Phase 3 Randomized Double-Blind Trial of Encorafenib, Binimetinib, and Pembrolizumab in BRAF V600E/K Mutation-Positive Metastatic or Unresectable Melanoma

The primary objective of this study is to determine the recommended Phase 3 dose (**RP3D**) of **encorafenib** and **binimetinib** when administered in combination with **pembrolizumab**. This is clinically relevant as it aims to establish the optimal dosing regimen for these agents in treating patients with **BRAF V600E/K mutation-positive metastatic or unresectable locally advanced melanoma**, potentially improving therapeutic outcomes and minimizing adverse effects.

Secondary objectives include:

• Assessing the overall safety and tolerability of encorafenib and binimetinib plus pembrolizumab.
• Evaluating the efficacy of the combination therapy.
• Characterizing the pharmacokinetics (**PK**) of encorafenib and binimetinib when combined with pembrolizumab.
• Comparing the efficacy of the triplet therapy (encorafenib, binimetinib, and pembrolizumab) versus placebo plus pembrolizumab with respect to progression-free survival (**PFS**) by blinded independent central review (**BICR**) assessment.

The clinical trial involves a total of **67 participants** diagnosed with **metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including histologically confirmed unresectable or metastatic cutaneous melanoma, documented evidence of a BRAF V600E or V600K mutation, and adequate tumor tissue submission for central laboratory testing. The trial includes individuals who have not received more than one prior systemic therapy for metastatic or locally advanced melanoma in the Safety Lead-In phase, and those who have not received prior first-line systemic therapy in the Phase 3 trial. Participants are required to have at least one measurable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, with adequate organ and cardiac function, including a left ventricular ejection fraction (LVEF) of 50% or higher. The trial population is characterized by a mix of genders and includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of a combination therapy involving **encorafenib**, **binimetinib**, and **pembrolizumab** compared to a placebo plus pembrolizumab in participants with **BRAF V600E/K mutation-positive metastatic or unresectable locally advanced melanoma**. The trial is structured in two phases: a safety lead-in phase to determine the recommended Phase 3 dose (RP3D) of encorafenib and binimetinib when combined with pembrolizumab, followed by a randomized Phase 3 to compare the efficacy of the combination therapy against the control. The primary endpoint for the safety lead-in phase is the incidence of dose-limiting toxicities (DLTs), while the primary endpoint for the randomized phase is the overall response (OR) as assessed by blinded independent central review (BICR) per RECIST v1.1 criteria.

The trial is expected to span approximately five years, with an estimated recruitment start date of January 15, 2021, and an anticipated end date of June 30, 2026. Participants will be involved in the study for a maximum treatment period of 24 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. Participants must meet specific inclusion criteria, such as being 18 years or older, having histologically confirmed unresectable or metastatic melanoma, and documented evidence of a BRAF V600E or V600K mutation. Exclusion criteria are not specified in the provided data.

Participants will be randomly assigned to either the treatment arm or the control arm, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial. The trial will be conducted in compliance with ethical standards and regulatory requirements. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the potential benefits of the combination therapy for patients with this specific type of melanoma.

The clinical trial involves the administration of **BINIMETINIB**, an experimental medication provided in the form of a film-coated tablet. The active substance, binimetinib, is a chemical entity. Participants will receive a maximum daily dose of 90 mg, administered orally. The treatment period is set for a maximum of 24 months. The administration of binimetinib will be monitored to ensure compliance with the dosing schedule.

**ENCORAFENIB** is another experimental medication used in this trial, provided as a hard capsule. The active substance, encorafenib, is also a chemical entity. Participants will receive a maximum daily dose of 450 mg, administered orally. The treatment duration is up to 24 months, with compliance monitoring in place to ensure adherence to the dosing regimen.

**KEYTRUDA** (pembrolizumab) is used as a comparator treatment in this study. It is provided as a 25 mg/mL concentrate for solution for infusion. Pembrolizumab is a biological product, specifically a protein. The maximum dose administered is 200 mg, delivered via intravenous infusion. The treatment period is up to 24 months, with participant compliance closely monitored.

The study also includes the use of placebos for both binimetinib and encorafenib. The **Binimetinib placebo** and **Encorafenib placebo** are used to maintain the double-blind nature of the trial. These placebos are administered in a manner consistent with their respective active counterparts, ensuring that the study's integrity is maintained.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for the randomized Phase 3 portion of the study is the **Objective Response (OR)**, defined as the confirmed Best Overall Response (BOR) of either Complete Response (CR) or Partial Response (PR), as determined by Blinded Independent Central Review (BICR) assessment per RECIST v1.1. This will be measured from randomization to the earliest of progressive disease (PD), the start of subsequent anticancer therapy, or death due to any cause.

Secondary endpoints include Progression-Free Survival (PFS), which is defined as the time from the date of randomization to the date of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first. Additionally, the Safety Lead-In phase will evaluate the incidence and severity of adverse events (AEs) graded according to the NCI CTCAE v4.03, as well as changes in clinical laboratory parameters, vital signs, and cardiac assessments. Plasma concentration-time profiles and pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib will also be assessed.