Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.
Authors: Brown Timothy J , Gupta Arjun , Sedhom Ramy , Karasic Thomas Benjamin , Yarchoan Mark 
Published: January 2021

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Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.