Relatlimab: A Comprehensive Clinical and Scientific Monograph on the First-in-Class LAG-3 Checkpoint Inhibitor

Executive Summary

Relatlimab is a first-in-class, human immunoglobulin G4 (IgG4) monoclonal antibody that represents a significant advancement in the field of immuno-oncology by targeting the Lymphocyte-Activation Gene 3 (LAG-3) immune checkpoint.[1] Developed by Bristol Myers Squibb (BMS) under the development code BMS-986016, Relatlimab is exclusively marketed as a fixed-dose combination with the established programmed death-1 (PD-1) inhibitor, nivolumab.[3] This combination product, branded as Opdualag, delivers a dual checkpoint blockade strategy in a single intravenous infusion.[5]

The mechanism of action of Relatlimab involves binding to the LAG-3 receptor on exhausted T-cells, thereby blocking its inhibitory signaling pathway. When co-administered with nivolumab, which blocks the separate PD-1 pathway, this dual inhibition synergistically restores T-cell effector function and enhances anti-tumor immunity.[1] This approach is designed to overcome the limitations of single-agent immunotherapy and provide a more robust anti-cancer response.

The cornerstone of Relatlimab's clinical validation is the pivotal Phase 2/3 RELATIVITY-047 trial. In this study, Opdualag demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to nivolumab monotherapy for patients with previously untreated, unresectable or metastatic melanoma.[5] The combination more than doubled the median PFS from 4.6 months with nivolumab alone to 10.1 months with Opdualag, with long-term follow-up confirming the durability of this benefit.[9]

The regulatory journey of Opdualag has highlighted differing interpretations of its clinical data. The U.S. Food and Drug Administration (FDA) granted a broad approval for advanced melanoma, irrespective of biomarker status.[8] In contrast, the European Medicines Agency (EMA) issued a more restrictive approval, limiting its use to patients whose tumors express low levels of PD-L1 (

<1%), based on an exploratory subgroup analysis.[11]

Clinically, the approval of Relatlimab validates LAG-3 as the third major druggable immune checkpoint pathway, following CTLA-4 and PD-1/PD-L1.[2] Opdualag establishes a new standard-of-care option for advanced melanoma, offering a compelling balance of enhanced efficacy over PD-1 monotherapy and a more manageable safety profile compared to the combination of nivolumab and the CTLA-4 inhibitor ipilimumab.[13] This favorable therapeutic index positions Relatlimab as a vanguard of next-generation immunotherapy combinations aimed at optimizing clinical outcomes while minimizing treatment-related toxicity.

Drug Profile and Physicochemical Properties

Nomenclature and Identifiers

Relatlimab is the designated International Nonproprietary Name (INN) and United States Adopted Name (USAN) for this therapeutic agent.[3] During its development by Bristol Myers Squibb, it was identified by the code BMS-986016.[3] Commercially, Relatlimab is not available as a standalone product. It is exclusively formulated and marketed in a fixed-dose combination with nivolumab under the brand name Opdualag.[5] In the United States, the official nonproprietary name for this combination product is nivolumab and relatlimab-rmbw, with the "-rmbw" suffix being a four-letter designation assigned by the FDA to distinguish it from other related biological products.[3]

The molecule is cataloged under several key registry numbers essential for scientific and regulatory tracking. Its Chemical Abstracts Service (CAS) Number is 1673516-98-7.[3] In major drug and chemical databases, it is listed with DrugBank ID DB14851, UNII (Unique Ingredient Identifier) AF75XOF6W3, and KEGG (Kyoto Encyclopedia of Genes and Genomes) ID D11350.[1]

Chemical and Biological Characteristics

Relatlimab is a biotechnology-derived product, classified as a protein-based therapy.[1] Specifically, it is a fully human monoclonal antibody of the immunoglobulin G4 (

IgG4) isotype with a kappa (κ) light chain.[14] The choice of an

IgG4 backbone is common for checkpoint inhibitors as it minimizes effector functions like antibody-dependent cell-mediated cytotoxicity (ADCC), thereby reducing the risk of depleting the target T-cells and focusing the drug's activity on receptor blockade.

The antibody is produced using recombinant DNA technology in a well-established mammalian expression system: Chinese Hamster Ovary (CHO) cells.[3] The generation process involved the immunization of transgenic mice engineered with human immunoglobulin miniloci, a method designed to produce high-affinity, fully human antibodies, thus minimizing the potential for immunogenicity in patients.[15]

The molecular structure of this large protein is complex. Its chemical formula is reported as C6472​H9922​N1710​O2024​S38​, though minor variations in elemental composition are sometimes cited in different databases (e.g., C6472​H9940​O2026​N1704​S38​).[1] These slight discrepancies are typical for large biologics and do not alter the fundamental identity of the molecule. The corresponding molar mass is approximately 145,288.79 g·mol−1, with an average protein weight estimated at 148,000 Daltons (Da).[1]

Formulation and Presentation

For clinical use, Relatlimab is supplied exclusively as Opdualag, a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for intravenous infusion.[5] It is provided as a concentrate in a single-dose vial. Each 20 mL vial contains a fixed-dose combination of 240 mg of nivolumab and 80 mg of relatlimab, which corresponds to a concentration of 12 mg/mL for nivolumab and 4 mg/mL for relatlimab.[18] The formulation is buffered with excipients including Polysorbate 80, trisodium citrate dihydrate, citric acid monohydrate, sodium chloride, diethylenetriaminepentaacetic acid, and water for injection to maintain stability and a physiological pH. Research-grade formulations are typically provided in a phosphate-buffered saline (PBS) solution at a pH of 7.4.[16]

Table 1: Relatlimab Drug Identification Summary

Property	Detail	Source(s)
INN/USAN	Relatlimab	3
Drug Class	Antineoplastic, Immune Checkpoint Inhibitor, LAG-3 Blocker	1
Brand Name (Combination)	Opdualag (with nivolumab)	3
Developer	Bristol Myers Squibb	3
Development Code	BMS-986016	3
DrugBank ID	DB14851	1
CAS Number	1673516-98-7	3
Molecular Type	Human IgG4 Monoclonal Antibody	1

Mechanism of Action and Pharmacodynamics

The LAG-3 Immune Checkpoint Pathway

The therapeutic activity of Relatlimab is rooted in its modulation of the Lymphocyte-Activation Gene 3 (LAG-3) pathway, a critical negative regulator of immune responses. LAG-3 (also known as CD223) is an immune checkpoint receptor that belongs to the immunoglobulin superfamily.[20] It is not expressed on naive, resting T-cells but is rapidly upregulated on the surface of activated CD4+ and CD8+ T-cells, as well as on regulatory T-cells (Tregs), following antigenic stimulation.[7]

In healthy physiological states, LAG-3 functions to limit excessive immune activation, thereby preventing autoimmunity and maintaining immune homeostasis.[21] However, in the context of cancer, tumor cells exploit this regulatory mechanism to evade destruction. The chronic exposure to tumor-associated antigens within the tumor microenvironment (TME) leads to high and sustained expression of LAG-3 on tumor-infiltrating lymphocytes (TILs).[1] This persistent signaling through the LAG-3 receptor contributes to a progressive state of T-cell dysfunction known as "exhaustion." Exhausted T-cells are characterized by a profound loss of effector functions, including diminished proliferative capacity, reduced production of key cytokines like interleukin-2 (IL-2), interferon-gamma (

IFNγ), and tumor necrosis factor (TNF), and impaired cytolytic activity.[1] This functional paralysis of the immune system allows tumors to grow unchecked.

The inhibitory signal is transmitted when LAG-3 on a T-cell engages with its ligands. The canonical and best-characterized ligand is the Major Histocompatibility Complex Class II (MHC II) molecule, which is expressed on antigen-presenting cells (APCs) like dendritic cells and macrophages, as well as on some tumor cells.[7] More recently, other ligands such as fibrinogen-like protein-1 (FGL1) have also been identified, further expanding the understanding of LAG-3's complex biology.[7]

Relatlimab's Molecular Engagement

Relatlimab is a high-affinity, human monoclonal antibody engineered to specifically target and block the function of the LAG-3 receptor.[2] It binds with high specificity to human LAG-3 expressed on the surface of T-cells.[7] Preclinical studies demonstrate its potent binding to primary activated human CD4+ T-cells with a half-maximal effective concentration (

EC50​) of 0.11 nM.[15]

The primary mechanism of action of Relatlimab is competitive antagonism. By occupying the ligand-binding site on the LAG-3 receptor, Relatlimab physically obstructs the interaction between LAG-3 and its ligands, most notably MHC II and FGL1.[7] This blockade is highly efficient, with in vitro studies showing half-maximal inhibitory concentrations (

IC50​) of 0.67 nM for preventing the LAG-3/MHC II interaction and an even more potent 0.019 nM for the LAG-3/FGL1 interaction.[15]

By severing this inhibitory connection, Relatlimab effectively "releases the brakes" on the T-cell. This reversal of LAG-3-mediated immunosuppression restores the effector functions of previously exhausted T-cells. The result is a reinvigoration of the anti-tumor immune response, characterized by enhanced T-cell proliferation, increased secretion of pro-inflammatory cytokines, and a restored capacity to recognize and kill cancer cells.[1]

Synergistic Action with PD-1 Blockade

A crucial aspect of Relatlimab's clinical utility is its synergistic relationship with PD-1 blockade. The LAG-3 and PD-1 pathways represent two distinct and non-redundant mechanisms of immune inhibition.[7] While both contribute to T-cell exhaustion, they do so through independent signaling cascades. TILs within the TME frequently co-express both LAG-3 and PD-1, and evidence suggests that their simultaneous signaling leads to a more profound and durable state of T-cell dysfunction than the activity of either checkpoint alone.[7]

This non-redundancy provides a strong rationale for dual checkpoint blockade. By targeting both pathways simultaneously with Relatlimab (anti-LAG-3) and nivolumab (anti-PD-1), it is possible to achieve a synergistic or additive therapeutic effect. This dual blockade results in a more comprehensive reactivation of the immune system, leading to greater T-cell activation and more potent anti-tumor activity than can be achieved by inhibiting either pathway in isolation.[1] The superior clinical efficacy of the Opdualag combination over nivolumab monotherapy, as demonstrated in the RELATIVITY-047 trial, serves as the definitive clinical validation of this powerful preclinical hypothesis.[7]

The development of this combination reflects a strategic evolution in immuno-oncology. The first-generation dual checkpoint blockade, combining nivolumab with the CTLA-4 inhibitor ipilimumab, established the principle that combination immunotherapy could yield superior outcomes to monotherapy, but at the cost of substantial toxicity.[13] The development of Relatlimab and its combination in Opdualag represents a second-generation approach. The goal was to identify a synergistic pairing that could enhance efficacy without the high rates of severe adverse events associated with CTLA-4 inhibition. The clinical data suggests this goal was achieved, as Opdualag provides a clear efficacy benefit over PD-1 monotherapy with a safety profile that is notably more manageable than that of the nivolumab/ipilimumab regimen.[10] This positions Relatlimab not just as an effective drug, but as the vanguard of a new R&D philosophy focused on optimizing the therapeutic index of immunotherapy combinations.

Furthermore, the mechanism of Relatlimab holds promise for addressing a major challenge in oncology: resistance to PD-1/PD-L1 inhibitors. Upregulation of alternative checkpoint pathways, including LAG-3, has been identified as a key mechanism through which tumors can evade or develop resistance to PD-1 blockade.[21] Therefore, the addition of Relatlimab is not merely about augmenting an existing response; it is a rational strategy to overcome this specific mode of resistance. This is supported by ongoing clinical investigations, such as arms within the NCI-MATCH trial, which are evaluating Opdualag specifically in patients whose cancers have progressed on prior PD-1/PD-L1 inhibitor therapy, aiming to salvage responses in this difficult-to-treat population.[13]

Pharmacokinetics

The pharmacokinetic (PK) profile of Relatlimab has been characterized from studies where it was administered as part of the Opdualag fixed-dose combination with nivolumab. Its properties are consistent with those of a typical human IgG4 monoclonal antibody and are well-suited for a combination therapy regimen.

Administration

Relatlimab is formulated for clinical use exclusively for intravenous (IV) administration.[3] It is delivered as a 30-minute infusion every four weeks as part of the Opdualag combination product.[1]

Distribution

Following intravenous administration, Relatlimab distributes primarily within the vascular and interstitial fluid compartments. The geometric mean volume of distribution at steady-state (Vd,ss​) is 6.6 liters.[1] This relatively low volume of distribution is characteristic of large protein therapeutics, indicating limited penetration into deep tissues and confinement mainly to the extracellular space.

Metabolism

As with other therapeutic proteins, Relatlimab is not metabolized by hepatic cytochrome P450 (CYP) enzymes. Instead, it is expected to undergo degradation through general, non-specific catabolic pathways distributed throughout the body.[1] This process involves cellular uptake and lysosomal degradation, where the antibody is broken down into smaller peptides and constituent amino acids, which are then recycled into the body's endogenous amino acid pool. This metabolic profile significantly reduces the potential for pharmacokinetic drug-drug interactions with small-molecule drugs that are substrates, inhibitors, or inducers of CYP enzymes.

Elimination

The elimination of Relatlimab is characterized by a slow clearance rate and a long half-life. The geometric mean systemic clearance (CL) at steady-state is 5.5 mL/h.[1] An interesting finding from clinical studies is that the clearance at steady-state appears to be approximately 10% lower than the clearance observed after the first dose, suggesting a time- or exposure-dependent change in its elimination kinetics.[1]

The slow clearance results in a long terminal elimination half-life. When administered alongside nivolumab, the geometric mean effective half-life (t1/2​) of Relatlimab is 26.2 days.[1] This extended half-life is the key pharmacokinetic property that supports the convenient every-4-week dosing interval, allowing for sustained therapeutic concentrations to be maintained between doses.[5]

The pharmacokinetic compatibility between Relatlimab and nivolumab was a fundamental enabler for the development of the Opdualag fixed-dose combination. Both antibodies possess long and similar half-lives, allowing their dosing schedules to be synchronized without compromising the therapeutic exposure of either component. This pharmacokinetic alignment was a prerequisite for creating a single-infusion product, which simplifies clinical administration, reduces patient burden, and minimizes the potential for dosing errors compared to administering two separate infusions.

Clinical Development and Efficacy

The clinical development program for Relatlimab has established its role as a key component of a new standard-of-care immunotherapy combination for advanced melanoma and is actively exploring its potential across a wide range of other malignancies and clinical settings.

The Pivotal RELATIVITY-047 Trial (NCT03470922)

The approval and clinical positioning of Relatlimab are primarily based on the results of the RELATIVITY-047 study, a landmark global, Phase 2/3, randomized, double-blind trial.[5]

Study Design and Patient Population

The trial enrolled 714 patients with previously untreated, unresectable or metastatic Stage III or IV melanoma.[5] The patient population was representative of those seen in clinical practice, with baseline characteristics comparable to other pivotal melanoma trials such as CheckMate 067.[24] Key exclusion criteria were designed to ensure patient safety and included active autoimmune disease, medical conditions requiring systemic corticosteroids, active or untreated brain metastases, and uveal melanoma.[5]

Patients were randomized in a 1:1 ratio to one of two treatment arms [5]:

• Experimental Arm (n=355): A fixed-dose combination of nivolumab 480 mg and relatlimab 160 mg (Opdualag), administered as a single intravenous infusion every 4 weeks.
• Control Arm (n=359): Nivolumab 480 mg monotherapy, administered as a single intravenous infusion every 4 weeks.

Treatment in both arms continued until disease progression, unacceptable toxicity, or withdrawal of consent.[9]

Endpoints

The primary endpoint of the trial was Progression-Free Survival (PFS), as determined by a Blinded Independent Central Review (BICR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).[5] Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).[9]

Efficacy Results from RELATIVITY-047

The RELATIVITY-047 trial successfully met its primary endpoint, demonstrating the superiority of the dual checkpoint blockade with Opdualag over PD-1 monotherapy.

Progression-Free Survival (PFS)

The addition of Relatlimab to nivolumab resulted in a statistically significant and clinically meaningful improvement in PFS. At the primary analysis, the median PFS was more than doubled in the combination arm: 10.1 months for Opdualag compared to 4.6 months for nivolumab monotherapy.[5] This corresponded to a Hazard Ratio (HR) of 0.75 (95% Confidence Interval [CI]: 0.62–0.92; p=0.0055), indicating a 25% reduction in the risk of disease progression or death for patients receiving the combination therapy.[5] At the 12-month mark, the PFS rate was 47.7% for the Opdualag arm versus 36.0% for the nivolumab arm.[25]

Overall Survival (OS) and Objective Response Rate (ORR)

In the initial analysis, the secondary endpoint of OS showed a favorable trend for the combination but did not reach statistical significance. The median OS was not reached in the Opdualag arm, compared to 34.1 months in the nivolumab arm (HR 0.80; 95% CI: 0.64–1.01).[5] The ORR was numerically higher for the combination, at 43% for Opdualag versus 34% for nivolumab.[24] The rates of complete response (CR) were similar between the two arms, at approximately 19-20%.[24]

Long-Term Follow-Up Data (4-Year Update)

Subsequent analyses with extended follow-up have reinforced the durable benefit of the Relatlimab-containing regimen.[10] With a minimum follow-up of 45.3 months, the separation of the PFS curves was maintained and even enhanced over time. The 4-year PFS rate was 30.6% for patients treated with Opdualag, compared to 23.6% for those who received nivolumab alone.[10]

The long-term OS data also showed a more pronounced and clinically meaningful separation. The 4-year OS rate was 52.0% in the Opdualag arm versus 42.8% in the nivolumab monotherapy arm.[10] Furthermore, the 4-year melanoma-specific survival (MSS) rates were 59.7% for the combination and 49.6% for monotherapy, underscoring the long-term, durable clinical benefit conferred by the addition of Relatlimab.[10]

Table 2: Efficacy Results from the RELATIVITY-047 Trial (All-Comer Population)

Efficacy Endpoint	Opdualag (Nivolumab + Relatlimab)	Nivolumab Monotherapy	Source(s)
Median PFS (Initial)	10.1 months (95% CI: 6.4–15.7)	4.6 months (95% CI: 3.4–5.6)	5
PFS Hazard Ratio	0.75 (95% CI: 0.62–0.92; p=0.0055)	---	5
12-Month PFS Rate	47.7%	36.0%	25
4-Year PFS Rate	30.6%	23.6%	10
Median OS (Initial)	Not Reached (95% CI: 34.2–NR)	34.1 months (95% CI: 25.2–NR)	5
OS Hazard Ratio (Initial)	0.80 (95% CI: 0.64–1.01)	---	5
4-Year OS Rate	52.0%	42.8%	10
Objective Response Rate	43%	34%	24

Broader Clinical Research Program

The success in advanced melanoma has spurred a broad and ambitious clinical development program to evaluate Relatlimab, as part of Opdualag, in other settings and tumor types.

Melanoma

The focus has expanded to earlier stages of the disease. The NCT05002569 trial is a Phase 3 study assessing Opdualag as an adjuvant (post-surgical) therapy for patients with completely resected Stage III-IV melanoma, comparing it against nivolumab monotherapy.[26] In the neoadjuvant (pre-surgical) setting, the Neo ReNi II trial (NCT05418972) is a Phase 2 study evaluating two doses of Opdualag in high-risk, clinical Stage II cutaneous melanoma, with pathological response as a key endpoint.[27]

Other Solid Tumors

The combination is being investigated across a portfolio of solid tumors, reflecting the potential for broad applicability of LAG-3 blockade.[13] Key ongoing studies are summarized in the table below. This expansive program aims to determine if the synergistic effect observed in melanoma can be replicated in other cancers, potentially establishing Opdualag as a foundational immunotherapy combination across oncology.

Table 3: Overview of Key Ongoing or Recent Clinical Trials for Relatlimab/Opdualag

Indication / Setting	Trial Identifier	Phase	Brief Description / Comparator	Source(s)
1L Advanced Melanoma	NCT03470922 (RELATIVITY-047)	2/3	Opdualag vs. Nivolumab monotherapy (Pivotal trial)	5
Adjuvant Melanoma (Stage III-IV)	NCT05002569	3	Opdualag vs. Nivolumab monotherapy	26
Neoadjuvant Melanoma (Stage II)	NCT05418972 (Neo ReNi II)	2	Single-arm study of neoadjuvant Opdualag	27
1L Non-Small Cell Lung Cancer (NSCLC)	NCT06561386	3	Opdualag + Chemo vs. Pembrolizumab + Chemo	28
1L Non-Small Cell Lung Cancer (NSCLC)	NCT04623775	2	Opdualag + Chemo vs. Nivolumab + Chemo	29
Advanced Liver Cancer (HCC)	NCT04567615 (RELATIVITY-073)	2	Opdualag in patients post-TKI therapy	30
Resectable Gastroesophageal Cancer	NCT03044613	1B	Opdualag + Chemoradiation (pre-operative)	31
Advanced Melanoma (Post-CPI)	NCT05629546	1	Opdualag + NK Cells after progression on checkpoint inhibitors	32

Regulatory Status and Approved Indications

The global regulatory journey of Opdualag has been swift, marked by expedited reviews, but has also resulted in a notable divergence in approved indications between major health authorities, reflecting different interpretations of the same clinical trial data.

U.S. Food and Drug Administration (FDA)

On March 18, 2022, the FDA approved Opdualag (nivolumab and relatlimab-rmbw) for medical use in the United States.[2] The approval process was accelerated through several of the FDA's expedited programs, including Priority Review, Fast Track Designation, and Orphan Drug Designation.[8] The review was also conducted under the Real-Time Oncology Review (RTOR) pilot program, which allows the FDA to review clinical data as it becomes available, ensuring that safe and effective treatments reach patients as early as possible.[8]

The FDA-approved indication is broad: for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.[8] This approval is for the first-line setting and is not restricted by a patient's BRAF mutation status or tumor PD-L1 expression level, reflecting the positive outcome of the RELATIVITY-047 trial in the overall "all-comer" patient population.[8]

European Medicines Agency (EMA) / European Commission (EC)

The European Commission, following a positive recommendation from the EMA's Committee for Medicinal Products for Human Use (CHMP), granted marketing authorization for Opdualag on September 15, 2022.[11] However, the European indication is significantly more restrictive than the one granted by the FDA.

In the European Union, Opdualag is indicated for the first-line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older with tumor cell PD-L1 expression < 1%.[11] This requires oncologists in the EU to perform a validated PD-L1 test before prescribing the therapy.[11]

The EMA's decision was based on an exploratory subgroup analysis of the RELATIVITY-047 data.[12] Regulators concluded that the benefit-risk balance was most favorable in this specific patient subgroup. In the PD-L1 <1% population, Opdualag demonstrated a median PFS of 6.7 months compared to 3.0 months for nivolumab monotherapy, a result the agency deemed sufficient for approval in this cohort.[11]

Other Regulatory Bodies

The approval of Opdualag was a global effort facilitated by Project Orbis, an initiative of the FDA's Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among international partners.[8] Besides the FDA and EMA, Opdualag has received marketing authorization from other major agencies, including the UK's Medicines and Healthcare products Regulatory Agency (MHRA) in January 2024 for adults and adolescents from age 12, and authorities in Australia (TGA) and Switzerland (Swissmedic).[8]

This divergence between the FDA's broad approval and the EMA's biomarker-restricted approval is a critical point of nuance. It stems from different regulatory philosophies regarding the use of data from exploratory subgroup analyses, which are typically considered hypothesis-generating rather than definitive. The FDA's approach was to approve based on the positive result of the primary endpoint in the overall trial population. The EMA, however, placed greater weight on the subgroup analysis, concluding that the magnitude of benefit in the PD-L1 ≥1% population was not sufficient to outweigh the increased toxicity of the combination. This regulatory split has created a fragmented global standard of care, where a patient's access to Opdualag depends on their geographic location and their tumor's PD-L1 status. It also raises a fundamental scientific question about the true predictive value of PD-L1 expression for dual LAG-3/PD-1 blockade, highlighting an area where further research is urgently needed to identify more robust and reliable biomarkers to guide treatment selection.

Table 4: Comparison of Global Regulatory Approvals for Opdualag

Regulatory Body	Approval Date	Approved Indication	Source(s)
U.S. FDA	March 18, 2022	Treatment of adult and pediatric patients (≥12 years) with unresectable or metastatic melanoma. (No biomarker restriction)	8
European Commission (EMA)	September 15, 2022	First-line treatment of advanced melanoma in adults and adolescents (≥12 years) with tumor cell PD-L1 expression < 1%.	11
UK MHRA	January 3, 2024	Treatment of advanced melanoma in adults and adolescents (≥12 years).	25

Safety Profile and Tolerability

The safety profile of Opdualag is characterized by a higher incidence of adverse reactions compared to nivolumab monotherapy, which is expected with combination immunotherapy. However, the toxicities are generally manageable and considered to have a more favorable profile than other dual checkpoint inhibitor combinations, such as nivolumab plus ipilimumab.

Overview of Adverse Reactions

Data from the RELATIVITY-047 trial provide a comprehensive overview of the safety of Opdualag.

• Common Adverse Reactions: The most frequently reported adverse reactions (occurring in ≥20% of patients) were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).[6]
• Common Laboratory Abnormalities: The most common laboratory abnormalities (≥20%) that worsened from baseline were decreased hemoglobin, decreased lymphocytes, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), and decreased sodium.[6]
• Serious Adverse Reactions: Serious adverse reactions occurred in 36% of patients treated with Opdualag. Fatal adverse reactions were rare, occurring in three patients (0.8%) and included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis.[9]
• Discontinuation and Interruption Rates: The increased toxicity of the combination is reflected in the treatment modification rates. Permanent discontinuation of therapy due to adverse reactions occurred in 18% of patients receiving Opdualag. Dosage interruptions due to adverse events were required in 43% of patients.[37] The rate of Grade 3/4 drug-related adverse events was 18.9% in the Opdualag arm, compared to 9.7% in the nivolumab monotherapy arm.[9]

While Opdualag is demonstrably more toxic than nivolumab alone, its safety profile represents a key clinical advantage when viewed in the broader context of combination immunotherapy. Cross-trial comparisons indicate that Opdualag is significantly better tolerated than the combination of nivolumab and the CTLA-4 inhibitor ipilimumab. For instance, serious, high-grade side effects were reported in less than 20% of patients receiving Opdualag, compared to nearly 60% of patients who received the nivolumab/ipilimumab combination in its pivotal trial.[13] This more favorable therapeutic index is a primary driver of its adoption as a new standard of care, as it extends the benefits of dual checkpoint blockade to a wider patient population, including those who may not be fit enough to tolerate the more aggressive toxicity profile of CTLA-4 inhibition.[5]

Warnings and Precautions: Immune-Mediated Adverse Reactions (IMARs)

The most significant risks associated with Opdualag are immune-mediated adverse reactions (IMARs). These occur when the reactivated immune system attacks normal organs and tissues. IMARs can be severe or fatal, can affect any organ system, and can occur at any time during treatment or even after discontinuation.[1] Early identification and prompt management are essential for the safe use of the therapy.

The general management strategy for IMARs involves withholding or permanently discontinuing Opdualag based on the severity of the reaction. For moderate (Grade 2) reactions, treatment is typically withheld. For severe (Grade 3) or life-threatening (Grade 4) reactions, treatment is permanently discontinued, and high-dose systemic corticosteroids (e.g., 1 to 2 mg/kg/day of prednisone or equivalent) are administered until the reaction improves to Grade 1 or less. This is followed by a slow corticosteroid taper over at least one month.[17]

Key IMARs observed with Opdualag in the RELATIVITY-047 trial are detailed in the table below.

Table 5: Key Immune-Mediated Adverse Reactions (IMARs) with Opdualag (from RELATIVITY-047)

Immune-Mediated Adverse Reaction	Overall Incidence (%)	Grade 3-4 Incidence (%)	Permanent Discontinuation Rate (%)	Source(s)
Myocarditis	1.7%	0.9% (Grade 3: 0.6%)	1.7%	1
Pneumonitis	3.7%	0.6% (Grade 3)	0.8%	17
Colitis	7.0%	1.1% (Grade 3)	2.0%	34
Hepatitis	6.0%	4.0% (Grade 4: 0.6%, Grade 3: 3.4%)	1.7%	34
Adrenal Insufficiency	4.2%	1.4% (Grade 3)	1.1%	12
Nephritis with Renal Dysfunction	2.0%	1.1% (Grade 3)	0.8%	6
Dermatologic Reactions	9.0%	0.6% (Grade 3)	0.0%	6
Hypothyroidism	17.0%	0.0%	0.3%	37

Other important IMARs, although less frequent, include endocrinopathies like hypophysitis and type 1 diabetes mellitus, as well as neurological toxicities such as meningitis, encephalitis, and Guillain-Barré syndrome.[1]

Prescribing and Administration

The clinical use of Opdualag requires adherence to specific guidelines for dosing, preparation, and administration to ensure patient safety and therapeutic efficacy.

Dosage and Schedule

• Recommended Dose: The approved dose of Opdualag is a fixed combination of 480 mg nivolumab and 160 mg relatlimab.[5]
• Dosing Schedule: This fixed dose is administered as a single intravenous infusion once every 4 weeks.[5]
• Treatment Duration: Therapy should be continued as long as a clinical benefit is observed or until the patient experiences unacceptable toxicity.[8]
• Dose Modifications: Dose escalation or reduction is not recommended. Management of adverse reactions requires either delaying a dose or permanently discontinuing treatment, based on the specific toxicity and its severity.[35]

Method of Administration

• Route: Opdualag is for intravenous use only and must not be administered as an intravenous push or bolus injection.[18]
• Infusion Time: The infusion should be administered over a period of 30 minutes.[1]
• Preparation: Aseptic technique must be used during preparation, as the product is preservative-free. The required volume can be withdrawn and administered either undiluted or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The final infusion volume should not exceed 160 mL, and the solution should be mixed by gentle inversion, not shaking.[17]
• Filtration: The infusion must be administered through an intravenous line containing a sterile, non-pyrogenic, low protein binding polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) in-line filter with a pore size of 0.2 to 1.2 micrometers.[17]
• Storage of Prepared Solution: Once prepared, the infusion solution is stable for a maximum of 8 hours at room temperature and room light. Alternatively, it can be stored under refrigeration at 2°C to 8°C (36°F to 46°F), protected from light, for no more than 24 hours from the time of preparation. The solution should not be frozen.[17]

Special Populations

• Pediatric Use: Opdualag is approved for pediatric patients aged 12 years and older who weigh at least 40 kg.[8] The European SmPC specifies a minimum weight of 30 kg.[18] A recommended dose has not been established for pediatric patients weighing less than these thresholds.[8] The safety and efficacy in children below 12 years of age have not been established.[33]
• Elderly Population: No dose adjustment is required for patients aged 65 years or older.[35]
• Renal and Hepatic Impairment: No dose adjustment is necessary for patients with mild or moderate renal or hepatic impairment. Data on the use of Opdualag in patients with severe renal or hepatic impairment are too limited to draw definitive conclusions.[35]

Contraindications and Key Precautions

• Contraindications: The U.S. Prescribing Information lists no contraindications for Opdualag.[37] The UK Summary of Product Characteristics (SmPC) lists hypersensitivity to the active substances or any of the excipients as a contraindication.[18]
• Embryo-Fetal Toxicity: Opdualag can cause fetal harm when administered to a pregnant woman. Based on animal studies and its mechanism of action, it poses a risk of abortion and premature infant death.[1] Females of reproductive potential must be advised of this risk and should use effective contraception during treatment and for at least 5 months following the last dose.[1]

Conclusion and Future Directions

Summary of Clinical Impact

Relatlimab, delivered as a component of the fixed-dose combination Opdualag, represents a landmark achievement in cancer immunotherapy. As the first-in-class LAG-3 inhibitor to receive regulatory approval, it has successfully validated LAG-3 as the third major clinically actionable immune checkpoint, joining the ranks of CTLA-4 and PD-1/PD-L1.[2]

For patients with advanced melanoma, Opdualag has established a new first-line standard of care. The RELATIVITY-047 trial unequivocally demonstrated its superiority over PD-1 monotherapy, a previous standard, by significantly improving progression-free survival with a durable, long-term benefit.[5] Perhaps its most critical contribution is its favorable therapeutic index. By offering a potent dual checkpoint blockade with a safety profile that is substantially more manageable than the nivolumab/ipilimumab combination, Opdualag provides a highly effective treatment option for a broader range of patients, solidifying its place in the clinical armamentarium.[13]

Unanswered Questions and Ongoing Research

Despite its success, the advent of Relatlimab raises new questions and defines the next frontiers of research in immuno-oncology.

• Optimal First-Line Combination: A pivotal unanswered question is the comparative efficacy and safety of Opdualag versus the nivolumab/ipilimumab combination. In the absence of a head-to-head clinical trial, treatment decisions are based on cross-trial comparisons and clinical judgment.[5] A prospective, randomized trial is needed to definitively establish the optimal first-line combination immunotherapy and to identify patient subgroups that may benefit more from one regimen over the other.
• Biomarker Development: The regulatory divergence between the FDA and EMA underscores the urgent need for better predictive biomarkers. The reliance of the EMA on an exploratory analysis of PD-L1 expression highlights the current uncertainty.[11] Future research must focus on identifying more robust biomarkers—whether genomic, transcriptomic, or protein-based—to more accurately select patients who will derive the most benefit from dual LAG-3/PD-1 blockade.
• Expansion into Other Settings and Tumors: The extensive clinical trial program for Opdualag is poised to redefine its role. Studies in the adjuvant and neoadjuvant settings for melanoma could shift the use of Relatlimab to much earlier stages of disease, with the goal of preventing recurrence.[26] The broad investigation across other solid tumors, including lung, liver, and colorectal cancers, will ultimately determine the full scope of Relatlimab's utility in oncology.[28]

The Future of LAG-3 Inhibition

The success of Relatlimab has catalyzed the entire field of LAG-3-targeted therapy. It has paved the way for the clinical development of other LAG-3 antagonists (e.g., fianlimab) and has intensified research into the fundamental biology of this complex checkpoint pathway.[39] The story of Opdualag provides a successful blueprint for the future of immuno-oncology: the development of rational, synergistic combinations that are designed not only to maximize efficacy but also to optimize safety. As the field moves beyond the high-toxicity paradigm of first-generation combinations, the principles demonstrated by the development of Relatlimab will likely guide the creation of the next wave of multi-agent immunotherapies, bringing more effective and better-tolerated treatments to patients with cancer.

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