Giulia Francesca Manfredi

Supplementary Figure S1. Early hepatic decompensation identifies patients with hepatocellular carcinoma treated with systemic therapy at highest risk of death. Clinical hepatic decompensation is associated with higher hazard ratio for death, compared to HCC radiological progression. Albumin-bilirubin (ALBI) grade, INR and macrovascular invasion are independent predictors of clinical hepatic decompensation.

Supplementary Table 3. Rates of HCC radiological progression or clinical hepatic decompensation as first event.

Supplementary Table S5. Full multivariable model of baseline predictors of clinical hepatic decompensation and HCC progression by competing risks analysis, with albumin-bilirubin (ALBI) included as continuous variable.

Purpose:The prognosis of patients with unresectable hepatocellular carcinoma (HCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation (CHD) following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early CHD within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with atezolizumab plus bevacizumab or sorafenib.Patients and Methods:Individual patient data from the IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risk analysis against HCC radiologic progression. Early CHD and HCC radiologic progression were assessed as predictors of OS by the time-dependent Cox model.Results:The 3- and 12-month rates of CHD were 7% and 12%, respectively, whereas the 3- and 12-month rates of HCC radiologic progression were 23% and 52%, respectively. Albumin–bilirubin grade 2 [subdistribution HR (sHR) = 1.79, 95% confidence interval (CI), 1.01–3.19; P = 0.049], INR (sHR = 1.97, 95% CI, 1.64–2.37; P < 0.001), and presence of neoplastic macrovascular invasion (sHR = 2.01, 95% CI, 1.14–3.54; P = 0.020) were independently associated with higher risk of CHD. Early CHD (HR = 7.56, 95% CI, 4.47–12.8) and early HCC radiologic progression (HR = 5.92, 95% CI, 4.03–8.69), as first events, were independently associated with higher mortality.Conclusions:This study provides robust evidence that early CHD is associated with the highest risk of death in patients with unresectable HCC undergoing systemic treatment. Within well-compensated participants, albumin–bilirubin, INR, and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.

Supplementary Table 4. Full multivariable model of baseline predictors of clinical hepatic decompensation and HCC progression by competing risks analysis.

Supplementary Table 2. Patient characteristics at baseline.

Supplementary Table 1. Representativeness of Study Participants.