Journal of hepatology · 2026
First-line durvalumab and tremelimumab in poor-prognosis unresectable hepatocellular carcinoma: Phase IIIb single-arm SIERRA study.
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Chan Stephen L, Kudo Masatoshi, Sangro Bruno, Kelley Robin Kate, Kim Jee Hyun, Pham Binh, Hong Jung Yong, Waldschmidt Dirk-Thomas, Marino Donatella, Gerolami René, Burgoyne Adam M, Masi Gianluca, Walsh Robert John, Marquardt Jens U, Emeribe Ugochinyere, Balaji Kavitha, Sun Peng, Baur Boris, Rimassa Lorenza
Аннотация
BACKGROUND & AIMS: Clinical trials in unresectable hepatocellular carcinoma (uHCC) often exclude patients with poor prognostic factors, including impaired liver function, poor functional status or main trunk portal vein thrombosis (Vp4). The dual immune checkpoint inhibitor regimen STRIDE (Single Tremelimumab Regular Interval Durvalumab) is a standard-of-care treatment for first-line uHCC. The phase IIIb SIERRA (NCT05883644) study previously reported early safety of STRIDE in participants of poor prognosis. Here, we present safety and efficacy results from the primary analysis of the SIERRA study.
METHODS: Adults with uHCC with either Child-Pugh B7/B8 liver function (Child-Pugh B7/B8 cohort), Eastern Cooperative Oncology Group performance status 2 (ECOG PS 2 cohort) or Vp4 (Vp4 cohort) were enrolled. All participants received STRIDE (tremelimumab 300 mg plus durvalumab 1500 mg once, followed by durvalumab 1500 mg every 4 weeks) until disease progression, unacceptable toxicity or withdrawal. Primary endpoints were Grade 3 or 4 adverse events possibly related to study treatment within 6 months of treatment initiation (Grade 3/4 PRAEs ≤6 months) and objective response rate (ORR; data cut-off: 22 September 2025).
RESULTS: In total, 111 participants were included (Child-Pugh B7/B8 n = 44, ECOG PS 2 n = 47, Vp4 n = 20). The incidence of Grade 3/4 PRAEs ≤6 months (95% confidence interval [CI]) was 19.8% (12.9-28.5): Child-Pugh B7/B8, 18.2% (8.2-32.7); ECOG PS 2, 19.1% (9.1-33.3); and Vp4, 25.0% (8.7-49.1). ORR (95% CI) was 14.4% (8.5-22.4): Child-Pugh B7/B8, 6.8% (1.4-18.7); ECOG PS 2, 21.3% (10.7-35.7); and Vp4, 15.0% (3.2-37.9).
CONCLUSIONS: SIERRA safety and efficacy findings were indicative of a favourable risk-benefit profile for STRIDE in this participant population with a high unmet need.
IMPACT AND IMPLICATIONS: Participants with poor prognosis (e.g. Child-Pugh B/C, Eastern Cooperative Oncology Group performance status >1 or main trunk portal vein thrombosis [Vp4]) remain underrepresented in global, phase III trials despite comprising up to 65% of patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. To address this unmet need, the phase IIIb SIERRA study (NCT05883644) evaluated STRIDE (Single Tremelimumab Regular Interval Durvalumab) in participants with poor prognostic factors. Safety and efficacy findings as per the co-primary endpoints are indicative of a favourable risk-benefit profile for STRIDE in this participant population with a high unmet need, with an incidence of Grade 3 or 4 PRAEs within 6 months of 19.8% and ORR of 14.4% in the total population. This is the first prospective interventional study to provide data informing the safety and efficacy of STRIDE in patients with uHCC in a previously underrepresented population of poor prognosis that are excluded from other phase III trials.
CLINICAL TRIAL NUMBER: NCT05883644.
METHODS: Adults with uHCC with either Child-Pugh B7/B8 liver function (Child-Pugh B7/B8 cohort), Eastern Cooperative Oncology Group performance status 2 (ECOG PS 2 cohort) or Vp4 (Vp4 cohort) were enrolled. All participants received STRIDE (tremelimumab 300 mg plus durvalumab 1500 mg once, followed by durvalumab 1500 mg every 4 weeks) until disease progression, unacceptable toxicity or withdrawal. Primary endpoints were Grade 3 or 4 adverse events possibly related to study treatment within 6 months of treatment initiation (Grade 3/4 PRAEs ≤6 months) and objective response rate (ORR; data cut-off: 22 September 2025).
RESULTS: In total, 111 participants were included (Child-Pugh B7/B8 n = 44, ECOG PS 2 n = 47, Vp4 n = 20). The incidence of Grade 3/4 PRAEs ≤6 months (95% confidence interval [CI]) was 19.8% (12.9-28.5): Child-Pugh B7/B8, 18.2% (8.2-32.7); ECOG PS 2, 19.1% (9.1-33.3); and Vp4, 25.0% (8.7-49.1). ORR (95% CI) was 14.4% (8.5-22.4): Child-Pugh B7/B8, 6.8% (1.4-18.7); ECOG PS 2, 21.3% (10.7-35.7); and Vp4, 15.0% (3.2-37.9).
CONCLUSIONS: SIERRA safety and efficacy findings were indicative of a favourable risk-benefit profile for STRIDE in this participant population with a high unmet need.
IMPACT AND IMPLICATIONS: Participants with poor prognosis (e.g. Child-Pugh B/C, Eastern Cooperative Oncology Group performance status >1 or main trunk portal vein thrombosis [Vp4]) remain underrepresented in global, phase III trials despite comprising up to 65% of patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. To address this unmet need, the phase IIIb SIERRA study (NCT05883644) evaluated STRIDE (Single Tremelimumab Regular Interval Durvalumab) in participants with poor prognostic factors. Safety and efficacy findings as per the co-primary endpoints are indicative of a favourable risk-benefit profile for STRIDE in this participant population with a high unmet need, with an incidence of Grade 3 or 4 PRAEs within 6 months of 19.8% and ORR of 14.4% in the total population. This is the first prospective interventional study to provide data informing the safety and efficacy of STRIDE in patients with uHCC in a previously underrepresented population of poor prognosis that are excluded from other phase III trials.
CLINICAL TRIAL NUMBER: NCT05883644.