Nivolumab (Opdivo)

Indications for Programmed Cell Death 1 (PD-1) Checkpoint Inhibitors

Castration-Resistant Prostate Cancer (see Prostate Cancer, Prostate Cancer)

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Colorectal Cancer (see Colorectal Cancer, Colorectal Cancer)

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Melanoma (see Melanoma, Melanoma)

Non-Small Cell Lung Cancer with Progression On/After Platinum-Based Chemotherapy (see Lung Cancer, Lung Cancer)

  • FDA Approval: nivolumab has been FDA-approved for both squamous and non-squamous non-small cell lung cancers
  • Patient with EGFR or ALK Mutations: need to have demonstrated disease progression (on approved EGFR or ALK-directed therapy) prior to receiving nivolumab

Renal Cell Carcinoma with Prior Anti-Angiogenic Therapy (see Renal Cancer, Renal Cancer)

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Pharmacology

Background

  • Programmed Cell Death 1 (PD-1) Checkpoint Inhibitor (see PD-1 Checkpoint Inhibitors, PD-1 Checkpoint Inhibitors): PD-1 is a key immune-checkpoint receptor expressed by activated T cells –> it mediates immunosuppression
    • T-Cells Encounter the Immunosuppressive PD-1 Ligands, PD-L1 (B7-H1) and PD- L2 (B7-DC), Which are Expressed by Tumor Cells and/or Stromal Cells

Mechanism of Action of Nivolumab

  • Nivolumab is a Fully Human IgG4 Monoclonal Antibody Which Binds to the PD-1 Receptor (Blocking the PD-L1 and PD-L2 Ligands from Binding): inhibition of the interaction between PD-1 and PD-L1 enhances T-cell responses in vitro and mediates anti-tumor activity
    • Combining Nivolumab with Ipilimumab (Anti-CTLA-4) Results in Even More Enhanced T-Cell Function Than Each Agent Alone (see Ipilimumab, Ipilimumab): improves anti-tumor response in metastatic melanoma

Metabolism

  • Elimination Half-Life (When Nivolumab is Administered Alone): 27 days
    • Elimination Half-Life (When Nivolumab is Administered with Ipilimumab): 25 days

Administration

  • IV

Dose Adjustment

  • Hepatic
    • Hepatic Impairment Prior to Initiation
      • Mild Impairment: no dosage adjustment necessary
      • Moderate Impairment: has not been studied
    • Hepatic Impairment During Treatment: see below
      • AST or ALT >5x Upper Limit of Normal or Total Bilirubin >3x Upper Limit of Normal: permanently discontinue nivolumab
  • Renal
    • Renal Impairment Prior to Initiation: no renal dose adjustment necessary
    • Renal Impairment During Treatment: see below

Adverse Effects

Dermatologic Adverse Effects

Pruritus (see Pruritus, Pruritus)

  • Epidemiology: occurs in 11-23% of cases

Rash

  • Epidemiology: occurs in 9-40% of cases
  • Management
    • Grade 4 Rash: discontinue nivolumab permanently and administer high-dose corticosteroids (see <a href=“http://mdnxs.com/topics-2/pharmacology/corticosteroids/” title=“C

Vitiligo (see Vitiligo, Vitiligo)

  • Epidemiology: occurs in <11% of cases

Endocrinologic Adverse Effects

Adrenal insufficiency (see Adrenal insufficiency, Adrenal insufficiency)

  • Epidemiology: occurs in <2% of cases
    • Median time to onset 3-5.8 mo (range: 15 days to 20.9 mo)
  • Management
    • Grade 2 Adrenal Insufficiency: discontinue nivolumab (and ipilimumab, if also being given)
    • Grade 3-4 Adrenal Insufficiency: discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids, Corticosteroids)

Diabetes Mellitus (DM) (see Diabetes Mellitus, Diabetes Mellitus)

  • Epidemiology: occurs in <2% of cases
    • Median time of onset 1.3-21.8 mo
  • Management
    • Type I Diabetes Mellitus: discontinue nivolumab permanently

Hyperthyroidism (see Hyperthyroidism, Hyperthyroidism)

  • Epidemiology: occurs in 1-4% of cases

Hypertriglyceridemia (see Hypertriglyceridemia, Hypertriglyceridemia)

  • Epidemiology: occurs in 32% of cases

Hypophysitis

  • Epidemiology: may occur
    • Median Latency to Onset: 27 days-11 mo
  • Management

Hypothyroidism (see Hypothyroidism, Hypothyroidism)

  • Epidemiology: occurs in 7-9% of cases
    • Median Latency to Onset: 2-5 mo (range: 1 day-13.8 mo)

Thyroiditis (see Thyroiditis, Thyroiditis)

  • Epidemiology: may occur

Gastrointestinal/Hepatic Adverse Effects

Anorexia (see Anorexia, Anorexia)

  • Epidemiology: occurs in 23-29% of cases

Colitis (see Colitis, Colitis)

  • Management
    • Grade 3 Colitis/Diarrhea (If Used with Ipilimumab): discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids, Corticosteroids)
    • Grade 4 Colitis/Diarrhea (If Used without Ipilimumab): discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids, Corticosteroids)

Constipation (see Constipation, Constipation)

  • Epidemiology: occurs in 23% of cases

Diarrhea (see Diarrhea, Diarrhea)

  • Management
    • Grade 3 Colitis/Diarrhea (If Used with Ipilimumab): discontinue nivolumab permanently
    • Grade 4 Colitis/Diarrhea (If Used without Ipilimumab): discontinue nivolumab permanently

Hepatitis (see Drug-Induced Hepatotoxicity, Drug-Induced Hepatotoxicity)

  • Management
    • AST or ALT >3-5x Upper Limit of Normal or Total Bilirubin >1-5-3x Upper Limit of Normal: withhold nivolumab –> may resume nivolumab upon recovery to grade 0-1 toxicity

Nausea/Vomiting (see Nausea and Vomiting, Nausea and Vomiting)

  • Epidemiology: nausea occurs in 28% of cases, vomiting occurs in 16-17% of cases

Hematologic Adverse Effects

Anemia (see Anemia, Anemia)

  • Epidemiology: occurs in 39% of cases

Lymphocytopenia

  • Epidemiology: occurs in 42% of cases

Neurologic Adverse Effects

Fatigue (see Fatigue, Fatigue)

  • Epidemiology: occurs in 49-56% of cases

Headache (see Headache, Headache)

  • Epidemiology: may occur

Immune-Mediated Encephalitis (see Encephalitis, Encephalitis)

  • Epidemiology: may occur
  • Management: discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids, Corticosteroids)

Pulmonary Adverse Effects

Pulmonary Toxicity

Renal Adverse Effects

Acute Kidney Injury (AKI) (see Acute Kidney Injury, Acute Kidney Injury)

  • Epidemiology: occurs in 11-42% of cases
  • Management
    • Cr >1.5-6x Upper Limit of Normal: withhold nivolumab, administer corticosteroids (with taper) –> may resume nivolumab upon recovery to grade 0-1 toxicity
    • Cr >6x Upper Limit of Normal: permanently discontinue nivolumab

Hypercalcemia (see Hypercalcemia, Hypercalcemia)

  • Epidemiology: occurs in 19% of cases

Hypocalcemia (see Hypocalcemia, Hypocalcemia)

  • Epidemiology: occurs in 13-23% of cases

Hyponatremia (see Hyponatremia, Hyponatremia)

  • Epidemiology: occurs in 20-35% of cases

Rheumatologic Adverse Effects

Peripheral Edema (see Peripheral Edema, Peripheral Edema)

  • Epidemiology: occurs in 12% of cases

Other Adverse Effects

Fever (see Fever, Fever)

  • Epidemiology: occurs in 17% of cases

References

  • Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2 [MEDLINE]
  • Anti-PD-1-Related Pneumonitis during Cancer Immunotherapy. N Engl J Med. 2015 Jul 16;373(3):288-90. doi: 10.1056/NEJMc1505197 [MEDLINE]