What Are Nivolumab and Relatlimab (Opdualag)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes (Initial approval date: March 18, 2022)
• Brand Name: Opdualag
• Active Ingredients: Nivolumab (PD-1 inhibitor) and Relatlimab (LAG-3 inhibitor)
• Route of Administration: Intravenous infusion (into a vein)
• Class: Immune checkpoint inhibitors (monoclonal antibodies)
• Category: Antineoplastic / Immunotherapy
• Manufacturer: Bristol Myers Squibb
• Distribution in Turkey: Not yet authorized in Turkey, but access may be possible through overseas medicine procurement procedures.
• Cancers for Which It Is Approved: Unresectable or metastatic melanoma in adults and children aged 12 and older

What Is Opdualag? How Does It Work?

Opdualag is a combination immunotherapy bringing together two different immune checkpoint inhibitors, nivolumab and relatlimab. It activates the immune system so that the body can recognize and destroy cancer cells. It is used particularly for advanced (metastatic) or unresectable malignant melanoma.

Nivolumab targets PD-1 (Programmed Death-1) on T cells and blocks the tumor's mechanism of escaping the immune system.

Relatlimab inhibits LAG-3 (Lymphocyte-Activation Gene 3), also on the T-cell surface, allowing T cells to remain active longer.

Simultaneous inhibition of these two mechanisms enables a stronger and more effective immune response against cancer.

How Does It Work?

PD-1 Blockade (Nivolumab): Tumor cells suppress the immune system by secreting the PD-L1 ligand. Nivolumab blocks PD-1 on T cells, removing this suppression and reactivating immunity.

LAG-3 Blockade (Relatlimab): Chronic stimulation increases LAG-3 expression on T cells and weakens their response. By targeting LAG-3, relatlimab helps T cells maintain function and mount a more durable antitumor response.

Synergistic Effect: Simultaneous PD-1 and LAG-3 inhibition substantially increases T-cell activity. This combination may achieve higher clinical responses than either agent alone.

FDA (US Food and Drug Administration) Approval History

• March 25, 2021: Bristol Myers Squibb announced that RELATIVITY-047, evaluating the anti-LAG-3 antibody relatlimab with Opdivo (nivolumab) in previously untreated metastatic or unresectable melanoma, had met its primary endpoint of disease-free survival (progression-free survival).
• September 20, 2021: The US Food and Drug Administration (FDA) accepted for Priority Review Bristol Myers Squibb's application for the fixed-dose combination of relatlimab (a LAG-3-blocking antibody) and nivolumab for unresectable or metastatic melanoma.
• March 18, 2022: The FDA approved Opdualag (nivolumab and relatlimab-rmbw) for unresectable or metastatic melanoma.

Authorization in Turkey

Not yet officially authorized in Turkey. It may be obtained from abroad under special Ministry of Health authorization procedures. It is not on the TİCK overseas medicine list.

Resistance Mechanisms

• Increased Immunosuppressive Cells in the Tumor Microenvironment: Increases in regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages may inhibit T-cell activity and cause drug resistance.
• Activation of Immune Checkpoints Other Than PD-L1 and LAG-3: Opdualag targets only PD-1 and LAG-3. Tumor cells may activate other immunosuppressive pathways, such as TIM-3 and TIGIT, to evade immunity, leading to secondary (acquired) resistance.
• Impaired Antigen Presentation (MHC Loss): MHC class I molecules must function properly for T cells to recognize tumor cells. If tumors suppress or eliminate this system, the immune system cannot recognize cancer cells and the drug becomes ineffective.
• T-Cell Exhaustion: Persistent tumors may cause functional T-cell exhaustion. These cells may then fail to respond adequately even when LAG-3 and PD-1 are inhibited.
• An Immunologically “Cold” Tumor: Some tumors develop an immune-cold structure by preventing immune cell infiltration, reducing the overall effect of immunotherapy.
• Genetic Evolution and Clonal Selection: Tumor subclones capable of immune escape are selected and become dominant. These clones may no longer be sensitive to existing immunotherapies.

Absorption

• Intravenous (IV) infusion.
• There is therefore no gastrointestinal absorption in the conventional sense; the drug enters the systemic circulation directly.
• Bioavailability is considered 100%.

Distribution

• Volume of distribution (Vd): approximately 8 L for nivolumab and 6–8 L for relatlimab.
• These values indicate that the antibodies circulate mainly in vascular and interstitial fluids.
• Plasma protein binding: monoclonal antibodies do not bind extensively; they target specific receptors.
• Target-specific distribution: nivolumab binds PD-1 on T cells, while relatlimab binds LAG-3.
• Distribution is greater in tissues rich in these target receptors, such as lymphoid tissue and the tumor microenvironment.

Metabolism

• As large peptide molecules, nivolumab and relatlimab do not undergo conventional hepatic metabolism through CYP enzymes.
• They are broken down by the reticuloendothelial system, including macrophages and lysosomes.
• Their protein structures are degraded intracellularly into amino acids, which are reused or eliminated.

Elimination

• No significant elimination through the kidneys or bile.
• Monoclonal antibodies are generally eliminated through nonhepatic pathways, namely intracellular breakdown (catabolism).
• Nivolumab half-life is approximately 25 days; relatlimab, approximately 23 days.
• These long half-lives make infusions every 3 weeks possible.

Dose Range

• A single-dose vial contains 240 mg nivolumab and 80 mg relatlimab in 20 mL. 2 vials of Opdualag provide 480 mg nivolumab + 160 mg relatlimab , the required dose.
• Administration: both agents are delivered as a fixed-dose combination in the same infusion solution.
• Intravenous infusion every 4 weeks (approximately 30 minutes)
• Treatment generally starts at a fixed dose without individual dose adjustment. Serious adverse reactions, such as immune-mediated hepatitis, colitis, nephritis or myocarditis, may require temporary interruption or permanent discontinuation in severe cases.
• No dose reductions are used; treatment is only interrupted or discontinued.
• Combination with other immunotherapies or targeted treatments is not currently recommended in routine clinical practice.

Drug Interactions

• No CYP450-Related Interactions Expected: Nivolumab and relatlimab are not metabolized by hepatic CYP450 enzymes like small molecules. Conventional drug interactions, such as with CYP3A4 inhibitors or inducers, are therefore not expected.
• Interactions With Immunosuppressive Drugs: Corticosteroids such as prednisone and dexamethasone, and other immunosuppressants such as cyclosporine and azathioprine, may reduce immunotherapy effectiveness. However, high-dose steroids are used temporarily only for serious immune adverse events. Low-dose or topical steroids are not thought to significantly affect Opdualag's action.
• Use With Live Vaccines: Because the immune system is reactivated, patients receiving Opdualag should not receive live attenuated vaccines, such as measles, varicella or BCG. If vaccination is needed, it should occur before immunotherapy, or inactivated vaccines should be preferred during treatment.
• Anticoagulants and NSAIDs: These do not interact directly on their own, but drugs that irritate the gastric mucosa, such as ibuprofen or aspirin, require caution if immune-mediated enteritis, colitis or gastritis develops during treatment.
• Combination With Other Immunotherapies: Combination with other checkpoint inhibitors, such as ipilimumab, is being evaluated in clinical trials and is not recommended routinely. Such combinations may increase toxicity.

Situations Requiring Attention

Immune-Mediated Organ Toxicities: Excessive immune activation may cause attacks on healthy tissues. The most frequently affected organs are:

• Skin: rash, itching, vitiligo
• Intestine: colitis, diarrhea, abdominal pain
• Liver: hepatitis (elevated AST/ALT)
• Lungs: pneumonitis (dry cough, shortness of breath)
• Thyroid and endocrine system: hypothyroidism, hypophysitis

Mild cases may receive symptomatic treatment while therapy continues. Serious cases may require corticosteroids and/or treatment interruption.

History of Autoimmune Disease: Pre-existing autoimmune diseases such as rheumatoid arthritis, lupus or multiple sclerosis may flare with Opdualag. Careful monitoring and consideration of alternative treatments when needed are recommended.

Infection Risk: Immune activation may increase susceptibility to opportunistic infections, particularly in the lungs, intestine and skin. Treatment should be deferred if active infection is present beforehand. Fever, cough and diarrhea should be monitored closely during therapy.

Corticosteroid Use: Serious immune adverse events may require corticosteroids such as prednisone. However, they may somewhat reduce Opdualag effectiveness and are used only temporarily when essential.

Pregnancy and Breastfeeding: Monoclonal antibodies may cross the placenta. Fetal toxicity has been observed in animals. Contraindicated in pregnancy; effective contraception is recommended. It should not be used during breastfeeding.

Live Vaccines: Vaccines that stimulate active immunity, such as measles, mumps and BCG, may be risky during this treatment. Live vaccines should not be given during therapy; inactivated vaccines may be preferred.

Regular Monitoring Before and During Treatment:

• Liver function tests
• Thyroid hormones (TSH, fT4)
• Pulmonary symptoms
• Skin and neurological status

These assessments are important for early detection of immune toxicities.

Side Effects 

• Fatigue 18%
• Itching (pruritus) 17%
• Rash (dermatitis) 13%
• Diarrhea 13%
• Muscle and joint pain (arthralgia / myalgia) 12%
• Nausea 11%
• Headache 10%
• Thyroid dysfunction (hypothyroidism/hyperthyroidism) 9%
• Abdominal pain 9%
• Dry skin 8%
• Cough 7%
• Fever (pyrexia) 6%
• Dry mouth 6%
• Anemia 5%
• Elevated liver enzymes (ALT/AST) 4%
• Pneumonitis (lung inflammation) 2.5%
• Colitis (intestinal inflammation) 2.3%
• Hypophysitis / adrenal insufficiency 1.5–2%
• Nephritis (kidney inflammation) 1%