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

• Castration-Resistant Prostate Cancer (see Prostate Cancer, [[Prostate Cancer]])
• Colorectal Cancer (see Colorectal Cancer, [[Colorectal Cancer]])
• Melanoma (see Melanoma, [[Melanoma]])
  • Pembrolizumab (Keytruda) Has Been FDA Approved (see Pembrolizumab, [[Pembrolizumab]])
• Non-Small Cell Lung Cancer with Progression On/After Platinum-Based Chemotherapy (see Lung Cancer, [[Lung Cancer]])
  • Nivolumab Has Been FDA-approved for Both Squamous and Non-Squamous Non-Small Cell Lung Cancers
• Renal Cell Carcinoma (see Renal Cancer, [[Renal Cancer]])

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Pharmacology

• 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
  • Pembrolizumab is a Monoclonal Antibody Against PD-1: inhibition of the interaction between PD-1 and PD-L1 enhances T-cell responses in vitro and mediates anti-tumor activity

Metabolism

• xxxx

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Administration

• xxxx

Dose Adjustment

• Hepatic:
• Renal:

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Adverse Effects

Dermatologic Adverse Effects

• Pruritus (see Pruritus, [[Pruritus]])
• Rash
• Vitiligo (see Vitiligo, [[Vitiligo]])

Endocrinologic Adverse Effects

• Hypophysitis
• Thyroiditis

Gastrointestinal/Hepatic Adverse Effects

• Anorexia (see Anorexia, [[Anorexia]])
• Colitis (see Colitis, [[Colitis]])
• Constipation (see Constipation, [[Constipation]])
• Diarrhea (see Diarrhea, [[Diarrhea]])
• Hepatitis (see xxxx, [[xxxx]])
• Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])

Neurologic Adverse Effects

• Fatigue (see Fatigue, [[Fatigue]])
• Headache (see Headache, [[Headache]])

Pulmonary Adverse Effects

Pulmonary Toxicity

• Epidemiology
  • Time of Onset: onset of pneumonitis occurs 7.4-24.3 months after the initiation of therapy
• Physiology: immune-mediated toxic effect
• Clinical Patterns
  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
    • Drug-related deaths have been reported in phase 1 trials
  • Pneumonia see Pneumonia, [[Pneumonia]])
  • Interstitial Pneumonia (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])
• Treatment: corticosteroids (see Corticosteroids, [[Corticosteroids]])

Other Adverse Effects

• Fever (see Fever, [[Fever]])

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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]