A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) with Pembrolizumab (MK-3475) in Combination with Transarterial Chemoembolization (TACE) Versus TACE in Participants with Incurable/Non-metastatic Hepatocellular Carcinoma (LEAP-012)

The primary objective of this study is to compare the combination of **pembrolizumab** and **lenvatinib** with transarterial chemoembolization (TACE) against placebo plus TACE in terms of progression-free survival (PFS) and overall survival (OS) in patients with incurable/non-metastatic hepatocellular carcinoma. This is clinically relevant as it aims to determine whether the addition of pembrolizumab and lenvatinib can improve survival outcomes in this patient population, potentially offering a new therapeutic option.

Secondary objectives include evaluating the combination of pembrolizumab and lenvatinib with TACE versus placebo plus TACE regarding:

• Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by blinded, independent central review (BICR).
• Safety and tolerability of the combination therapy.
• Efficacy outcomes per RECIST 1.1 assessed by BICR.

The clinical trial involves a total of **349 participants** diagnosed with **incurable/non-metastatic hepatocellular carcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of hepatocellular carcinoma localized to the liver and not amenable to curative treatment. Individuals with controlled blood pressure and adequate organ function were considered eligible. The trial also includes participants with a history of Hepatitis C or B, provided certain conditions are met. The study population is characterized by a diverse range of health statuses, and the trial includes vulnerable populations. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, and **controlled** study designed to evaluate the safety and efficacy of **lenvatinib** in combination with **pembrolizumab** and transarterial chemoembolization (TACE) compared to TACE alone in participants with incurable/non-metastatic **hepatocellular carcinoma**. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints, with secondary endpoints including objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) among others. The study is expected to run from July 2020 to August 2030, with a maximum treatment period of 24 months for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed diagnosis of hepatocellular carcinoma, adequate organ function, and controlled blood pressure. Following randomization, participants will receive either the investigational combination therapy or placebo in conjunction with TACE. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial is structured to ensure rigorous assessment of the investigational treatment's impact on the specified endpoints, with blinded, independent central review employed to evaluate progression-free survival according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL **concentrate for solution for infusion**. This biologic agent is administered via **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 6800 mg over a treatment period of up to 24 months. Pembrolizumab is a protein-based therapeutic agent developed by Merck Sharp & Dohme BV, and it is utilized in this study to evaluate its efficacy in combination with other treatments for hepatocellular carcinoma.

**Lenvatinib** is another experimental medication used in this trial, provided in **capsule** form. It is a chemical compound administered **orally** with a maximum daily dose of 4 mg and a total maximum dose of 2920 mg over a 24-month period. Lenvatinib, developed by Merck & Co. Inc., is being evaluated for its potential benefits when used in combination with pembrolizumab and transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma.

The study also includes a **placebo** for Lenvatinib, which serves as a control to assess the efficacy of the active treatment. The placebo is designed to mimic the appearance and administration route of the active drug but contains no active substance. Similarly, a **placebo** for Keytruda, consisting of normal commercial saline, is used to maintain the double-blind nature of the trial. These placebos are critical for ensuring unbiased assessment of the treatment outcomes.

In addition to the experimental medications, the trial involves the use of standard-of-care therapy, specifically **transarterial chemoembolization (TACE)**. TACE is a procedure that delivers chemotherapy directly to the liver tumor via **intraarterial use**, allowing for localized treatment of hepatocellular carcinoma. The combination of TACE with the investigational drugs aims to enhance therapeutic efficacy and improve patient outcomes.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-free Survival (PFS)** per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and **Overall Survival (OS)**. These endpoints will be evaluated by a blinded, independent central review (BICR) to ensure objectivity and accuracy in the assessment of the trial outcomes.

Secondary endpoints will provide additional insights into the efficacy of the treatment regimen. These include PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Objective Response Rate (ORR) per mRECIST, Disease Control Rate (DCR) per mRECIST, Duration of Response (DOR) per mRECIST, and Time to Progression (TTP) per mRECIST. Furthermore, the trial will monitor the percentage of participants who experience at least one adverse event (AE), serious adverse event (SAE), or hepatic event of clinical interest (ECI), as well as the percentage of participants who discontinue the study drug due to an AE. ORR, DCR, DOR, and TTP will also be assessed per RECIST 1.1.