Nivolumab Immunotherapy (OPDIVO) For Solid Tumors: Indication, Side Effect & Mechanism of Action

Nivolumab a-k-a OPDIVO is a FDA-approved checkpoint inhibitor drug for the treatment of a subset of cancer types. 

It is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. 

Indication of Nivolumab Immunotherapy

Nivolumab (OPDIVO) is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of: 

  • Patients with BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent.  
  • Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent.
  • Patients with unresectable or metastatic melanoma, in combination with ipilimumab.
  • Patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting.
  • Patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. 
  • Patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. 
  • Patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with ipilimumab. 
  • Adult patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or more lines of systemic therapy that includes autologous HSCT
  • Patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy
  • Patients with locally advanced or metastatic urothelial carcinoma who
    • have disease progression during or following platinum-containing chemotherapy 
    • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
    • adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
    • patients with hepatocellular carcinoma who have been previously treated with sorafenib

Side Effects & Warnings of Nivolumab

Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis.

 Immune-mediated colitis: Withhold OPDIVO when given as a single agent for moderate or severe and permanently discontinue for life-threatening colitis. Withhold OPDIVO when given with ipilimumab for moderate and permanently discontinue for severe or life-threatening colitis.

Immune-mediate hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation.

Immune-mediated endocrinopathies: Withhold for moderate or severe and permanently discontinue for life-threatening hypophysitis. Withhold for moderate and permanently discontinue for severe or life-threatening adrenal insufficiency. Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. Monitor for hyperglycemia. Withhold for severe and permanently discontinue for life-threatening hyperglycemia. 

Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation. (5.5)  Immune-mediated skin adverse reactions: Withhold for severe and permanently discontinue for life-threatening rash. 

Immune-mediated encephalitis: Monitor for changes in neurologic function. Withhold for new-onset moderate to severe neurological signs or symptoms and permanently discontinue for immune-mediated encephalitis.

Infusion reactions: Discontinue OPDIVO for severe and life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 

Complications of allogeneic HSCT after OPDIVO: Monitor for hyperacute graft-versus-host-disease (GVHD), grade 3-4 acute GVHD, steroid requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. Transplant-related mortality has occurred.

Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception.

Adverse Reaction associated with Nivolumab

Most common adverse reactions (20%) in patients were: 

OPDIVO as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain. 

OPDIVO with ipilimumab for melanoma: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. 

OPDIVO with ipilimumab for renal cell carcinoma: fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite


Formulation of Nivolumab/OPDIVO: 

It is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.


Mechanism of Action of Nivolumab

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits Tcell 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. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity. 

Pharmacokinetics of Nivolumab: 

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent OPDIVO and OPDIVO with ipilimumab. OPDIVO as a single agent: The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO as a 60- minute intravenous infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady-state. The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. OPDIVO with ipilimumab: When OPDIVO 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29%, and the CL of ipilimumab was unchanged. When OPDIVO 3 mg/kg was administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab and ipilimumab were unchanged. When administered in combination, the CL of nivolumab increased by 20% in the presence of antinivolumab antibodies and the CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies. 

Formulations of Nivolumab:

OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.

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