Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody.1 Relatlimab-rmwb is a lymphocyte activation gene-3 (LAG-3) blocking antibody.1
Nivolumab and relatlimab-rmbw is a fixed-dose combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody, used for the treatment of adult and pediatric patients ≥12 years of age with unresectable or metastatic melanoma.1 It has been designated an orphan drug by FDA for this use.2 Guidelines recommend nivolumab and relatlimab-rmbw as one of several first-line treatment options for unresectable or metastatic melanoma.6, 7
The efficacy of nivolumab and relatlimab-rmbw for the treatment of metastatic or unresectable stage III or IV melanoma was evaluated in the phase 2/3, randomized, double-blind, RELATIVITY-047 trial (NCT03470922).1, 3 A total of 714 previously untreated patients with advanced melanoma were randomly assigned to receive the fixed-dose combination of nivolumab and relatlimab-rmbw (nivolumab 480 mg and relatlimab-rmbw 160 mg) or nivolumab alone (480 mg); both treatments were given by IV infusion every 4 weeks until disease progression or unacceptable toxicity occurred.1, 3 The primary outcome was progression-free survival; additional outcomes included overall survival and overall response rate.1, 3
Enrolled patients were a median 63 years of age (range, 20-94 years), were primarily white (97%) and male (58%), and had Eastern Cooperative Oncology Group (ECOG) performance scores of 0 (67%) or 1 (33%).1, 3 Stage IV disease was present in 92% of patients.1, 3 The median progression-free survival was 10.1 months with nivolumab and relatlimab-rmbw compared to 4.6 months with nivolumab alone.1, 3 Disease progression or death occurred in 51% of patients who received nivolumab and relatlimab-rmbw and 59% of patients who received nivolumab alone.1, 3 Death occurred in 39% of patients treated with nivolumab and relatlimab-rmbw and 45% of patients treated with nivolumab alone.1, 3 Overall response rate was 43% among patients treated with nivolumab and relatlimab-rmbw and 33% among patients treated with nivolumab alone.1, 3 A complete response was seen in 16% of patients in the nivolumab and relatlimab-rmbw group and 14% of patients in the nivolumab group.1, 3
Treatment of melanoma is based on the stage of the disease at the time of diagnosis; standard treatment modalities for unresectable stage III and stage IV melanoma include intralesional therapy (e.g., talimogene laherparepvec), immunotherapy (e.g., pembrolizumab, nivolumab, ipilimumab), signal transduction inhibitors (e.g., vemurafenib, dabrafenib, trametinib, cobimetinib, encorafenib, binimetinib), chemotherapy, and palliative local therapy.5
The American Society of Clinical Oncology (ASCO) guideline on systemic therapy for melanoma recommends nivolumab and relatlimab as a first-line option for patients with unresectable and/or metastatic cutaneous melanoma (regardless of BRAF mutation status); other first-line options for all patients with unresectable or metastatic melanoma include nivolumab plus ipilimumab followed by nivolumab, nivolumab alone, and pembrolizumab alone.6 Patients with BRAF V600 mutant disease may also be treated with dabrafenib plus trametinib, encorafenib plus binimetinib, or vemurafenib plus cobimetinib first line.6 The guideline expresses no preference between any of these treatment regimens, and recommends a shared decision making approach to treatment selection.6 Consult the ASCO guideline for more details.6
The Society for Immunotherapy of Cancer guideline on immunotherapy for the treatment of melanoma recommends that patients with unresectable or metastatic cutaneous melanoma receive either nivolumab plus ipilimumab, nivolimab plus relatlimab, single-agent nivolumab, or single-agent pembrolizumab as first-line therapy, regardless of BRAF mutation status.7 Nivolumab plus ipilimumab may be preferred in patients with poor prognostic features (e.g., liver metastases, brain metastases, BRAF mutations, high lactate dehydrogenase).7 Consult the guideline for more details.7
Nivolumab and relatlimab-rmbw is administered by IV infusion.1 It is available as a solution in single-dose vials containing 240 mg nivolumab and 80 mg relatlimab per 20 mL (12 mg and 4 mg per mL).1 The solution is clear to opalescent and colorless to slightly yellow.1 Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white particles.1 Nivolumab and relatlimab-rmbw does not contain a preservative.1 Store unopened vials at 2-8ºC in the original carton to protect from light; do not freeze or shake.1
Nivolumab and relatlimab-rmbw may be administered diluted or undiluted.1 If administering the undiluted solution, withdraw the required volume of drug and transfer to a compatible IV container.1 The drug is compatible with di(2-ethylhexyl)phthalate (DEHP) plasticized polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), and polyolefin IV bags.1 If preparing a diluted solution, dilute the drug with 0.9% sodium chloride or 5% dextrose to prepare an infusion meeting the final concentration and maximum infusion volume parameters specified in Table 1.1 Mix the diluted solution by gentle inversion.1 Do not shake.1
Patient Group | Maximum Infusion Volume | Concentration Rangea |
|---|---|---|
Adult and pediatric patients ≥12 years of age weighing ≥40 kg | 160 mL | Nivolumab: 3-12 mg/mL Relatlimab: 1-4 mg/mL |
Adult patients weighing <40 kg | 4 mL/kg | Nivolumab: 3-12 mg/mL Relatlimab: 1-4 mg/mL |
aThe concentration range in each group includes 12 mg/mL nivolumab and 4 mg/mL relatlimab as the upper limit, which represents a scenario in which the drug product is infused without dilution.
The prepared solution can be stored at room temperature and room light for no more than 8 hours from the time of preparation to the end of the infusion; discard if not used within 8 hours of preparation.1 The prepared solution can also be stored under refrigeration at 2-8°C with protection from light for no more than 24 hours from the time of preparation: this includes the time allowed for the bag to come to room temperature and the duration of the infusion.1 Discard the refrigerated solution if not used within 24 hours from the time of preparation.1 Do not freeze.1
Administer the prepared solution by IV infusion over 30 minutes through an IV line containing a sterile, non-pyrogenic, low protein binding in-line polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) filter (pore size of 0.2-1.2 micrometer).1 Flush the IV line at the end of the infusion.1 Do not co-administer other drugs through the same IV line.1
The recommended dosage of nivolumab and relatlimab-rmbw in adults is 480 mg nivolumab and 160 mg relatlimab IV every 4 weeks until disease progression or unacceptable toxicity occurs.1
The recommended dosage of nivolumab and relatlimab-rmbw in pediatric patients ≥12 years of age who weigh ≥40 kg is 480 mg nivolumab and 160 mg relatlimab IV every 4 weeks until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
No dosage reductions are recommended.1 In general, withhold nivolumab and relatlimab-rmbw for severe (grade 3) immune-related adverse reactions.1 Permanently discontinue treatment for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated adverse reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating steroids.1 See Table 2 for recommended dosage modifications for adverse reactions that require management different from these general guidelines. 1
Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
Immune-mediated Adverse Reactions | ||
Pneumonitis | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Colitis | Grade 2 or 3 | Withholda |
Grade 4 | Permanently discontinue | |
Hepatitis | AST or ALT increases to >3 and ≤8 times ULN or total bilirubin increases to >1.5 and ≤3 times ULN | Withholda |
AST or ALT increases to >8 times ULN regardless of baseline or total bilirubin increases to >3 times ULN | Permanently discontinue | |
Endocrinopathiesb | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
Nephritis with renal dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
Grade 4 increased blood creatinine | Permanently discontinue | |
Exfoliative dermatologic reactions | Suspected SJS, TEN, or DRESS | Withhold |
Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
Myocarditis | Grade 2, 3, or 4 | Permanently discontinue |
Neurological toxicities | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Other Adverse Reactions | ||
Infusion-related reactions | Grade 1 or 2 | Interrupt or slow the rate of infusion |
Grade 3 or 4 | Permanently discontinue |
aResume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
bDepending on clinical severity, consider withholding for grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
DRESS, drug rash with eosinophilia and systemic symptoms; SJS, Stevens Johnson syndrome; TEN, toxic epidermal necrolysis; ULN, upper limit normal.
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe and Fatal Immune-Mediated Adverse Reactions
Nivolumab and relatlimab-rmbw potentially breaks peripheral tolerance and induces immune-mediated adverse reactions; these may be severe or fatal and may occur in any organ system or tissue.1 Immune-mediated adverse reactions can occur any time after starting treatment with lymphocyte activation gene-3 (LAG-3) and programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) blocking antibodies.1 These reactions usually occur during treatment, but can also manifest after discontinuation.1
Early identification and management of immune-mediated adverse reactions is essential.1 Monitor patients closely for symptoms and signs that may be clinical manifestations of immune-mediated adverse reactions.1 Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.1 If an immune-mediated adverse reaction is suspected, initiate appropriate workup to exclude alternative etiologies, including infection.1 Institute medical management promptly, including specialty consultation as appropriate.1
Depending on the severity of the immune-mediated adverse reaction, withhold or permanently discontinue nivolumab and relatlimab-rmbw.1 In general, if treatment interruption or discontinuation is required, administer systemic corticosteroid therapy (1-2 mg/kg per day prednisone or equivalent) until improvement to grade 1 or less.1 Upon improvement, initiate corticosteroid taper and continue to taper over at least 1 month.1 Consider use of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.1
Nivolumab and relatlimab-rmbw can cause immune-mediated pneumonitis, which may be fatal.1 In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher among patients who have received prior thoracic radiation.1
Immune-mediated pneumonitis occurred in 3.7% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 2.3 and 0.6%, respectively.1 Pneumonitis led to permanent discontinuation of nivolumab and relatlimab-rmbw in 0.8% of patients and treatment interruption in 1.4% of patients.1
Systemic corticosteroids were required in all patients with pneumonitis.1 Resolution of pneumonitis occurred in 85% of the 13 patients.1 All 5 patients who had treatment withheld for pneumonitis reinitiated treatment after symptom improvement, and none of these patients had recurrence of pneumonitis.1
Nivolumab and relatlimab-rmbw can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology.1 A common symptom included in the definition of colitis was diarrhea.1 Cytomegalovirus infection or reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.1
Immune-mediated colitis or diarrhea occurred in 7% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 4.5 and 1.1%, respectively.1 Colitis led to permanent discontinuation of nivolumab and relatlimab-rmbw in 2% of patients and treatment interruption in 2.8% of patients.1
Systemic corticosteroids were required in all patients with diarrhea or colitis.1 Resolution occurred in 83% of the 24 patients.1 Of the 10 patients in whom treatment was withheld, 9 reinitiated treatment after symptom improvement and 67% had recurrence of colitis.1
Nivolumab and relatlimab-rmbw can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology.1
Immune-mediated hepatitis occurred in 6% of patients receiving nivolumab and relatlimab-rmbw, including grade 2, 3, and 4 adverse reactions in 1.4, 3.4, and 0.6%, respectively.1 Hepatitis led to permanent discontinuation of nivolumab and relatlimab-rmbw in 1.7% of patients and treatment interruption in 2.3% of patients.1
Systemic corticosteroids were required in all patients with hepatitis.1 Resolution occurred in 70% of the 20 patients.1 Of the 8 patients in whom treatment was withheld, 6 reinitiated treatment after symptom improvement and 50% had recurrence of hepatitis.1
Immune-mediated endocrinopathies
Adrenal insufficiency: Nivolumab and relatlimab-rmbw can cause primary or secondary adrenal insufficiency.1 For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated.1 Withhold nivolumab and relatlimab-rmbw depending on severity.1
Adrenal insufficiency occurred in 4.2% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 2.5 and 1.4%, respectively.1 Adrenal insufficiency led to permanent discontinuation of nivolumab and relatlimab-rmbw in 1.1% of patients and treatment interruption in 0.8% of patients.1
Hormone replacement was required in 87% of the 15 patients with adrenal insufficiency.1 A similar number required systemic corticosteroids.1 Resolution occurred in 33% of the 15 patients.1 Of the 3 patients in whom treatment was withheld, 3 reinitiated treatment after symptom improvement.1
Hypophysitis: Nivolumab and relatlimab-rmbw can cause immune-mediated hypophysitis, which can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.1 Hypophysitis can cause hypopituitarism.1 Initiate hormone replacement as clinically indicated.1 Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.1
Hypophysitis occurred in 2.5% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 1.4 and 0.3%, respectively.1 Hypophysitis led to permanent discontinuation of nivolumab and relatlimab-rmbw in 0.3% of patients and treatment interruption in 0.6% of patients.1
Hormone replacement and systemic corticosteroids were required in all 9 patients with hypophysitis.1 Resolution occurred in 22% of the 9 patients.1 Of the 2 patients in whom treatment was withheld, none reinitiated treatment after symptom improvement.1
Thyroid disorders: Nivolumab and relatlimab-rmbw can cause immune-mediated thyroid disorders, including thyroiditis, hyperthyroidism, and hypothyroidism.1 Thyroiditis can present with or without endocrinopathy.1 Hypothyroidism can follow hyperthyroidism.1 Initiate hormone replacement or medical management as clinically indicated.1 Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.1
Thyroiditis occurred in 2.8% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 adverse reactions in 1.1% of patients.1 Thyroiditis did not lead to permanent discontinuation of nivolumab and relatlimab-rmbw.1 Treatment interruption occurred in 0.3% of patients.1 Systemic corticosteroids were required in 20% of the 10 patients with thyroiditis.1 Resolution occurred in 90% of the 10 patients.1 For the 1 patient in whom treatment was withheld, treatment was reinitiated after symptom improvement without recurrence of thyroiditis.1
Hyperthyroidism occurred in 6% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 adverse reactions in 1.4%.1 Hyperthyroidism did not lead to permanent discontinuation of nivolumab and relatlimab-rmbw.1 Treatment interruption occurred in 0.3% of patients.1 Systemic corticosteroids were required in 23% of the 22 patients with hyperthyroidism.1 Resolution occurred in 82% of the 22 patients.1 For the 1 patient in whom treatment was withheld, treatment was reinitiated after symptom improvement without recurrence of hyperthyroidism.1
Hypothyroidism occurred in 17% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 adverse reactions in 11%.1 Hypothyroidism led to permanent discontinuation of nivolumab and relatlimab-rmbw in 0.3% of patients and treatment interruption in 2.5% of patients.1 Systemic corticosteroids were not required in any of the patients with hypothyroidism.1 Resolution occurred in 12% of the 59 patients.1 Of the 9 patients in whom treatment was withheld, 6 reinitiated treatment after symptom improvement and 33% had recurrence of hypothyroidism.1
Type 1 diabetes, which can present as diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes.1 Initiate treatment with insulin as clinically indicated.1 Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.1
Diabetes, a grade 3 adverse reaction, occurred in 0.3% of patients receiving nivolumab and relatlimab-rmbw; no cases of diabetic ketoacidosis were reported.1 Diabetes did not lead to permanent discontinuation or interruption of nivolumab and relatlimab-rmbw in any patient.1
Immune-mediated nephritis with renal dysfunction
Nivolumab and relatlimab-rmbw can cause immune-mediated nephritis, defined as requiring use of corticosteroids and no clear alternate etiology.1 Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.1
Immune-mediated nephritis and renal dysfunction occurred in 2% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 0.8 and 1.1%, respectively.1 Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of nivolumab and relatlimab-rmbw in 0.8% of patients and treatment interruption in 0.6% of patients.1
Systemic corticosteroids were required in all 7 patients with nephritis and renal dysfunction.1 Nephritis and renal dysfunction resolved in 71% of the 7 patients.1 Of the 2 patients in whom treatment was withheld, 1 reinitiated treatment after symptom improvement without recurrence of nephritis or renal dysfunction.1
Immune-mediated dermatologic adverse reactions
Nivolumab and relatlimab-rmbw can cause immune-mediated rash or dermatitis, defined as requiring use of corticosteroids and no clear alternate etiology.1 Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies.1 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.1 Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.1
Immune-mediated rash occurred in 9% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 3.4 and 0.6%, respectively.1 Immune-mediated rash did not lead to permanent discontinuation of nivolumab and relatlimab-rmbw.1 Treatment interruption occurred in 1.4% of patients.1
Systemic corticosteroids were required in 88% of the 33 patients with immune-mediated rash.1 Rash resolved in 70% of the 33 patients.1 Of the 5 patients in whom treatment was withheld, 4 reinitiated treatment after symptom improvement and 25% of these patients had recurrence of immune-mediated rash.1
Nivolumab and relatlimab-rmbw can cause immune-mediated myocarditis, defined as requiring use of corticosteroids and no clear alternate etiology.1 Patients with cardiac or cardiopulmonary symptoms should be assessed for potential myocarditis.1 If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1-2 mg/kg per day), and promptly arrange cardiology workup.1 If clinically confirmed, permanently discontinue nivolumab and relatlimab-rmbw for grade 2, 3, or 4 myocarditis.1
Myocarditis occurred in 1.7% of patients receiving nivolumab and relatlimab-rmbw, including grade 2 and 3 adverse reactions in 1.1 and 0.6%, respectively.1 Myocarditis led to permanent discontinuation of nivolumab and relatlimab-rmbw in 1.7% of patients.1
Systemic corticosteroids were required in all 6 patients with myocarditis.1 Myocarditis resolved in all patients.1
Other immune-mediated adverse reactions
The following clinically significant immune-mediated adverse reactions occurred in <1% of patients who received nivolumab and relatlimab-rmbw or were reported with the use of other PD-1/PD-L1 blocking antibodies: pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy, uveitis, iritis, pancreatitis (including increases in serum amylase and lipase), gastritis, duodenitis, myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.1
Uveitis, iritis, and other ocular inflammatory toxicities can occur; some cases may be associated with retinal detachment, and various grades of visual impairment, including blindness, can occur.1 If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.1
Nivolumab and relatlimab-rmbw can cause severe infusion-related reactions.1 Discontinue for severe or life-threatening reactions, and interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions.1
Infusion-related reactions occurred in 7% of patients who received nivolumab and relatlimab-rmbw as a 60-minute infusion.1
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Serious and fatal complications can occur in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with PD-1/PD-L1 receptor blocking antibodies.1 Transplant-related complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT, and may include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome without an identified infectious cause.1
Follow patients closely for evidence of transplant-related complications and intervene promptly.1 Consider the benefits and risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and data from animal studies, nivolumab and relatlimab-rmbw can cause fetal harm.1 In animal reproduction studies, nivolumab administration from the onset of organogenesis through delivery led to increased abortion and premature infant death.1
Advise pregnant females of the potential risk to a fetus.1 Verify pregnancy status of females of reproductive potential prior to starting treatment with nivolumab and relatlimab-rmbw.1 Advise females of reproductive potential to use effective contraception during treatment with nivolumab and relatlimab-rmbw and for at least 5 months after the last dose.1
During the initial 24-month treatment period in the RELATIVITY-047 trial, the incidence of anti-nivolumab antibodies with nivolumab and relatlimab-rmbw was 3.8%, and the incidence of neutralizing antibodies was 0.3%.1 The incidence of anti-nivolumab antibodies in patients treated with nivolumab alone was 5.9% and the incidence of neutralizing antibodies was 0.4%.1 The incidence of anti-relatlimab antibodies in the nivolumab and relatlimab-rmbw group was 5.6% and the incidence of neutralizing antibodies was 0.3%.1
Because of the low incidence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of nivolumab and relatlimab-rmbw is unknown.1
There are no data on the use of nivolumab and relatlimab-rmbw in pregnant females to evaluate a drug-associated risk.1 Based on animal data and the mechanism of action, nivolumab and relatlimab-rmbw can cause fetal harm when administered to a pregnant females.1 Human immunoglobulin G4 (IgG4) is known to cross the placenta; therefore, nivolumab and relatlimab have the potential to be transmitted from the mother to the developing fetus.1 The effects of nivolumab and relatlimab-rmbw are likely to be greater during the second and third trimesters of pregnancy.1 Advise patients of the potential risk to a fetus, and verify pregnancy status of females of reproductive potential prior to initiating therapy.1
The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis to delivery at exposure levels 9-42 times higher than those observed with the clinical dose of 3 mg/kg.1 Nivolumab resulted in a non-dose-dependent increase in spontaneous abortion and increased neonatal death.1 In surviving infants, no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters were observed throughout the 6-month postnatal period.1
There are no available animal data on relatlimab.1 Administration of a murine surrogate anti-LAG-3 antibody to mice beginning on gestation day 6 did not result in maternal or developmental effects in either syngeneic or allogeneic breedings.1
There are no data regarding the presence of nivolumab and relatlimab-rmbw in human milk, effects on the breastfed infant, or effects on milk production.1 Because nivolumab and relatlimab may be excreted in human milk and there is potential for serious adverse effects in the breastfed infant, advise patients not to breastfeed during treatment with nivolumab and relatlimab-rmbw and for at least 5 months after the last dose.1
Females and Males of Reproductive Potential
Nivolumab and relatlimab-rmbw can cause fetal harm when administered to pregnant females.1 Verify the pregnancy status of females of reproductive potential prior to initiating nivolumab and relatlimab-rmbw.1
Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose of nivolumab and relatlimab-rmbw.1
The safety and effectiveness of nivolumab and relatlimab-rmbw for the treatment of unresectable or metastatic melanoma have been established in pediatric patients ≥12 years of age who weigh ≥40 kg based on evidence from an adequate and well-controlled study in adults and additional pharmacokinetic analyses in pediatric patients.1 The pharmacokinetics of monoclonal antibodies and the course of unresectable or metastatic melanoma are sufficiently similar in adults and pediatric patients ≥12 years of age weighing ≥40 kg to allow extrapolation from adult patients.1
The safety and effectiveness of nivolumab and relatlimab-rmbw have not been established in pediatric patients ≥12 years of age who weigh <40 kg, or in pediatric patients <12 years of age.1
Of the 355 patients treated with nivolumab and relatlimab-rmbw in the RELATIVITY-047 trial, 47% of patients were ≥65 years of age, 29% were 65-74 years of age, 17% were 75-84 years of age, and 1.7% were ≥85 years of age.1 No overall differences in safety or effectiveness were observed between elderly and younger patients.1
Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and AST greater than ULN, or total bilirubin >1 to 1.5 times ULN with any AST) and moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST) did not have a clinically important effect on the clearance of nivolumab and relatlimab-rmbw.1 The effects of severe hepatic impairment on the pharmacokinetics of nivolumab and relatlimab-rmbw are unknown.1
Mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89 mL/min/1.73m2) did not have a clinically important effect on the clearance of nivolumab and relatlimab-rmbw.1 The effects of severe renal impairment on the pharmacokinetics of nivolumab and relatlimab-rmbw are unknown.1
The most common adverse reactions with an incidence ≥20% are musculoskeletal pain, fatigue, rash, pruritus, and diarrhea.1 The most common laboratory abnormalities (incidence ≥20%) are decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium.1
Nivolumab and relatlimab-rmbw is a fixed-dose combination of 2 human immunoglobulin G4 (IgG4) monoclonal antibodies.1 Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab-rmwb is a lymphocyte activation gene-3 (LAG-3) blocking antibody.1
Binding of the PD-1 ligands, programmed death ligand-1 (PD-L1) and PD-L2, to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production.1 Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.1 Nivolumab binds to the PD-1 receptor, blocks interaction with PD-L1 and PD-L2, and reduces PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.1 In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.1
Relatlimab-rmwb binds to the LAG-3 receptor, blocks interaction with its ligands (including major histocompatibility complex [MHC] II), and reduces LAG-3 pathway-mediated inhibition of the immune response.1 Antagonism of this pathway promotes T-cell proliferation and cytokine secretion.1
The combination of nivolumab and relatlimab-rmwb results in increased T-cell activation compared to the activity of either antibody alone.1 In murine syngeneic tumor models, LAG-3 blockage potentiates the anti-tumor activity of PD-1 blockage, inhibiting tumor growth and promoting tumor regression.1
Steady-state concentrations of relatlimab-rmwb were reached by 16 weeks with an every 4-week regimen and systemic accumulation was 1.9-fold.1 The average concentration of relatlimab-rmwb after the first dose increased dose proportionally at doses ≥160 mg every 4 weeks.1 The half-life of relatlimab-rmwb following administration of nivolumab 480 mg and relatlimab 160 mg every 4 weeks is 26.2 days.1 The half-life of nivolumab is 26.5 days.1 The following factors had no clinically important effect on the clearance of nivolumab and relatlimab-rmbw: age (17-92 years), sex, and race.1 Exposures of nivolumab and relatlimab-rmwb in pediatric patients ≥12 years of age weighing ≥40 kg are expected to be in the range of exposures in adult patients at the recommended dosage.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 240 mg nivolumab and 80 mg relatlimab per 20 mL (12 mg and 4 mg per mL) | Opdualag® (single-dose vials) | Bristol-Meyers Squibb |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions February 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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