 3 weeks in 4-week cycles (rego-80/pembro or rego-120/pembro): rego-80/pembro in the dose-defining phase; rego-80/pembro or rego-120/pembro in 2 dose-expansion cohorts. The primary objective was to assess safety; antitumor activity was a secondary objective. The MTD of regorafenib was 120 mg/day plus pembrolizumab; 4/19 patients receiving rego-120/pembro experienced dose-limiting toxicities [grade 3 increased AST with grade 1/2 increased bilirubin (n=2), and grade 3 rash (n=2)]. The most common treatment-emergent adverse events (TEAEs) in the overall safety cohort (n=57) were diarrhea (53%) and fatigue (51%). The most common grade ≥3 TEAEs were increased AST (18%) and hypertension (16%). Dose modifications due to study drug-related adverse events were less frequent with rego-80/pembro than with rego-120/pembro. The objective response rate (ORR) in 54 response-evaluable patients was 31% and the disease control rate (DCR) was 89%. Exploratory analyses suggested an association between lower angiogenesis and transforming growth factor-β signaling before treatment and response.
CONCLUSIONS: Treatment with rego/pembro is feasible in patients with advanced HCC with a manageable safety profile. ORR and DCR are promising and consistent with other immunotherapy combinations in this setting.