Nivolumab and Relatlimab-rmbw - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

An IgG4 (type of immunoglobulin) antibody made entirely of human tissue called Nivolumab targets the immunological checkpoint programmed death receptor-1 (PD-1). The entire production process for this antibody involved using mice, and it was then grafted onto the human kappa and IgG4 Fc or immunoglobulin G subclass 4 fragment crystallizable regions, with the mutation S228P, to increase stability and decrease variability.

The developer of it is Bristol Myers Squibb. The U.S. Food and Drug Administration (FDA) approved Relatlimab-rmbw and Nivolumab together on March 18, 2022. Patients 12 years of age and older with advanced melanoma (skin cancer) are treated with this fixed-dose combination of monoclonal antibodies.

Drug Group

Relatlimab and Nivolumab belong to the monoclonal antibody drug class. Relatilimab and Nivolumab are administered in a fixed-dose combination. Nivolumab is a PD-1-blocking antibody that targets the inhibitory checkpoint protein PD-1 (programmed death receptor-1). The LAG-3 (lymphocyte activation gene-3) protein, another checkpoint receptor, is the target of Relatlimab, an antibody that blocks LAG-3. When used in conjunction, Relatlimab and Nivolumab offer a dual checkpoint inhibition approach that strengthens the immune system's capacity to fight cancer cells in patients with advanced melanoma.

Indications

A combination of Relatlimab, a blocking antibody for lymphocyte activation gene-3 (LAG-3), and Nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, is recommended for the treatment of adult and pediatric patients with unresectable or metastatic melanoma 12 years of age or older.

Dosage Forms and Available Strengths

The single-dose vial injection of 240 mg (milligrams) of Nivolumab and 80 mg of Relatlimab per 20 mL or milliliters (12 mg and 4 mg per mL).

Warnings and Precautions

Immune-Mediated Adverse Reactions:

• The term "immune-mediated adverse reactions" refers to a group of adverse reactions that can affect any organ system or tissue and have the potential to be severe or fatal. These reactions include pneumonitis (lung inflammation), colitis (colon inflammation), hepatitis (liver inflammation), immune-mediated endocrinopathies (conditions resulting from the immune system's reaction to anti-cancer medications, specifically immune checkpoint inhibitors), adverse reactions in the dermatologic system, renal dysfunction-causing immune-mediated arthritis (joint inflammation), and myocarditis (heart muscle inflammation).

• Look for prompt detection and handling. Assess thyroid function, liver enzymes, and creatinine at baseline and regularly during therapy.

• Depending on the nature and intensity of the response, withhold or permanently stop.

Infusion-Related Reactions: Depending on the severity of the reaction, stop Nivolumab and Relatlimab-rmbw temporarily, reduce the infusion pace, or stop it entirely.

Allogeneic Hematopoietic Stem Cell Treatment Complications: Patients with allogeneic stem cell transplantation before or after receiving PD-1 or PD-L1 blocking antibody treatment may experience fatal and other severe consequences.

Embryo-Fetal Toxicity: Relatlimab and Nivolumab may be harmful to the fetus. Women should be made aware that they may become pregnant, and taking effective contraception can lower their chances of getting pregnant.

For Patients

What Is Advanced Melanoma?

Metastatic melanoma, sometimes called stage IV melanoma or advanced melanoma, is a type of melanoma in which the cancerous cells expand from their original site to distant organs like the liver, brain, lungs, bones, digestive tract, and lymph nodes. Through tissues, blood vessels, or lymph nodes, the tumor cells can escape the immune system's natural defenses and finally settle in organs where they can proliferate. Depending on where the cancer is located, symptoms may include lymph node enlargement and pain, lung breathing problems or a chronic cough, liver toxicity, swelling in the abdomen, or jaundice (elevated bilirubin levels in the blood). Advanced melanoma patients may experience exhaustion, appetite loss, and unintentional weight loss.

How Do Nivolumab and Relatlimab-rmbw Work?

Monoclonal antibodies called Nivolumab and Relatlimab-rmbw treat specific cancers, including melanoma. By targeting T-cells' programmed death receptor 1 (PD-1) on an immune system level, Nivolumab enhances the immune system's capacity to identify and combat cancer cells. By strengthening the body's natural defenses against cancer, it inhibits the spread of the disease. Relatlimab-rmbw boosts the immune system's defense against cancer cells by targeting LAG-3, a cell-surface receptor in some T cells. When these medications are taken together, they produce a stronger treatment that might be more effective than either one taken alone.

What Are the Benefits of Nivolumab and Relatlimab-rmbw?

• Immunotherapy medications such as Relatlimab-rmbw and Nivolumab improve the body's defenses against metastatic melanoma.

• By specifically targeting the PD-1 receptor on T-cells, Nivolumab improves the immune system's ability to identify and combat cancer cells.

• Compared to conventional chemotherapy (drugs that destroy cancer cells), it has increased patients' overall survival.

• It has less severe side effects; some individuals respond to it long after they stop using it.

• By targeting the T cell's LAG-3 or lymphocyte-activation gene 3 receptor, Relatlimab-rmbw strengthens the immune system's defense against cancerous cells.

• Combining these medications may enhance progression-free survival and yield better results.

However, individual reactions to these medications can differ, so it is crucial to discuss treatment options with a medical professional.

How Are Nivolumab and Relatlimab-rmbw Administered?

• Patients who weigh at least 88.1 pounds, whether adult or pediatric, should receive an IV (intravenous) dose of 480 mg of Nivolumab and 160 mg of Relatlimab every four weeks.

• Give an intravenous infusion of Nivolumab and Relatlimab-rmbwfor 30 minutes.

• Refer to the complete prescribing information for instructions on preparing and administering the injection and dosage adjustments for adverse reactions.

What Are the Side Effects of Nivolumab and Relatlimab-rmbw?

Relatilimab and Nivolumab may have adverse consequences. Inform the doctor if any of the subsequent symptoms are severe or enduring:

• Weakness or discomfort in the muscles.

• Headache.

• Decreased hunger.

Certain adverse effects of Nivolumab and Relatlimab may be dangerous. Call the physician right away if patients have any of these symptoms of Nivolumab and Relatlimab, or seek emergency care:

• Breathlessness.

• Fresh or turning into a worse cough.

• Coughing with blood

• Diarrhea.

• Chest pain.

• Discomfort or soreness in the abdominal area.

• Feces that are bloody, sticky, tarry, or black.

• Fatigue or weakness.

• Feeling cold.

• Voice becoming deeper or more hoarse.

• Accelerated heart rate.

• More sweating.

• Weight fluctuations (gain or decrease).

• Alterations in behavior or mood (such as decreased sexual desire, impatience, or forgetfulness).

• Hand or foot pain, tingling, burning, or numbness.

• Headaches, particularly those that are strange or persistent.

• Confusion.

• Fever.

• Hair thinning.

• Hives, blisters, rash, or itching on the skin.

• Constipation.

• Nausea.

• Drowsiness.

• Lightheadedness or fainting.

• Yellowing of the skin or eyes, black urine, increased susceptibility to bleeding or bruises, appetite loss, low energy, or stomach ache on the right side.

• Increased thirst.

• Urination, either more or less.

• Facial, limb, leg, foot, or ankle edema

• Urine with blood.

• Visual abnormalities, such as light sensitivity.

• Fruity-smelling breath.

• Painful sores in the genital area, nose, mouth, or throat.

Relatilimab and Nivolumab may have additional adverse effects. If patients have any odd side effects while taking Relatilimab with Nivolumab, contact the doctor who prescribed it.

What Are the Things to Inform the Doctor Before Taking Nivolumab and Relatlimab-rmbw?

• Inform the doctor and pharmacist before using Nivolumab and Relatlimab if patients have an allergy (hypersensitivity reaction) to any of the ingredients in Nivolumab and Relatlimab, other drugs, or any combination of these substances.

• Inform the doctor and pharmacist about the vitamins, nutritional supplements, herbal items, prescription and over-the-counter drugs, and vitamins patients now take or intend to take. It may be necessary for the doctor to monitor patients closely for any side effects or to modify the prescription dosages.

• If patients have received an organ transplant, let the physician know. Additionally, inform the physician if patients currently have or have ever had any of the following conditions: lupus, which is an autoimmune disease in which the immune system attacks many tissues and organs, including the skin, joints, blood, and kidneys; any kind of lung disease or breathing issues; or thyroid, kidney, or liver disease. An autoimmune disease is a condition in which the immune system attacks a healthy part of the body. Examples include Crohn's disease, which causes pain, diarrhea, weight loss, fever, and ulcerative colitis, characterized by inflammation and sores in the colon's lining (large intestine) and rectum.

• Inform the doctor if patients intend to get pregnant or are already pregnant. Pregnancy testing is required before the administration of Nivolumab and Relatlimab. One should not become pregnant while taking Nivolumab and Relatlimab injections. Throughout treatment with Nivolumab and Relatlimab injections, as well as for at least five months following the last dosage, one should use an effective birth control method to avoid getting pregnant. Consult the doctor about birth control options that are suitable for the patient. Contact the physician right away if one becomes pregnant while receiving an injection of Relatlimab and Nivolumab. The fetus may be harmed by Nivolumab and Relatlimab injections.

• Inform the doctor if the patient is nursing a child or intends to do so. When taking Nivolumab and Relatlimab injections and five months after the final dose, the patient should not breastfeed.

Dietary Considerations

Maintain a regular diet as advised by the doctor.

Missed Dose

One must follow all of the appointments to obtain Nivolumab and Relatlimab injections. Ask the doctor when to schedule the next medication if one misses an appointment.

Overdose

Even if there are no symptoms like an upper respiratory tract infection, rash, pruritus (itching), cough, or peripheral edema (swelling), the patient should still get in touch with a medical expert, the hospital emergency room, or a regional poison control center right away if they have taken too many Nivolumab and Relatlimab injections.

Storage and Handling

Usually, a hospital or clinic stores Nivolumab and Relatlimab injections. The vial and carton labels specify the expiration date, which should not be exceeded. Keep it chilled (2°C) Celsius) to 8°C) (35.6°F (degrees Fahrenheit) to 39°F) to prevent freezing. Keep the original packaging in storage to keep the light out, and place it out of reach for children. Vials not opened can be kept for up to 72 hours at a regulated room temperature. It is recommended that any unused portions of the infusion solution be disposed of according to local regulations rather than being reused.

For Doctors

What Are the Pharmacological Aspects of Nivolumab and Relatlimab-rmbw?

Pharmacodynamics: Nivolumab prevents T-cells from receiving PD-1 inhibitory signals. Due to its frequent administration every two to four weeks, its duration of action is long. Patients should be informed about the potential for immune-mediated side effects, infusion-related side effects, problems from allogeneic hematopoietic stem cell transplantation, and embryo-fetal damage.

Mechanism of Action: PD-1 receptors of T-cells are occupied by the ligands PD-L1 and PD-L2, which prevent these cells from acting. Tumor cells express PD-L1 and PD-L2. By binding to PD-1, Nivolumab prevents PD-L1 and PD-L2 from suppressing T-cell activity, thereby, enabling the restoration of a patient's tumor-specific T-cell response.

Pharmacokinetics:

• Absorption: According to pharmacokinetic studies, Nivolumab appears to exhibit linear pharmacokinetics, with dose-proportionate increases in peak concentration and AUC (area under the curve). Peak plasma concentrations occur one to four hours apart. Following the administration of a dose of 10 mg/kg (milligrams per kilogram), the pharmacokinetic parameters of absorption are reported to have the following values: Cmax (maximum concentration), Tmax (time to peak drug concentration), and AUC of 242 µg/kg (micrograms per kilogram), 2.99 hours, and 68100 µg.h/mL (micrograms, hour per milliliters), respectively.

• Distribution: It has been observed that the volume of distribution at a steady state at a dose of 10 mg/kg of Nivolumab is 91.1 mL/kg (milliliters per kilogram). It is reported that the volume of distribution is 8 L (liters) at doses between 0.1 and 20 mg/kg.

• Metabolism: Nivolumab's specific metabolism has yet to be the focus of official research. Yet, as a human monoclonal antibody, it has been hypothesized that it breaks down into individual amino acids and small peptides.

• Excretion: Although the specific elimination pathway of Nivolumab is unknown, its serum half-life is around 20 days, and its elimination half-life is 26.7 days. 9.4 mL/h (milliliters per hour) is the predicted clearance rate; this may go up with body weight.

Drug Interactions

Some of the drugs that interact with Nivolumab and Relatlimab-rmbw include:

• Betamethasone.

• Budesonide.

• Cortisone.

• Deflazacort.

• Dexamethasone.

• Efgartigimod alfa.

• Hydrocortisone.

• Idelalisib.

• lenalidomide

• Methylprednisolone.

• Pomalidomide.

• Prednisolone.

• Prednisone.

• Rozanolixizumab.

• Thalidomide.

• Triamcinolone.

Clinical Studies

The purpose of the RELATIVITY-047 trial was to assess the efficacy of Nivolumab and Relatlimab-rmbw, a Nivolumab-based therapy for Stage III or IV melanoma that has spread or is incurable. 714 participants who had previously had melanoma therapy were enrolled in the trial. Nivolumab 480 mg was given to patients in a randomized fashion every four weeks until the disease progressed or the toxicity was intolerable.

Progression-free survival (PFS) was the main effectiveness outcome measure; overall survival (OS) and overall response rate (ORR) were the other metrics. Twelve weeks following randomization, tumor assessments were carried out. The trial population comprised 58 percent men, 97 percent white, 0.7 percent African Americans, seven percent Hispanics, and American Indian/Alaskan Native. According to the study, patients randomized to the Nivolumab and Relatlimab-rmbw arms showed a statistically significant improvement in PFS compared to the Nivolumab arm.

Use in Specific Populations

• Pregnancy: When given to a pregnant woman, Nivolumab and Relatlimab-rmbw, an intravenous injection that contains Relatlimab and Nivolumab, may be harmful to the fetus. When Nivolumab was administered to monkeys, there was a rise in abortions and early infant mortality. The consequences of pregnancy are probably more pronounced in the second and third trimesters. Pregnant women's Nivolumab and Relatlimab-rmbw are not well documented.

• Breastfeeding: Patients should refrain from breastfeeding while receiving Nivolumab and Relatlimab-rmbw medication or for at least five months following the final dosage due to the paucity of information regarding Nivolumab and Relatlimab's effects on human milk and milk production.

• Pediatric Use: Nivolumab and Relatlimab-rmbw have comparable safety and efficacy to adult treatments for pediatric patients with metastatic or unresectable melanoma who are 12 or older. A suggested dosage has yet to be determined for juvenile patients weighing less than 88.18 pounds and younger than 12.

• Geriatric Use: The safety and efficacy of Nivolumab and Relatlimab-rmbw treatment in RELATIVITY-047 did not significantly differ between younger and elderly patients.