pembrolizumab

General

Genetic Implications: Genetic Implications

Pronunciation:
pem-broe-li-zoo-mab


Trade Name(s)

  • Keytruda

Ther. Class.
antineoplastics

Pharm. Class.
monoclonal antibodies
programmed death-1 inhibitors

Indications

  • Unresectable or metastatic melanoma.
  • Adjuvant treatment of melanoma with involvement of lymph node(s) following complete resection.
  • Genetic implication  First-line treatment of patients with stage III non-small cell lung cancer (NSCLC), who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) and have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations (as monotherapy).
  • Genetic implication Metastatic NSCLC expressing PD-L1 (TPS ≥1%) that has progressed on or after platinum-containing chemotherapy (as monotherapy). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
  • First-line treatment of metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (in combination with pemetrexed and platinum chemotherapy).
  • Metastatic small-cell lung cancer (SCLC) that has progressed on or after platinum-containing chemotherapy and ≥1 other previous line of therapy.
  • First-line treatment of metastatic non-squamous NSCLC (in combination with carboplatin and either paclitaxel or nab-paclitaxel [albumin-bound]).
  • Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed on or after platinum-containing chemotherapy.
  • First-line treatment of metastatic or unresectable, recurrent HNSCC (in combination with platinum and fluorouracil).
  • Genetic implication First-line treatment of metastatic or unresectable, recurrent HNSCC expressing PD-L1 (combined positve score [CPS] ≥1).
  • Refractory classical Hodgkin lymphoma (cHL) in patients who have relapsed after ≥3 prior lines of therapy.
  • Genetic implication Locally advanced or metastatic urothelial carcinoma in patients whose tumors express PD-L1 (CPS ≥10) and who are not eligible for cisplatin-containing chemotherapy or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
  • Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or within 12 mo of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • Unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.
  • Unresectable or metastatic, MSI-H, or mismatch repair deficient colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  • Genetic implication  Recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1) that has progressed on or after ≥2 prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
  • Genetic implication Recurrent or metastatic cervical cancer expressing PD-L1 (CPS ≥1) that has progressed on or after chemotherapy.
  • Refractory primary mediastinal large B-cell lymphoma in patients who have relapsed after ≥2 prior lines of therapy (should not be used in patients who require urgent cytoreductive therapy).
  • Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
  • Recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).
  • First-line treatment of advanced renal cell carcinoma (RCC) (in combination with axitinib).
  • Genetic implication Recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus expressing PD-L1 (CPS ≥10) that has progressed after ≥1 prior lines of systemic therapy.
  • Advanced endometrial carcinoma that is not MSI-H or dMMR in patients who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation (in combination with lenvatinib).

Action

Programmed death (PD) receptor-1–blocking antibody (an IgG4 kappa immunoglobulin) that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 resulting in inhibition of T-cell proliferation and decreased cytokine production.

Therapeutic Effect(s):

Decreased spread of melanoma, NSCLC, SCLC, HNSCC, cHL, urothelial carcinoma, MSI-H, gastric tumors, cervical cancer, endometrial cancer, esophageal cancer, primary mediastinal large B-cell lymphoma, HCC, MCC, and RCC.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism and Excretion: Unknown.

Half-life: 26 days.

TIME/ACTION PROFILE (response)

ROUTEONSETPEAKDURATION
IVwithin 3 mounknownmay persist for >8.8 mo

Contraindication/Precautions

Contraindicated in:

  • OB:  Pregnancy (may cause fetal harm);
  • Lactation: Discontinue pembrolizumab or discontinue breast feeding.

Use Cautiously in:

  • Moderate to severe hepatic impairment;
  • Solid organ transplant recipients (may ↑ risk of rejection);
  • Rep:  Women of reproductive potential;
  • Pedi:  Children <2 yr (safety and effectiveness not established for cHL, MSI-H cancer, primary mediastinal large B-Cell lymphoma, or MCC); Children <18 yr (safety and effectiveness not established for all other indications);
  • Pedi:  Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: dizziness, fatigue, headache, insomnia

Derm: BULLOUS PEMPHIGOID, EXFOLIATIVE DERMATITIS, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, pruritus, rash, immune-mediated dermatitis, vitiligo

EENT: immune-mediated optic neuritis

Endo: IMMUNE-MEDIATED HYPOPHYSITIS, immune-mediated hypothyroidism, immune-mediated hyperthyroidism, immune-mediated type 1 diabetes

GI: IMMUNE-MEDIATED COLITIS, IMMUNE-MEDIATED HEPATITIS, ↓ appetite, constipation, diarrhea, nausea

GU: IMMUNE-MEDIATED NEPHRITIS

Hemat: anemia

MS: IMMUNE-MEDIATED RHABDOMYOLYSIS, arthralgia, back pain, extremity pain, myalgia, immune-mediated myasthenic syndrome

Resp: IMMUNE-MEDIATED PNEUMONITIS

Misc: INFUSION-RELATED REACTIONS, SEPSIS

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

None noted.

Route/Dosage

Melanoma

IV (Adults): 200 mg every 3 wk until disease progression or unacceptable toxicity;  Adjuvant treatment– 200 mg every 3 wk until disease recurrence, unacceptable toxicity, or up to 12 mo in patients without disease recurrence.

NSCLC or HNSCC

IV (Adults): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo in patients without disease progression. If being administered in combination with chemotherapy, should be administered prior to chemotherapy when given on the same day.

SCLC, Urothelial Carcinoma, Gastric Cancer, Cervical Cancer, Endometrial Carcinoma, Esophageal Cancer, HCC, or RCC

IV (Adults): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo in patients without disease progression.

cHL, MSI-H Cancer, Primary Mediastinal Large B-Cell Lymphoma, or MCC

IV (Adults): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo in patients without disease progression.

IV (Children ≥2 yr): 2 mg/kg (max = 200 mg) every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo in patients without disease progression.

Availability

Lyophilized powder for injection (requires reconstitution and dilution): 50 mg/vial

Solution for injection: 25 mg/mL

Assessment

  • Monitor for signs and symptoms of immune-mediated pneumonitis (shortness of breath, chest pain, new or worse cough) periodically during therapy. Evaluate with x-ray. Treat with corticosteroids for ≥Grade 2 pneumonitis.  If Grade 2 immune-mediated pneumonitis occurs,  hold pembrolizumab. Resume therapy in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.  If Grades 3 or 4 or recurrent Grade 2 occur,  permanently discontinue therapy.
  • Monitor for signs and symptoms of colitis (diarrhea, abdominal pain, mucus or blood in stool, with or without fever).   If Grades 2 or 3 immune-mediated colitis occur,  hold dose. Resume therapy in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.  If Grade 4 occurs,  permanently discontinue pembrolizumab.
  • Assess for signs and symptoms of immune-mediated hepatitis (yellowing of skin or whites of eyes, unusual darkening of urine, unusual tiredness, pain in right upper stomach) before each dose.  If AST or ALT ≥5 times upper limit of normal (ULN) if baseline <2 times ULN; AST or ALT >3 times baseline if baseline ≥2 times ULN; total bilirubin >2.0 mg/dL if baseline <1.5 mg/dL; or total bilirubin >3.0 mg/dL, regardless of baseline levels occur in patients with hepatocellular carcinoma,  hold dose. Resume therapy in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.  If ALT or AST >10 times ULN; or Child-Pugh score greater ≥9 points; gastrointestinal bleeding suggestive of portal hypertension; or new onset of clinically detectable ascites; or encephalopathy occur in patients with hepatocellular carcinoma,  permanently discontinue pembrolizumab.  If AST or ALT >3 but ≥5 times ULN or total bilirubin >1.5 but ≥3 times ULN in patients without hepatocellular carcinoma occurs,  hold dose. Resume therapy in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.  If in patients without liver metastases, AST or ALT >5 times ULN or total bilirubin >3 times ULN or in patients with liver metastasis and Grade 2 AST or ALT at baseline, with an increase in AST or ALT of 50% or more relative to baseline that persists for at least 1 wk occurs,  permanently discontinue pembrolizumab.
  • Monitor for signs and symptoms of infusion-related reactions (rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, fever).  If Grades 1 or 2 infusion-related reactions occur,  hold or slow rate of infusion.  If Grades 3 or 4 reactions occur,  stop infusion and permanently discontinue therapy.
  • Monitor for clinical signs and symptoms of hypophysitis (persistent or unusual headache, extreme weakness, dizziness or fainting, vision changes) during therapy.  If Grade 3 or 4 immune-mediated endocrinopathies occur,  hold dose until clinically stable.
  • Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome or toxic epidermal necrolysis. If Grade 3 or suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN) occurs, hold dose. If Grade 4 or confirmed SJS or TEN occur, permanently discontinue therapy.

Lab Test Considerations:

Obtain a negative pregnancy test prior to starting therapy.

Monitor for changes in renal function. Treat with corticosteroids for ≥Grade 2 nephritis. If Grade 2 nephritis occurs, hold dose. Resume therapy in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. If Grade 3 or 4 nephritis occurs, permanently discontinue therapy.
  • Monitor for changes in thyroid function at start of and periodically during therapy, and as indicated based on clinical evaluation. Administer corticosteroids for ≥Grade 3 hyperthyroidism, withhold pembrolizumab for severe (Grade 3) hyperthyroidism and resume therapy when recovery to Grade 0 to 1. Permanently discontinue for life-threatening (Grade 4) hyperthyroidism. Manage hypothyroidism with thyroid replacement without interruption of therapy or corticosteroids.
  • Monitor serum blood glucose. May cause hyperglycemia or other signs and symptoms of diabetes.

Potential Diagnoses

Implementation

IV Administration

  • Intermittent Infusion:  Reconstitute by injecting 2.3 mL of sterile water for injection along vial walls; swirl slowly, do not shake. Allow up to 5 min for bubbles to clear. Solution is clear to slightly opalescent, colorless to slightly yellow; do not administer solution if discolored or contains particulate matter other than translucent to white proteinaceous particles. Solution is stable at room temperature for up to 4 hr and 24 hr if refrigerated. Diluent:   0.9% NaCl. Mix using gently inversion. Concentration: 1 mg/mL to 10 mg/mL.
  • Rate: Infuse through a sterile, non-pyrogenic, low-protein binding 0.2 micron to 0.5 micron in-line or add-on filter over 30 min.
  • Y-Site Incompatibility: Do not administer other drugs through same infusion line.

Patient/Family Teaching

  • Explain purpose of pembrolizumab to patient.
  • Advise patient to notify health care professional immediately if signs and symptoms of pneumonitis, colitis, hepatitis, kidney problems (change in amount or color of urine), hormone gland problems (rapid heart beat, weight loss, increased sweating, weight gain, hair loss, feeling cold, constipation, deepening of voice, muscle aches, dizziness or fainting, persistent or unusual headache) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  Advise female patient of reproductive potential to use highly effective contraception and avoid breast feeding during and for ≥4 mo after last dose; may cause fetal harm.
  • Emphasize importance of keeping scheduled appointments for blood work or other laboratory tests.

Evaluation/Desired Outcomes

Decreased spread of melanoma, NSCLC, SCLC, HNSCC, cHL, urothelial carcinoma, MSI-H, gastric tumors, cervical cancer, endometrial cancer, esophageal cancer, primary mediastinal large B-cell lymphoma, HCC, MCC, and RCC.

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