Phase 3 Randomized Study of Relatlimab-Nivolumab vs. Regorafenib or Trifluridine/Tipiracil in Late-Line Metastatic Colorectal Cancer

The primary objective of this study is to compare the **efficacy** of the relatlimab-nivolumab fixed-dose combination (FDC) to the investigator's choice of standard of care therapy, which includes regorafenib or TAS-102, in participants with late-line **metastatic colorectal cancer**. This comparison is crucial for determining the potential benefits of the relatlimab-nivolumab FDC in improving treatment outcomes for patients with this advanced stage of cancer, particularly those with a PD-L1 combined positive score (CPS) of ≥1.

Secondary objectives include: - Comparing the antitumor activity based on the objective response rate (ORR) by blinded independent central review (BICR) of the relatlimab-nivolumab FDC to the standard of care therapy in the same patient population. - Evaluating the antitumor efficacy based on progression-free survival (PFS) by BICR. - Assessing deterioration-free survival (DeFS) of the relatlimab-nivolumab FDC compared to the standard of care therapy. These secondary objectives aim to provide a comprehensive understanding of the potential clinical benefits of the relatlimab-nivolumab FDC in managing late-line metastatic colorectal cancer.

The clinical trial involves a total of **450 participants** diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of colorectal cancer with adenocarcinoma histology, and must have experienced progression during or shortly after standard therapies. The trial includes individuals who have undergone at least one but not more than four prior lines of therapy, including treatments such as fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR therapies, where applicable. Participants are required to have measurable disease according to RECIST v1.1 criteria and sufficient tumor tissue for PD-L1 expression evaluation. The trial population also includes vulnerable groups, ensuring a comprehensive assessment of the investigational treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy of a **relatlimab-nivolumab** fixed-dose combination compared to standard care therapies, **regorafenib** or **trifluridine + tipiracil** (TAS-102), in participants with later-line **metastatic colorectal cancer**. The trial aims to assess overall survival (OS) as the primary endpoint, with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and the rate of adverse events (AEs). The study is expected to conclude by May 31, 2028, with recruitment having commenced on March 31, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed colorectal cancer, prior treatment history, and measurable disease per RECIST v1.1. Following randomization, participants will receive either the investigational treatment or the comparator therapy. Regular follow-up visits will be conducted to monitor treatment efficacy and safety, assess tumor response, and document any adverse events. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant discontinues the study.

The expected duration of participant involvement is contingent upon the treatment arm and individual response, with a maximum treatment period of 24 months for the comparator therapies. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the investigational therapy's efficacy and safety profile in this patient population.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **experimental medication** is a fixed-dose combination of **Relatlimab** and **Nivolumab**, provided as a **solution for infusion**. This combination is administered via **intravenous use**. The maximum daily dose is set at 9999 mg, with no specified maximum treatment period, allowing for continuous administration as deemed necessary by the study protocol. The active substances, **Relatlimab** and **Nivolumab**, are proteins classified under "Protein - Other" origin, and the product is developed by Bristol-Myers Squibb International Corporation.

One of the comparator treatments is **Lonsurf**, available in two formulations: 20 mg/8.19 mg and 15 mg/6.14 mg **film-coated tablets**. Both formulations contain the active substances **Trifluridine** and **Tipiracil Hydrochloride**, which are of chemical origin. The tablets are administered **orally**, with a maximum daily dose of 70 mg/m² and a maximum treatment period of 24 weeks. The product is manufactured by Les Laboratoires Servier (Suresnes) and is authorized for use in the European Union.

Another comparator treatment is **Stivarga**, which consists of 40 mg **film-coated tablets** containing the active substance **Regorafenib**. This medication is also administered **orally**, with a maximum daily dose of 160 mg and a treatment period of up to 24 weeks. Regorafenib is of chemical origin, and the product is developed by Bayer AG. This treatment serves as a standard-of-care therapy option in the study.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the protocol. The study aims to compare the efficacy of the experimental treatment against the standard-of-care therapies in participants with late-line metastatic colorectal cancer.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include **Overall Survival (OS)** in randomized participants with PD-L1 CPS (combined positive score) ≥ 1, as well as OS in all randomized participants. Secondary endpoints encompass a range of measures, including the **Objective Response Rate (ORR)** by Blinded Independent Central Review (BICR) per RECIST v1.1, **Progression-Free Survival (PFS)** by BICR, and **Duration of Response (DoR)** by BICR, all evaluated in both participants with PD-L1 CPS ≥ 1 and all randomized participants. Additionally, the trial will monitor the rate of adverse events (AEs), serious adverse events (SAEs), select AEs, immune-mediated adverse events (IMAEs), AEs leading to discontinuation, and abnormalities in specific clinical laboratory assessments.

Quality of life assessments will be conducted using the EORTC QLQ-C30 scale, focusing on physical function and global health status. The time until definitive deterioration in these scores will be measured for participants with PD-L1 CPS ≥ 1 and all randomized participants. The trial will also evaluate PFS, ORR, and DoR by investigator per RECIST v1.1. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on metastatic colorectal cancer.