Neoadjuvant Combination Therapy of Lenvima Plus Transcatheter Arterial Chemoembolization (TACE) for Transplant-Eligible Patients With Large 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. The purpose of this trial is to examine if combination therapy of lenvatinib (LENVIMA®, Eisai Inc., Woodcliff Lake, NJ) plus transcatheter arterial chemoembolization (TACE) will promote tumor necrosis evidenced by explant pathology in patients with large HCC (>5 cm). TACE blocks blood supply to the tumor and induces tumor necrosis, but this causes hypoxia and subsequent angiogenesis.

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.

Liver transplantation provides the ultimate curative option for patients with HCC with improved overall survival (OS) and recurrence-free survival (RFS) of 85% and 92% at 4 years, respectively, compared to 18.4% without transplantation. To limit disease progression and promote tumor stability while on the transplant waitlist, patients with unresectable HCC typically undergo neoadjuvant treatment. Although the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of neoadjuvant therapy for the management of HCC, no clear-cut guidelines are given regarding the type of LRT or other therapeutic agents. LRT effectively improves 2-yr OS between 20-60% and TACE can achieve complete response in 65.2% of patients. LRT is utilized for preventing tumor growth while on the waitlist and to downstage large tumors to standard Milan Criteria (reduce tumor size to ≤ 5cm). Based on the United Network of Organ Sharing (UNOS) criteria, down-staging of tumors to Milan allows the addition of artificial Model for End-stage Liver Disease (MELD) points to patients while waiting for transplantation to decrease their waiting time. Such additional points afford patients with HCC a timely transplantation since they do not exhibit manifestations of liver failure that drives the MELD score toward transplantation.

Large tumors (>5 cm) commonly require multiple TACE procedures and response failure results in dropout/removal from the transplant waiting list. Despite the partial success of TACE, incomplete tumor necrosis following TACE increases the risk of disease progression and drop-out while waiting for transplantation. Thus, robust neoadjuvant therapies that yield superior tumor necrosis are needed to thwart disease progression and reduce dropout from the transplant waitlist. Additionally, achieving superior tumor necrosis may be accompanied by improved OS and RFS post-transplantation.

Lenvatinib is an inhibitor of the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF receptor substrate 2α (FRS2α) phosphorylation.