Hepatocellular carcinoma second-line systemic therapies.

544 Background: In the United States in 2024, there were 29,365 new cases of hepatocellular carcinoma (HCC). Historically, few treatments existed for HCC until sorafenib’s approval in 2007. Meaningful treatment advances included approval of Atezolizumab plus Bevacizumab (Atezo/Bev) in 2020 and Tremelimumab plus Durvalumab (Trem/Durva) in 2022. However, optimal second-line systemic therapy and outcomes after current first-line therapies are unclear. Methods: Patients treated with systemic therapy for HCC between January 2018 and December 2024 were reviewed. Data collected included demographics, comorbidities, prior liver-directed therapy, systemic therapy selection, and survival. Summary statistics were computed. Kaplan-Meier analyses were performed to compare overall survival (OS) and progression-free survival (PFS) between second-line immunotherapy, tyrosine kinase inhibitor (TKI), and ramucirumab cohorts. Results: We reviewed 131 patients. Median age was 67.3 years with 71.0% male. In the cohort 72.5% had cirrhosis, 49.6% type 2 diabetes, and 31.3% history of alcohol use disorder. First-line systemic therapy included sorafenib (30.5%), nivolumab (21.4%), lenvatinib (20.6%), Atezo/Bev (16.0%), and Trem/Durva (6.1%). Therapy was discontinued due to progression in 42.0% of cases and toxicity in 22.1%. Among first-line immunotherapy recipients, 12.5% developed immunotherapy-related adverse events (irAEs). Fifty patients (38.2%) received second-line therapy: 25 immunotherapy (50.0%), 20 TKI (40.0%), and 5 ramucirumab (10.0%). Second-line therapy was given to 38.1% and 20.0% of first-line Atezo/Bev and Trem/Durva patients, respectively. Most common reasons for not obtaining second-line systemic therapy included patient choice (26.7%) and poor performance status (25.2%). Esophageal varices were present in 22.0% of patients. Six patients receiving immunotherapy (24.0%) developed irAEs. Median OS after second-line systemic therapy was 9.8 months; 10.4 months for immunotherapy, 9.8 months for TKI, and 20.2 months for ramucirumab (p = 0.825). Median PFS was 3.9 months; 3.9 months for immunotherapy, 3.1 months for TKI, and 4.9 months for ramucirumab (p = 0.55). Conclusions: Approximately one-third of patients receiving first-line systemic therapy proceeded to second-line treatment. Patient choice or declining performance status were leading barriers. While no statistically significant survival differences were observed, a higher OS and PFS was seen with ramucirumab. Further prospective studies are needed to elucidate factors influencing optimal second-line systemic therapy in HCC. Systemic therapy selection. Systemic Therapy First Line Second Line Atezolizumab + Bevacizumab 21 4 Tremelimumab + Durvalumab 8 0 Ipilimumab + Nivolumab 1 6 Nivolumab, Durvalumab, Pembrolizumab, Atezolizumab 34 15 Cabozantinib 0 2 Lenvatinib 27 11 Sorafenib 40 3 Regorafenib 0 4 Ramucirumab 0 5 Data presented as number of patients.