Early Safety Results from the Phase 3b SIERRA Study of Durvalumab and Tremelimumab as First-Line Treatment for Participants with Unresectable Hepatocellular Carcinoma and a Poor Prognosis.

[INTRODUCTION] Subgroups of people with unresectable hepatocellular carcinoma (uHCC) are often excluded from clinical trials due to adverse prognostic factors. The SIERRA (NCT05883644) study assesses the efficacy and safety of STRIDE (Single Tremelimumab Regular Interval Durvalumab) in clinically relevant subgroups of uHCC with poorer prognosis, including participants with more decompensated hepatic function, worse performance status, or more advanced disease than the HIMALAYA (NCT03298451) study.

[METHODS] SIERRA is a phase 3b, single-arm, multicenter study that enrolled participants with uHCC with: Child-Pugh (CP) class of B7 or B8 with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, without main trunk portal vein thrombosis (PVT) (CP B7/B8 cohort); CP class A with ECOG PS 2, without main trunk PVT (ECOG PS 2 cohort); or CP class A with ECOG PS 0-1 with evidence of chronic main trunk PVT (Vp4 cohort). Participants received STRIDE (tremelimumab 300 mg plus durvalumab 1,500 mg once followed by durvalumab 1,500 mg every 4 weeks). This preplanned early safety analysis occurred once ∼60 participants had been followed for ≥6 months (data cutoff: September 27, 2024). Co-primary endpoints are incidence of grade 3/4 adverse events (AEs) possibly related to study treatment (PRAEs) within 6 months of treatment initiation and objective response rate. The study is ongoing.

[RESULTS] This analysis included 98 participants (CP B7/B8 cohort, = 35; ECOG PS 2 cohort, = 44; Vp4 cohort, = 19). Median (Q1-Q3) number of cycles of durvalumab was 4.0 (2.0-8.0). Incidence of grade 3/4 PRAEs occurring within 6 months of treatment was 19.4% (95% confidence interval, 12.1-28.6) overall. Incidence of serious AEs was 32.7%. PRAEs, leading to death, occurred in 2.0% of participants.

[CONCLUSION] The safety profile of STRIDE was manageable and consistent with the HIMALAYA study in participants with poorer prognosis than in HIMALAYA.