Abstract IA15: Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge
Authors: Galle Peter R 
Published: September 2022

Abstract
Trial Design and Endpoint Definition in general is more complex in hepatocellular carcinoma compared to other solid tumors. It took decades of research until the first systemic treatment was defined in 2007 as a result of the SHARP and the ASIA-Pacific trials. The demonstration of Sorafenib’s anti-tumor efficacy in advanced HCC to a large extend was owing to the concentration on patients with good liver function, avoiding the confounding impact of liver cirrhosis. In intermediate stage HCC trial design is even more challenging: intermediate stage HCC is a heterogeneous disease with a broad spectrum of tumor burden, variable liver function, and radiological intervention with transarterial chemoembolization (TACE) as a standard procedure which is far beyond standardization. Several trials have been launched either combining TACE with systemic therapy or comparing TACE vs. systemic therapy. Several issues in this setting are questioning overall survival as preferred endpoint: with an expected survival in excess of 2.5 years and several systemic therapies available, the competing risks of death (liver disease) and the contribution of post-trial treatments are increasingly impacting OS and obscuring the effectiveness of the trial-specific intervention. This is exemplified by the TACTICS trial, comparing TACE + Sorafenib with TACE, where a solid PFS benefit for the combination (HR: 0.661) did not translate into OS (HR: 0.861), possibly because of a more than 20% higher rate of post-treatment medication in the TACE-only group. Thus, there is an obvious need for surrogate markers, indicative of increased survival time but shifting overall survival analysis into secondary endpoints. We recently started the ABC-HCC trial, a phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma. Here we are using a pragmatic and real-life endpoint, Time to failure of treatment strategy (TTFS) as primary endpoint. TTFS is defined as Time from randomization until failure of strategy, i.e. radiologic progression or lack of radiologic response AND any of the following: the loss of clinical benefit OR unacceptable toxicity OR liver function deterioration OR therapy not further applicable for other reasons Secondary endpoints comprise OS, Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to loss of systemic treatment options (TTSYS), Progression free survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to deterioration of liver function, Safety, and QoL (Patient Reported Outcome; PRO). The trial includes an exploratory biomarker analysis. The ABC-HCC and other trials will give us information on the role of systemic therapy in intermediate stage HCC in the upcoming years.
Citation Format: Peter R Galle. Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA15.