Nivolumab (Opdivo)

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

Castration-Resistant Prostate Cancer (see Prostate Cancer)

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Colorectal Cancer (see Colorectal Cancer)

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Melanoma (see Melanoma)

FDA-Approved Agents
- Nivolumab (Opdivo)
- Pembrolizumab (Keytruda) (see Pembrolizumab, [[Pembrolizumab]])
Clinical Efficacy
- Trial of Combination Nivolumab + Ipilimumab vs Monotherapy in Untreated Melanoma (NEJM, 2015) [MEDLINE]: among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone
  - In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone

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

FDA Approved Agents
- Nivolumab: approved for both squamous and non-squamous non-small cell lung cancers
Patients 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)

FDA Approved Agents
- Nivolumab

Urothelial Cell Carcinoma (see Urothelial Cell Carcinoma)

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Pharmacology

Background

Nivolumab is an Immune Checkpoint Inhibitor Directed Against the Programmed Cell Death Protein 1 (PD-1) (see Programmed Cell Death Protein 1 Checkpoint Inhibitors): fully human IgG4 monoclonal antibody against PD-1 (receptor), inhibiting interaction of the PD-L1 (B7-H1) and PD-L2 ligands (B7-DC) with PD-1
- PD-1 is a Key Immune-Checkpoint Receptor Expressed by Activated T-Cells: PD-1 mediates immunosuppression
  - Immune Checkpoint Inhibitors Against PD-1 (Nivolumab, Pembrolizumab) (see Pembrolizumab)
- 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
  - Immune Checkpoint Inhibitors Against PD-L1 (Atezolizumab, Durvalumab, Avelumab, and BMS-946559) (see Atezolizumab, Durvalumab, and Avelumab)
- Inhibition of the interaction between PD-1 and PD-L1 enhances T-cell responses in vitro and mediates anti-tumor activity
- Combining Nivolumab with the Immune Checkpoint Inhibitor, Ipilimumab (Anti-CTLA-4), Results in Even More Enhanced T-Cell Function Than Each Agent Alone (see 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

Dosage

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

Cardiovascular Adverse Effects

Autoimmune Myocarditis (see Myocarditis)

Epidemiology
- Cases Have Been Reported with Immune Checkpoint Inhibitors (Neurology, 2017) [MEDLINE] (J Curr Med Chem. 2018) [MEDLINE] (JAMA Oncol, 2018) [MEDLINE] (Cancer Manag Res, 2019) [MEDLINE]
  - Against CTLA-4 (Ipilimumab) (see Ipilimumab)
  - Against PD-1 (Nivolumab, Pembrolizumab) (see Pembrolizumab)
  - Against PD-L1 (Atezolizumab, Durvalumab, Avelumab, and BMS-946559) (see Atezolizumab, Durvalumab, and Avelumab)
Physiology
- PD-1 and PD-L1 Can Be Expressed in Rodent and Human Cardiac Myocytes
Clinical
- Arrhythmias
- Congestive Heart Failure (CHF) (see Congestive Heart Failure)

Heart Block

Epidemiology
- Case Reports (Neurology, 2017) [MEDLINE]

Dermatologic Adverse Effects

Pruritus (see 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 Corticosteroids)

Vitiligo (see Vitiligo)

Epidemiology
- Occurs in <11% of Cases

Endocrinologic Adverse Effects

Adrenal insufficiency (see 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)

Diabetes Mellitus (DM) (see 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)

Epidemiology
- Occurs in 1-4% of Cases

Hypertriglyceridemia (see Hypertriglyceridemia)

Epidemiology
- Occurs in 32% of Cases

Hypophysitis

Epidemiology
- May Occur
- Median Latency to Onset: 27 days-11 mo
Management
- Grade 4 Hypophysitis: discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids)

Hypothyroidism (see Hypothyroidism)

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

Thyroiditis (see Thyroiditis)

Epidemiology: may occur

Gastrointestinal/Hepatic Adverse Effects

Anorexia (see Anorexia)

Epidemiology
- Occurs in 23-29% of Cases

Colitis (see Colitis)

Epidemiology
- Fatal Cases Have Been Reported (JAMA Oncol, 2018) [MEDLINE]
Management
- Grade 3 Colitis/Diarrhea (If Used with Ipilimumab): discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids)
- Grade 4 Colitis/Diarrhea (If Used without Ipilimumab): discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids, [[Corticosteroids]])

Constipation (see Constipation)

Epidemiology
- Occurs in 23% of Cases

Diarrhea (see 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)

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)

Epidemiology
- Nausea Occurs in 28% of Cases
- Vomiting Occurs in 16-17% of Cases

Hematologic Adverse Effects

Anemia (see Anemia)

Epidemiology
- Occurs in 39% of Cases

Lymphocytopenia

Epidemiology
- Occurs in 42% of Cases

Neurologic Adverse Effects

Fatigue (see Fatigue)

Epidemiology
- Occurs in 49-56% of Cases

Headache (see Headache)

Epidemiology: may occur

Immune-Mediated Encephalitis (see Encephalitis)

Epidemiology
- May Occur (JAMA Oncol, 2018) [MEDLINE]
Management
- Discontinue Nivolumab Permanently and Administer High-Dose Corticosteroids (see Corticosteroids)

Myasthenia Gravis (see Myasthenia Gravis)

Epidemiology
- Case Reports (Neurology, 2017) [MEDLINE]

Pulmonary Adverse Effects

Pulmonary Toxicity

Epidemiology
- Median Latency to Onset: 1.6-7.2 mo (range: 2 days-22.3 mo)
Physiology
- Immune-Mediated Toxic Effect
Clinical Patterns
- Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
  - Drug-Related Deaths Have Been Reported in Phase 1 Trials
- Interstitial Pneumonia (see Interstitial Lung Disease)
- Pneumonia (see Pneumonia)
Treatment
- Grade 2 Pneumonitis: administer high-dose corticosteroids (see Corticosteroids)
  - Prednisone (see Prednisone): 1-2 mg/kg/day
- Grade 3-4 Pneumonitis: discontinue nivolumab permanently and administer high-dose corticosteroids (see Corticosteroids)
  - Prednisone (see Prednisone): 1-2 mg/kg/day

Renal Adverse Effects

Acute Kidney Injury (AKI) (see 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)

Epidemiology
- Occurs in 19% of Cases

Hypocalcemia (see Hypocalcemia)

Epidemiology
- Occurs in 13-23% of Cases

Hyponatremia (see Hyponatremia)

Epidemiology
- Occurs in 20-35% of Cases

Rheumatologic Adverse Effects

Myositis (see Myositis)

Epidemiology
- Case Reports (Neurology, 2017) [MEDLINE]

Peripheral Edema (see Peripheral Edema)

Epidemiology
- Occurs in 12% of Cases

Other Adverse Effects

Fever (see 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]
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. 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]
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23 [MEDLINE]
Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016 Jun;60:210-25. doi: 10.1016/j.ejca.2016.02.024 [MEDLINE]
Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017 Sep 12;89(11):1127-1134. doi: 10.1212/WNL.0000000000004359 [MEDLINE]
Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue. J Curr Med Chem. 2018;25(11):1327-1339. doi: 10.2174/0929867324666170407125017 [MEDLINE]
Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018 Dec 1;4(12):1721-1728. doi: 10.1001/jamaoncol.2018.3923 [MEDLINE]
Cardiac toxicity of immune-checkpoint inhibitors: a clinical case of nivolumab-induced myocarditis and review of the evidence and new challenges. Cancer Manag Res. 2019 May 16;11:4541-4548. doi: 10.2147/CMAR.S185202. eCollection 2019 [MEDLINE]