Real-World Outcomes in the Evolving Second-Line Systemic Therapy Landscape in Hepatocellular Carcinoma

Objectives: Historically, few treatments existed for hepatocellular carcinoma (HCC) until sorafenib’s approval in 2007. Meaningful treatment advances included approval of atezolizumab plus bevacizumab in 2020 and tremelimumab plus durvalumab 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 2018 and 2025 were retrospectively reviewed. Demographics, clinical characteristics, treatment history, and survival outcomes were collected. Survival was analyzed using Kaplan-Meier methods. Univariable and multivariable analyses were conducted. Results: In total, 143 patients were reviewed (median age 67.4; 72.0% male). First-line systemic therapy included sorafenib (28.0%), nivolumab (21.0%), lenvatinib (18.9%), atezolizumab/bevacizumab (16.1%), and tremelimumab/durvalumab (8.4%). Fifty-two patients (36.4%) received second-line therapy: immunotherapy (48.1%), TKI (40.4%), and ramucirumab (11.5%). AFP ≥400 was present in 48.1% of second-line patients. Leading barriers to second-line treatment were patient choice (40.7%) and poor performance status (38.5%). Median overall survival after second-line therapy was 8.5, 9.1, and 9.3 months for TKI, immunotherapy, and ramucirumab, respectively ( P =0.903). Median progression-free survival was 3.1, 3.9, and 3.7 months ( P =0.598). Conclusions: One third of patients received second-line therapy, with patient choice and declining performance status as leading barriers. Ramucirumab’s underutilization, comparable efficacy, and favorable toxicity profile make it worthy of increased consideration for second-line systemic therapy. Prospective studies are needed to elucidate factors influencing optimal second-line therapy in HCC.