Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment

Abstract

Purpose: Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit.

Protocol: LEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child-Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety.

Statistics: The planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint.

Discussion: LEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment.

Clinicaltrials: gov NCT04246177.

Keywords: Intermediate-stage hepatocellular carcinoma; Lenvatinib; Pembrolizumab; Transarterial chemoembolization.

Fig. 1

LEAP-012 study design. AFP α-fetoprotein; ALBI albumin-bilirubin; BW body weight; cTACE conventional TACE; DEB-TACE drug-eluting bead TACE; ECOG PS Eastern Cooperative Oncology Group performance status; HCC hepatocellular carcinoma; IV intravenously; PD progressive disease; Q6W once every 6 weeks; QD once daily; R randomization; RECIST Response Evaluation Criteria in Solid Tumors; TACE transarterial chemoembolization ^aStratification by study site was selected to minimize the effect of variations in TACE technique, instrumentation/imaging and other procedure-related heterogeneity across study sites. ^bTumor burden (6 and 12 rule): ≤ 6 vs. > 6 but ≤ 12 vs. > 12. Tumor burden = largest tumor size (in cm) + number of tumors. ^cTACE will be limited to 2 treatments per tumors according to site-prespecified modality (cTACE or DEB-TACE)