nivolumab/relatlimab (Rx)

>10%

All grades

• Musculoskeletal pain (45%)
• Fatigue (39%)
• Decreased hemoglobin (37%)
• Decreased lymphocytes (32%)
• Increased AST (30%)
• Rash (28%)
• Increased ALT (26%)
• Pruritus (25%)
• Diarrhea (24%)
• Decreased sodium (24%)
• Increased alkaline phosphatase (19%)
• Increased creatinine (19%)
• Headache (18%)
• Nausea (17%)
• Hypothyroidism (17%)
• Decreased appetite (15%)
• Cough (15%)
• Vitiligo (<15%)
• Adrenal sufficiency (<15%)
• Myocarditis (<15%)
• Hepatitis (<15%)

1-10%

Grade 3-4

• Musculoskeletal pain (4.2%)
• Increased ALT (3.2%)
• Decreased hemoglobin (2.7%)
• Decreased lymphocytes (2.5%)
• Increased AST (2.3%)
• Fatigue (2%)
• Diarrhea (2%)
• Rash (1.4%)
• Decreased sodium (1.2%)

<1%

Grade 3-4

• Nausea (0.6%)
• Decreased appetite (0.6%)
• Increased alkaline phosphatase (0.6%)
• Headache (0.3%)
• Cough (0.3%)

Contraindications

None

Cautions

Severe infusion-related reactions can occur; discontinue if severe or life-threatening infusion reactions occurs

Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with a PD-1/PD-L1 receptor blocking antibody; closely monitor for evidence of GVHD and intervene promptly; consider benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody after allogeneic HSCT

May cause fetal harm when administered to pregnant females

Immune-mediated adverse reactions

• Immune-mediated adverse reactions (IMARs), which may be severe or fatal, can occur
• IMARs can manifest during treatment and after discontinuation
• Closely monitor for symptoms and signs that may be clinical manifestations of underlying IMARs; evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment
• If IMARs are suspected, initiate appropriate workup to exclude alternative etiologies, including infection; promptly institute medical management, including specialty consultation as appropriate
• May cause immune-mediated pneumonitis; incidence of pneumonitis is higher in patients who have received prior thoracic radiation and treated with other PD-1/PD-L1 blocking antibodies
• Immune-mediated encephalitis can occur; withhold therapy in patients with new-onset moderate-to-severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate-to-severe neurologic deterioration
• Other clinically significant and potentially fatal IMARs (eg, myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, hepatitis, nephritis) can occur after discontinuation

• Immune-mediated endocrinopathies

  • Immune-mediated hypophysitis; monitor
  • Immune-mediated hypothyroidism and hyperthyroidism reported; monitor for changes in thyroid function and initiate thyroid hormone replacement as needed; administer hormone replacement therapy for hypothyroidism; initiate medical management for control of hyperthyroidism
  • Adrenal insufficiency may occur; monitor for signs and symptoms of adrenal insufficiency during and after treatment
  • May cause type 1 diabetes mellitus; monitor for hyperglycemia
  • Hypothyroidism can follow hyperthyroidism
  • Thyroiditis may not lead to permanent discontinuation and may be reinitiated after symptoms improvement without reoccurrence
  • Type 1 diabetes mellitus may present with diabetic ketoacidosis; initiate treatment with insulin as clinically indicated

• Immune-mediated skin reactions

  • May cause immune-mediated rash, including SJS, and TEN; for symptoms or signs of SJS or TEN, withhold therapy and refer patient for specialized care for assessment and treatment

• Immune-mediated colitis

  • Immune-mediated colitis reported, defined as requiring use of corticosteroids and no clear alternate etiology; common symptom in definition of colitis reported to be diarrhea
  • Cytomegalovirus infection/reactivation also reported in patients with corticosteroid-refractory immune-mediated colitis
  • For corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies

Pregnancy

Based on mechanism of action, fetal harm may occur when administered to pregnant females

No data are available on use in pregnant females to evaluate drug-associated risks

Advise patients of potential risks to fetus

Verify pregnancy status before initiating

Human IgG4 is known to cross the placenta; therefore, nivolumab and relatlimab may transmit from mother to developing fetus; effects are likely to be greater during second and third trimesters of pregnancy

Contraception

• Females of reproductive potential: Use effective contraception during treatment with nivolumab and for at least 5 months following last dose of therapy

Animal data

• Nivolumab: IV administration (administered twice weekly during organogenesis) in monkeys resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death
• Relatlimab: No animal data are available; when anti-LAG-3 antibodies were administered beginning on gestation day 6 in mice using syngeneic and allogeneic breeding models, no maternal or developmental effects were observed

Lactation

There are no data on presence of nivolumab and relatlimab in human milk, effects on breastfed infants, or effects on milk production

Advise patients not to breastfeed during treatment and for at least 5 months after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Combination results in increased T-cell activation compared to activity of either antibody alone

Relatlimab

• Human IgG4 monoclonal antibody that binds to lymphocyte activation gene-3 (LAG-3), blocks interaction with its ligands, including MHC II, and reduces LAG-3 pathway-mediated inhibition of the immune response
• Antagonism of this pathway promotes T cell proliferation and cytokine secretion

Nivolumab

• Human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD -L2, and reduces PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response
• Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production; 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

Absorption

Peak plasma concentration at steady-state

• Relatlimab: 62.2 mcg/mL
• Nivolumab: 187 mcg/mL

Steady-state reached at

• Relatlimab: 16 weeks

Distribution

Vd (steady-state)

• Relatlimab: 6.6 L
• Nivolumab: 6.6 L

Elimination

Clearance (steady-state)

• Relatlimab: 5.5 mL/hr
• Nivolumab: 7.6 mL/hr

Half- life

• Relatlimab: 26.2 days
• Nivolumab: 26.5 days

IV Incompatibilities

Do not coadminister other drugs through same IV line

IV Compatibilities

Diluted solutions

• 0.9% NaCl
• Dextrose 5% (D5W)

Compatible IV bags

• Di(2-ethylhexyl)phthalate (DEHP)-plasticized polyvinyl chloride (PVC)
• Ethyl vinyl acetate (EVA)
• Polyolefin (PO)

IV Preparation

Visually inspect vial for particulate matter and discoloration before administering; solution is a clear to opalescent, colorless to slightly yellow solution; discard if solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white particles

Use aseptic technique to assure sterility as product has no preservatives

Can be administered diluted or undiluted

Further dilution

• Withdraw required drug volume and transfer into an 0.9% NaCl or D5W infusion bag; drug is compatible with DEHP-PVC, EVA, or PO IV bags
• Mix by gentle inversion; do not shake
• Discard any used or empty vials remaining

Final concentration and maximum infusion volumes by patient group

• ≥12 years and ≥40 kg: Up to 160 mL of 0.9% NaCl or D5W
• Adults who weigh <40 kg: 4 mL/kg  
• Nivolumab concentration range: 3-12 mg/mL
• Relatlimab concentration range: 1-4 mg/mL
• 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

IV Administration

Infuse over 30 minutes through an IV line containing sterile, nonpyrogenic, low-protein binding in-line polyethersulfone, nylon, or polyvinylidene fluoride filter (pore size: 0.2-1.2 micrometer)

Flush IV line at end of infusion

Do not coadminister other drugs through same IV line

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF); do NOT freeze
• Protect from light

Diluted solution

• Protect from light
• Expiration time includes from preparation time, time for equilibration of infusion bag to room temperature, and duration of infusion
• Store at room temperature and room light for ≤8 hr; discard if not used within 8 hr, OR
• Refrigerate at 2-8°C (36-46°F) for up to 24 hr; do NOT freeze; discard prepared solution if not used within 24 hr