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

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.

Although survival benefit of TACE alone has been demonstrated in patients with intermediate HCC, particularly in the 50% of whom achieve objective response [10][11][12], there is evidence that patients with high tumor burden or who do not respond to TACE do not derive clinical benefit from this procedure [13,14]. Additionally, it is formally contraindicated in certain patients, e.g., patients with macrovascular invasion or liver failure [4,6,8]. Therefore, there is an urgent need for novel therapies to improve outcome in this heterogeneous patient population.
Angiogenesis plays a role in tumor growth, and angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are elevated in patients with HCC [15][16][17]. Patients with HCC have significantly higher serum VEGF levels compared with healthy individuals, and elevated levels are associated with venous invasion and advanced disease [15]. Furthermore, an elevated serum VEGF level is associated with significantly worse overall and disease-free survival. Similarly, FGF signaling is implicated in development and progression of HCC [16,17].
Lenvatinib is a potent multikinase inhibitor that selectively inhibits VEGF receptors 1-3, FGF receptors 1-4, platelet-derived growth factor receptor a, RET, and KIT and is approved in the first-line treatment setting for patients with advanced HCC [18]. In an open-label phase 3 study, lenvatinib demonstrated non-inferiority to sorafenib in overall survival (OS) and showed a safety profile consistent with previous studies [19]. The anti-tumor activity of lenvatinib is related to anti-proliferative effects and selective inhibition of FGF-signaling pathways, the latter being a key differentiating feature between lenvatinib and other multikinase inhibitors such as sorafenib [20].
Intact immune surveillance is an important mechanism against neoplastic growth [21]. Programmed cell death protein 1 (PD-1) and its ligand, PD-L1, play a role in the immune response and tumor immune evasion [22][23][24][25]. In patients with HCC, PD-L1 is prognostic of outcome, with high PD-L1 expression associated with significantly poorer prognosis than low PD-L1 expression [26]. Additionally, PD-1 level correlates with disease progression and is predictive of post-operative recurrence [23]. PD-L2, another ligand of PD-1, has been found to be overexpressed on tumor cells and is associated with poor clinical outcomes, especially in patients with HCC [27].
Pembrolizumab is a humanized monoclonal antibody against PD-1 and when combined with lenvatinib has shown promising antitumor activity and a manageable safety profile in patients with unresectable HCC not amenable to TACE in the phase 1b study KEYNOTE-524 study (Eisai Study 116; NCT03006926) [28]. Restoring antitumor immune activity and inhibiting angiogenesis may complement the locoregional necrosis achieved with TACE [8].
High-level evidence is required to support therapies indicated in medical guidelines for the treatment and management of HCC. Recommendations for clinical trial design and endpoints in HCC establish the importance of appropriate patient selection criteria (e.g., BCLC stage, Child-Pugh classification), stratification and randomization factors (e.g., Child-Pugh classification, a-fetoprotein level, geographical region, albumin-bilirubin [ALBI] grade and tumor burden) and trial endpoints (e.g., OS and progression-free survival [PFS]) [9]. Here, we describe the rationale and design for the prospective, double-blind, randomized phase 3 LEAP-012 study (NCT04246177), which is being conducted to investigate the efficacy and safety of lenvatinib plus pembrolizumab in combination with TACE compared with TACE alone in patients with intermediate-stage HCC not amenable to curative treatment.

Materials and Methods
LEAP-012 is designed to investigate oral lenvatinib plus intravenous pembrolizumab in combination with TACE compared with oral plus intravenous placebos in combination with TACE in patients with intermediate-stage HCC (Fig. 1). Patients will be randomly assigned 1:1 (stratified by study site, a-fetoprotein, Eastern Cooperative Oncology Group performance status, ALBI grade [29] and tumor burden) [30]. Stratification by study site was selected to minimize the effect of variations in TACE technique, instrumentation/imaging and other potential procedure-related heterogeneity across study sites. Specifically, each site is required to select the TACE modality (i.e., conventional TACE [cTACE] or drug-eluting bead-TACE [DEB-TACE]) and the chemotherapy agent (i.e., epirubicin, doxorubicin, or cisplatin) that will be used at that site. Other parameters, including chemotherapy dosing, DEB bead size, cTACE Lipiodol quantity, catheter size, and any additional agents used for hemostasis, will be selected by the interventional radiologist or hepatologist for each participant. Lenvatinib (or matching oral placebo) will be administered at 8 mg (\ 60 kg) or 12 mg (C 60 kg) according to body weight orally once daily (QD) until disease progression or unacceptable toxicity; continuation of lenvatinib beyond 2 years of therapy requires consultation with the sponsor. Pembrolizumab (or matching saline placebo) will be administered at 400 mg intravenously every 6 weeks (Q6W) for up to 2 years or until disease progression or unacceptable toxicity. TACE will be administered per site prespecified modality (e.g., cTACE or DEB-TACE).
Systemic therapy with lenvatinib and pembrolizumab or matching placebos is planned to begin on day of random assignment (or, in special circumstances, up to 3 days after random assignment) and the first TACE will be administered 2 to 4 weeks after the start of systemic therapy. TACE is limited to 2 treatments per lesion, and the second treatment of any lesion is only permitted after confirmatory imaging per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) determines there is remaining viable tumor. If split TACE (a second procedure targeting previously untreated tumors) is required, it must be performed C 1 month after the first TACE and before the first imaging evaluation. Lenvatinib will be held 2 days before and C 7 days after TACE, with resumption contingent on postembolization syndrome recovery.

Eligibility Criteria
Eligibility criteria are described in Table 1. Briefly, patients must be C 18 years old with confirmed diagnosis of HCC by radiology according to American Association for the Study of Liver Diseases guidelines [5], histology or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) that is localized to the liver without portal vein thrombosis and not amenable to curative treatment.

Planned Sample Size and Study Period
The study sample size is * 950 and was calculated to permit the accumulation of sufficient OS events in 5 years to achieve 90% power for the OS primary endpoint. Patients will be randomly assigned in a 1:1 ratio to oral lenvatinib plus intravenous pembrolizumab in combination with TACE or oral plus intravenous placebos in combination with TACE.
Recruitment for the LEAP-012 study began in April 2020 and is ongoing at 165 sites in Australia, Brazil, Chile, China, Colombia, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Netherlands, New Zealand, Portugal, Puerto Rico, South Korea, Spain, Taiwan, Thailand, Turkey, Ukraine, UK and the USA.

Outcomes and Endpoints
The dual primary endpoints of the LEAP-012 study are PFS assessed by blinded independent central review (BICR) per RECIST 1.1 and OS (Table 2). Secondary endpoints are PFS assessed by BICR per modified RECIST (mRECIST) [31]; objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to progression (TTP), all assessed by BICR per RECIST 1.1 and mRECIST; and safety and tolerability. Tertiary/exploratory endpoints are PFS, PFS after the next line of therapy (PFS2), ORR, DCR, DOR and TTP (all assessed by the investigator per RECIST 1.1), biomarker analyses and patient-reported outcomes (PROs).

Study Procedures
Tumor imaging will be performed by computed tomography or magnetic resonance imaging every 9 weeks until disease progression, the start of new anticancer treatment, withdrawal of consent or death, whichever occurs first. Objective response will be confirmed by a repeat imaging assessment performed at least 4 weeks after the first sign of complete or partial response. Following the first 9-week imaging scan, a second TACE may be performed to treat any previously treated tumors. TACE is limited to 2 treatments per tumor. In the case of treatment discontinuation without centrally verified disease progression, efforts to continue monitoring disease status by tumor imaging during treatment are encouraged.
Adverse events will be monitored throughout the study and up to 90 days (120 days for serious adverse events) after last dose or 30 days after last dose if the patient initiates new anticancer therapy, whichever occurs first during the follow-up period, and will be graded according to the Common Terminology Criteria for Adverse Events, version 5.0. PROs will be collected on day 1 of cycle 1 and every other cycle up to cycle 35.

Statistics
Efficacy endpoints will be evaluated in the intention-totreat population, which includes all randomly assigned patients analyzed according to randomized treatment group; DOR is based on the population of responders. The nonparametric Kaplan-Meier method will be used to estimate PFS and OS. The hypothesis of treatment difference in PFS and OS will be tested by a re-randomization test based on the stratified log-rank test, and a stratified Cox proportional hazards model with Efron's method of tie handling will be used to estimate the magnitude of treatment difference. The stratified Miettinen and Nurminen  Progression-free survival 2 is defined as the time from randomization to second/subsequent disease progression after initiation of new anticancer therapy including locoregional or systemic therapy, or death from any cause, whichever occurs first Molecular (genomic, metabolic, and/or proteomic) biomarkers Molecular (genomic, metabolic and/or proteomic) biomarker assessment includes determinants of response or resistance to treatments, using blood and/or tumor tissue Health-related QOL EORTC QLQ-C30 EORTC QLQ-HCC18 EQ-5D-5L Health-related QOL assessments include Global scores of the EORTC QLQ-C30 and EORTC QLQ-HCC18 Time to deterioration will be evaluated for EORTC QLQ-C30 and EORTC QLQ-HCC18 global health status/QOL Time to deterioration is the time to first onset of a 10 point or more decrease from baseline EQ-5D-5L health utility score  with weights proportional to the stratum size will be used for comparison of ORR between treatment arms. Safety analyses will be conducted in the as-treated population, which includes all randomly assigned patients who received C 1 dose of study drug, according to the study intervention received. PRO analyses will be based on a PRO full analysis set population that includes patients who received C 1 dose of study drug and completed at least 1 PRO assessment. Ethical Approval The study protocol was approved by the relevant ethics committee or institutional review board at each participating center, and the study is being conducted in accordance with standards of Good Clinical Practice and the Declaration of Helsinki.

Discussion
Informed Consent For this type of study, informed consent was not required.
Consent for Publication For this type of study, consent for pubslication was not required.
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