P-161 Trial in progress: Neoadjuvant combination therapy of lenvatinib plus transcatheter arterial chemoembolization (TACE) for transplant-eligible patients with large hepatocellular carcinoma

Hepatocellular carcinoma HCC is the third leading cause of cancer death worldwide with more than 230,000 cases of HCC since 2000 and an estimated 42,000 new cases next year. In 2015, HCC was the leading diagnosis among liver transplant recipients (27.2%). Transplantation of patients diagnosed with HCC is largely based on tumor size since this is thought to correlate with posttransplant outcomes. However, emerging evidence shows that tumor stability or response to locoregional therapy (LRT) can be surrogate markers of favorable biology and improved outcomes following transplantation LRT, including TACE or radiofrequency ablation, that promote tumor stability (defined as no tumor progression in 6 months) serve as bridging therapies to liver transplantation. In tumors that respond to ablation, LRT further augments the success of liver transplantation and reduces the risk of HCC recurrence post-transplant. The purpose of this trial is to examine if combination therapy of lenvatinib plus TACE will promote tumor necrosis evidenced by explant pathology in patients with large HCC (>5 cm). Vascular endothelial growth factor (VEGF) inhibitors have emerged as key players in promoting tumor regression of Hepatocellular carcinoma (HCC). The potential synergistic effect of transcatheter arterial chemoembolization (TACE) in combination with VEGF inhibitors in transplant-eligible patients with HCC has not yet been defined. This strategy of combined therapy may lead to improved tumor necrosis and favorable post-transplant overall survival (OS) and recurrence-free survival (RFS. We hypothesize that lenvatinib combined with TACE will improve tumor necrosis compared to TACE alone in transplant-eligible patients with HCC beyond Milan Criteria (> 5 cm). To test this hypothesis, we propose a regimen of six months of neoadjuvant Lenvatinib in combination with TACE prior to transplantation. We aim to improve the response (defined as the percent tumor necrosis present on the explanted liver at the time of transplantation) by adding lenvatinib in combination with TACE. The study is a phase 2, Single-center, two arms: Intervention arm (n=50): prospectively enrolled to receive lenvatinib for 6 months prior to transplantation. We anticipate having to enroll 50 participants so that 33 reach transplantation. Control arm (n=33): historical controls matched to transplanted participants in the intervention arm based on tumor size, age, etiology (viral vs. non-viral) of liver disease, and a number of TACE procedures. The primary objective is to measure the efficacy of using lenvatinib with TACE to elicit tumor necrosis as evidenced by explant pathology in transplant-eligible patients with large HCC. Secondary Endpoints are the proportion of adverse events with a grade 3 or higher score based on the Common Terminology Criteria for Adverse Events (CTCAE) v.5, response rate (RR) of lenvatinib following TACE by assessing radiologic images using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and the proportion of tumors that are down-staged to standard Milan criteria (tumors < 5cm) based on CT/MRI imaging. An interim analysis will be performed to assess efficacy after 35 patients become evaluable. The study is open with 50 patients enrolled at the time of submission. NCT05171335. The authors.