O-5 Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA study

Abstract

In the phase 3 HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), a single, high priming dose of tremelimumab (anti-CTLA-4) plus durvalumab (anti-PD-L1) in the STRIDE regimen significantly improved overall survival (OS) vs sorafenib, and durvalumab monotherapy was noninferior to sorafenib (Abou-Alfa et al. J Clin Oncol 2022;40[suppl 4]. Abs 379). Liver function is frequently impaired in patients with HCC, and it is important to evaluate the efficacy and safety of systemic therapies for these patients. HIMALAYA included patients with Child-Pugh Score class A. Baseline liver function was evaluated using albumin-bilirubin (ALBI) score (log10[bilirubin] x 0.66−albumin x 0.085), an objective measure based on laboratory values. Exploratory analyses assessed OS, objective response rate (ORR), duration of response (DoR), time-to-response (TTR), and safety in patients classified into ALBI grade 1 (score ≤-2.60), ALBI grade 2 (score >-2.60 to ≤-1.39), and ALBI grade 3 (score >-1.39) subgroups. OS hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model adjusting for treatment, etiology, ECOG performance status, and macrovascular invasion. Due to small sample size, outcomes for the ALBI grade 3 subgroup (STRIDE, n=1; durvalumab, n=2; sorafenib, n=1) were combined with the ALBI grade 2 subgroup. Patients randomized to STRIDE, durvalumab, and sorafenib were classified as ALBI grade 1 (n=217, n=198, and n=203, respectively) or ALBI grade 2/3 (n=175, n=191, and n=186, respectively). Baseline demographics and disease characteristics in the subgroups were similar across treatment arms. In patients with ALBI grade 1, OS HRs (95% CIs) were 0.79 (0.62-1.01) for STRIDE vs sorafenib, consistent with the full analysis set (0.78 [96% CI, 0.65-0.93]), and 0.91 (0.71-1.15) for durvalumab vs sorafenib, numerically higher than the full analysis set (0.86 [96% CI, 0.73-1.03]). Median OS (95% CI) was 23.43 months (19.19-28.75) with STRIDE, 21.16 months (17.38-25.86) with durvalumab, and 19.02 months (15.67-23.16) with sorafenib; 36-month OS rates were 38.0%, 27.0%, and 27.3%, respectively. ORRs were 21.7% for STRIDE, 18.7% for durvalumab, and 7.4% for sorafenib. Median (interquartile range [IQR]) DoR was 22.34 months (8.71-Not reached [NR]), 23.26 months (7.43-NR), and 22.06 months (6.51-25.99), respectively; median TTR (IQR) was 2.07 months (1.84-3.94), 1.91 months (1.81-3.98), and 3.52 months (1.84-5.49), respectively. In patients with ALBI grade 2/3, OS HRs (95% CIs) were 0.83 (0.65-1.05) for STRIDE vs sorafenib and 0.87 (0.69-1.09) for durvalumab vs sorafenib. Median OS (95% CI) was 11.30 months (9.33-14.19) with STRIDE, 12.29 months (9.30-16.03) with durvalumab, and 9.72 months (7.23-11.76) with sorafenib; 36-month OS rates were 21.8%, 22.5%, and 12.9%, respectively. ORRs were 18.3% for STRIDE, 15.2% for durvalumab, and 2.7% for sorafenib. Median (IQR) DoR was 26.55 months (7.43-NR), 13.83 months (7.43-27.43), and 12.25 months (7.69-NR), respectively; median TTR (IQR) was 3.52 months (1.91-5.40), 3.65 months (1.94-3.94), and 9.10 months (7.79-11.01), respectively. Safety in the ALBI subgroups was generally consistent with the full analysis set. STRIDE showed a favorable benefit-risk profile compared with sorafenib across ALBI subgroups. STRIDE and durvalumab may represent new treatment options in uHCC for patients with less optimal liver function.