A Multicenter, Open-label, Phase 3 Study to Evaluate the Long-term Safety and Efficacy in Participants who are Currently on Treatment or in Follow-up in Studies That Include Pembrolizumab

The primary objective of this study is to estimate the **overall survival (OS)** in participants with advanced tumors who are currently on treatment or in follow-up in studies that include pembrolizumab. This objective is clinically relevant as it provides critical insights into the long-term efficacy of pembrolizumab, a checkpoint inhibitor, in extending the lifespan of patients with advanced malignancies.

Secondary objectives include:

• Estimating the Duration of Response (DOR) and Duration of Complete Response (DOCR) per evaluation criteria used in the parent trial by investigator assessment for participants who have received or are receiving First Course Phase trial treatment with pembrolizumab or a pembrolizumab-based combination. This is important for understanding the sustained efficacy of the treatment.
• Evaluating the safety and tolerability of pembrolizumab or a pembrolizumab-based combination in participants who receive it as First or Second Course Phase trial treatment. This is crucial for assessing the risk-benefit profile of the therapy.

The clinical trial involves a total of **2345 participants** diagnosed with **advanced tumors**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their involvement in parent pembrolizumab studies, and they are currently receiving pembrolizumab, pembrolizumab-based combinations, or lenvatinib. The trial includes individuals who are not pregnant or breastfeeding and who meet specific health criteria, such as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and demonstrating adequate organ function. Lifestyle considerations include the requirement for controlled blood pressure for those receiving lenvatinib and adherence to effective contraceptive methods for women of childbearing potential. The trial also involves a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed as a **Phase III**, open-label study to evaluate the long-term safety and efficacy of **pembrolizumab** in participants with advanced tumors. The trial aims to estimate the overall survival (OS) of participants who are currently on treatment or in follow-up from previous studies involving pembrolizumab. The study is expected to run from August 2018 to May 2028, with participants involved for a maximum treatment period of 36 months for pembrolizumab and 120 months for **lenvatinib**. The trial includes a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as current treatment status and adequate organ function. Follow-up visits will monitor the duration of response, adverse events, and overall survival. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects. Participants may be terminated early from the study if they experience serious adverse events, fail to comply with study protocols, or withdraw consent. The trial's primary endpoint is overall survival, with secondary endpoints including the duration of response and the incidence of adverse events. The study employs a controlled methodology, ensuring rigorous data collection and analysis to support the trial's objectives.

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 pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose of pembrolizumab is 400 mg, with a total maximum dose of 10,000 mg over a treatment period of up to 36 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified as a protein of other origin. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to pembrolizumab, the trial includes the administration of **lenvatinib**, which is provided in capsule form. Lenvatinib is administered orally, with a maximum daily dose of 24 mg and a total maximum dose of 87,600 mg over a treatment period of up to 120 months. Lenvatinib is a chemical-based therapeutic agent. The dosing schedule for lenvatinib is designed to optimize therapeutic outcomes while monitoring participant compliance to ensure proper adherence to the prescribed regimen.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The trial focuses on evaluating the long-term safety and efficacy of the experimental medications, with a primary objective of estimating overall survival in participants currently on treatment or in follow-up from previous studies involving pembrolizumab.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)**. This endpoint is critical in evaluating the long-term benefits of the treatment regimen involving **pembrolizumab** and **lenvatinib**. Secondary endpoints include the **Duration of Response (DOR)** and **Duration of Complete Response (DOCR)**, as per the evaluation criteria used in the parent study. Additionally, the trial will monitor the number of participants experiencing serious adverse events (SAEs), adverse events of special interest (AEOSI), clinically significant adverse events (CSAE), events of clinical interest (ECI), and those who discontinue study treatment due to an adverse event (AE).

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial duration, which is estimated to conclude by May 2028. The trial is designed as a multicenter, open-label, Phase 3 study, focusing on participants who are currently on treatment or in follow-up from previous studies involving pembrolizumab. The trial aims to confirm the safety and efficacy of the treatment in the target population, with a particular emphasis on overall survival as the primary measure of efficacy.