A Randomized, Double-Blind Phase 2/3 Trial of Relatlimab and Nivolumab Versus Nivolumab Monotherapy in Untreated Metastatic or Unresectable Melanoma

The primary objective of this study is to compare **progression-free survival (PFS)** of BMS-986213 to nivolumab monotherapy in participants with previously untreated, unresectable, or metastatic melanoma. This comparison is crucial as it evaluates the efficacy of the combination therapy in delaying disease progression, which is a significant clinical endpoint in the management of advanced melanoma.

Secondary objectives include:

• Comparing overall survival (OS) of BMS-986213 to nivolumab monotherapy in subjects with previously untreated, unresectable, or metastatic melanoma.
• Comparing the objective response rate (ORR) of BMS-986213 to nivolumab in subjects with unresectable or metastatic melanoma.
• Estimating the treatment effect, measured by ORR, in subgroups based on combinations of LAG-3 expression and PDL-1 status.
• Evaluating duration of response (DOR), disease control rate (DCR), and PFS rates at pre-specified time points based on BICR assessments using RECIST v1.1.
• Assessing the 1- and 2-year landmark OS in the randomized population and in subgroups based on combinations of LAG-3 expression and PDL-1 status.
• Assessing safety and tolerability of the treatments.

The clinical trial involves a total of **660 participants** diagnosed with **previously untreated metastatic or unresectable melanoma**. The study population includes both male and female subjects, with an age range encompassing young adults to older adults. Participants were selected based on specific inclusion criteria, such as having histologically confirmed Stage III (unresectable) or Stage IV melanoma, and not having received prior systemic anticancer therapy for their condition. Additionally, tumor tissue from an unresectable or metastatic site must be provided for biomarker analyses. The trial does not specify particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that special ethical considerations are in place to protect these participants. The selection process ensures a representative sample of individuals affected by this condition, allowing for a comprehensive evaluation of the trial's objectives.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy of **Relatlimab** combined with **Nivolumab** versus Nivolumab monotherapy in participants with previously untreated metastatic or unresectable **melanoma**. The trial is structured in two phases, Phase 2 and Phase 3, with the primary objective of comparing progression-free survival (PFS) between the treatment groups. The trial is expected to conclude by December 16, 2025, with recruitment having commenced on April 11, 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed Stage III (unresectable) or Stage IV melanoma and the absence of prior systemic anticancer therapy for the condition. Tumor tissue from an unresectable or metastatic site must be provided for biomarker analyses. Following randomization, participants will receive the investigational products via **intravenous infusion**. The study includes regular follow-up visits to monitor safety, efficacy, and any adverse events, with assessments conducted by a Blinded Independent Central Review (BICR).

The expected duration of participant involvement in the trial is until the end-of-study visit, which will occur after the final assessment of the primary and secondary endpoints, including overall survival (OS), objective response rate (ORR), and duration of response (DOR). Conditions that may lead to early termination from the study include the occurrence of serious adverse events (SAEs), disease progression, or withdrawal of consent by the participant. The trial is conducted under the sponsorship of Bristol-Myers Squibb International Corporation, with the investigational products being Nivolumab/Relatlimab and OPDIVO 10 mg/mL concentrate for solution for infusion.

The clinical trial involves the administration of **Nivolumab/Relatlimab**, a combination therapy provided as a **solution for infusion**. This investigational product is identified by the sponsor product code BMS-986213 and is manufactured by Bristol-Myers Squibb International Corporation. The active substances in this formulation are **nivolumab** and **relatlimab**, both of which are proteins of non-specific origin. The solution is administered intravenously, with a maximum daily dose and total dose amount set at 9999 mg. The treatment period is not explicitly limited, allowing for administration as per the study protocol requirements.

In addition to the experimental combination therapy, the trial also includes a comparator treatment using **OPDIVO**, a commercially available formulation of **nivolumab**. OPDIVO is provided as a 10 mg/mL concentrate for solution for infusion, also administered intravenously. The maximum daily dose for OPDIVO is 480 mg, with no specified maximum total dose, allowing for flexible dosing schedules as per clinical judgment. This product is authorized for use in the European Union and is produced by Bristol-Myers Squibb Pharma EEIG. The administration of both treatments is monitored to ensure participant compliance and adherence to the dosing schedule outlined in the study protocol.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**, which will be measured in both the Phase 2 and Phase 3 portions of the study. The assessment of PFS will be conducted by a Blinded Independent Central Review (BICR). In the Phase 3 portion, the primary endpoint is the comparison of PFS between the combination therapy of BMS-986213 (Nivolumab/Relatlimab) and nivolumab monotherapy in participants with previously untreated, unresectable, or metastatic melanoma.

Secondary endpoints for the Phase 3 portion include **Overall Survival (OS)** and **Objective Response Rate (ORR)**, both assessed by a BICR. In the Phase 2 portion, secondary endpoints include ORR, Duration of Response (DOR), PFS in subgroups, OS, and various safety parameters such as the number of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to discontinuation, deaths, and laboratory abnormalities. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the therapeutic benefit of the investigational product compared to the control.