Background/Objectives: Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients. Methods: This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit. Results: In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6–13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0–4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients. Conclusions: In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.

BACKGROUND AND AIMS:The outcome of patients with HCC who achieved complete response (CR) to immune-checkpoint inhibitor (ICI)-based systemic therapies is unclear. APPROACH AND RESULTS:Retrospective study of patients with HCC who had CR according to modified Response Evaluation Criteria in Solid Tumors (CR-mRECIST) to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based noncurative systemic therapies, 174 (4.4%) achieved CR-mRECIST, and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; Barcelona-Clinic Liver Cancer-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95% CI: 29.9-34.4) months. One- and 3-year overall survival rates were 98% and 86%. One- and 3-year recurrence-free survival rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after the first mRECIST CR had a longer recurrence-free survival than those who discontinued immunotherapy earlier ( p =0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7). CONCLUSIONS:Overall survival and recurrence-free survival of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.

Background and Aim: Age and biological sex are risk factors for hepatocellular carcinoma (HCC) occurrence, but their impact on overall survival (OS) is a matter of debate. This study aims to investigate how sex and age at diagnosis, along with other associated factors (i.e., comorbidities, etiologies, therapy) impact OS in the HCC population. Method: Data from two HCC cohorts—a prospective registry from the University Hospital of Bern, Switzerland, and a retrospective registry from General Hospital Vienna, Austria—were combined and analyzed. Clinical and laboratory data were reviewed, and OS was compared using Kaplan-Meier curves and the log-rank test. Cox regression models with penalized splines were applied to examine how age at diagnosis influenced OS. Results: Of 1547 HCC patients, 1284 (84.1%) were male. Females were older (67 vs. 63 years, p < 0.001) and had lower rates of liver cirrhosis (p < 0.001), cardiac comorbidities (p < 0.001), and diabetes (p < 0.001). No significant difference in median OS between men and women was observed (18 months vs. 16 months, p = 0.304). Mortality risk increased with age, particularly between 60 and 70 years. However, after adjusting for treatment, the age effect became non-significant (p = 0.171). Conclusions: After controlling the model for therapy, neither age nor sex independently influenced OS in HCC patients, underscoring the impact of therapy on survival.

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0 & PLUSMN;9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.37.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pre-treated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for pro-spective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy. & COPY; 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose Our aim is to describe the role of immune checkpoint inhibitors (ICI) in clinical practice by providing the patient and tumor characteristics as well as survival and toxicity rates by sex. Methods We used electronic health records to identify patients treated at the Cancer Center of the University Hospital Bern, Switzerland between January 1, 2017 and June 16, 2021. Results We identified 5109 patients, 689 of whom (13.5%) received at least one dose of ICI. The fraction of patients who were prescribed ICI increased from 8.6% in 2017 to 22.9% in 2021. ICI represented 13.2% of the anticancer treatments in 2017 and increased to 28.2% in 2021. The majority of patients were male (68.7%), who were older than the female patients (median age 67 vs. 61 years). Over time, adjuvant and first line treatments increased for both sexes. Lung cancer and melanoma were the most common cancer types in males and females. The incidence of irAEs was higher among females (38.4% vs. 28.1%) and lead more often to treatment discontination in females than in males (21.1% vs. 16.8%). Independent of sex, the occurrence of irAEs was associated with greater median overall survival (OS, not reached vs. 1.1 years). Female patients had a longer median OS than males (1.9 vs. 1.5 years). Conclusions ICI play an increasingly important role in oncology. irAEs are more frequent in female patients and are associated with a longer OS. More research is needed to understand the association between patient sex and toxicity and survival.

Background and Aim: Although cirrhosis is a classical risk factor for the development of hepatocellular carcinoma (HCC), its absence does not exclude this risk. We aimed to assess the clinical characteristics and outcomes of cirrhotic HCC (C-HCC) and non-cirrhotic HCC (NC-HCC) patients. Methods: Patients consecutively included in a prospective HCC cohort (University Hospital Bern) were analysed. They were categorised into two groups, based on the basis of histology or combined radiological and laboratory characteristics. Results: 20.4% of patients were NC-HCC. This group was characterized by a higher median age and a higher female prevalence compared to the C-HCC group. Non-alcoholic fatty liver disease (NAFLD) (25.7%) and HBV infection (14.9%) were the main risk factors in this group, whereas alcohol abuse (26%) and HCV (21.6%) in C-HCC, P<0.001. 19.4% of them were diagnosed during a screening programme. Resection was performed in 54.5% of NC HCC patients despite the advanced stage (BCLC stage B and C). No statistically significant difference in survival rate was observed between C and NC-HCC patients (24 months vs. 33.9 months, P=0.162). In multivariate analysis, in the NC-HCC group each unit increase in BMI was associated with mortality while liver transplantation and resection were positively associated with survival. In the C-HCC group, the BCLC stage C was negatively associated with survival while all the therapeutic lines were negative factors for mortality. Conclusion: NC-HCC patients were diagnosed more often outside a screening programme. The patients were older, with a higher female prevalence and despite an advanced stage, were often amenable to surgery.

Schwacha‐Eipper, Birgit1,2; Minciuna, Iulia1; Banz, Vanessa2; Dufour, Jean François*,1,2 Author Information