Pembrolizumab

Mechanism of Action

Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2

PD-1 and PD-L1

• PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions; PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound
• This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
• Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells

Pharmacokinetics

Steady-state concentration reached by 18 weeks of q3wk dosing

Half-life: 26 days

Clearance: 0.22 L/day

Pembrolizumab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Pembrolizumab is used to treat:

• advanced skin cancer (melanoma) that has spread to other parts of the body or cannot be surgically removed;

• a certain type of non-small cell lung cancer, if your tumor has a specific genetic marker for which your doctor will test;

• head and neck cancer that has spread to other parts of the body, or has come back after prior treatment;

• classical Hodgkin lymphoma in adults and children;

• a certain type of bladder and urinary tract cancer that has spread to other parts of the body or cannot be surgically removed; and

• a type of cancer that laboratory testing proves to be a microsatellite instability-high or a mismatch repair deficiency solid tumor.

Pembrolizumab is often given after other cancer medicine has been tried without success.

Pembrolizumab was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis to treat lung cancer or head and neck cancer. In clinical studies, tumors responded to this medicine. However, it has not been shown that pembrolizumab can improve symptoms or lengthen survival time.

Pembrolizumab may also be used for purposes not listed in this medication guide.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Pembrolizumab powder for injection must be reconstituted and diluted prior to administration.1 (See Storage under Stability.)

Do not infuse simultaneously through the same IV line with other drugs.1

Administer using a sterile, nonpyrogenic, low-protein-binding 0.2- to 5-μm inline or add-on filter.1

Reconstitute vial containing 50 mg of pembrolizumab with 2.3 mL of sterile water for injection to provide a solution containing 25 mg/mL; direct diluent toward wall of vial.1 Gently swirl vial to ensure dissolution.1 Allow solution to stand for up to 5 minutes to let bubbles dissipate.1 Do not shake reconstituted solution.1

Reconstituted solution should be clear to slightly opalescent and colorless to slightly yellow.1 Do not use if foreign particles other than translucent to white proteinaceous particles are present.1

Dilute appropriate dose in a sufficient volume of 0.9% sodium chloride injection to yield a final concentration of 1–10 mg/mL.1 Mix the diluted solution by gentle inversion.1 Discard any partially used vials.1

Administer by IV infusion over 30 minutes.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adults

2 mg/kg every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Discontinue therapy in patients experiencing any life-threatening immune-mediated adverse effect, patients with persistent grade 2 or 3 immune-mediated adverse effects that do not recover to grade 0 or 1 within 12 weeks of the last dose of pembrolizumab, and those unable to reduce corticosteroid dosage to ≤10 mg of prednisone (or equivalent) daily within 12 weeks.1 (See Warnings/Precautions under Cautions.)

Discontinue therapy if severe or grade 3 immune-mediated adverse effects recur.1

If grade 2 immune-mediated pneumonitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Pneumonitis under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, discontinue drug.1

If grade 2 or 3 immune-mediated colitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis occurs, discontinue drug.1

For ALT or AST concentrations >3 to 5 times the ULN or total bilirubin concentrations >1.5 to 3 times the ULN, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Hepatic Effects under Cautions.)

For ALT or AST concentrations >5 times the ULN or total bilirubin concentrations >3 times the ULN, discontinue drug.1

If ALT or AST concentration increases by ≥50% from baseline for ≥1 week in patients with liver metastasis and baseline grade 2 serum aminotransferase elevations, discontinue drug.1

If symptomatic or grade 2 immune-mediated hypophysitis or grade 3 immune-mediated hyperthyroidism occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Endocrine Effects under Cautions.)

If grade 3 immune-mediated hypophysitis occurs, interrupt therapy or discontinue drug.1

If grade 4 immune-mediated hyperthyroidism or hypophysitis occurs, discontinue drug.1

If grade 2 immune-mediated nephritis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Renal Effects under Cautions.)

If grade 3 or 4 immune-mediated nephritis occurs, discontinue drug.1

If grade 3 or 4 infusion-related reactions occur, discontinue drug.1

If any other severe or grade 3 immune-mediated adverse effects occur, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Other Immune-mediated Effects under Cautions.)

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment: No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Moderate or severe preexisting hepatic impairment: Not studied; no dosage recommendations at this time.1

Renal Impairment

Mild, moderate, or severe preexisting renal impairment: No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No special dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

For all uses of pembrolizumab:

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may cause very bad side effects. Sometimes these may be life-threatening. These may happen in the lungs, bowels, liver, kidney, pituitary gland, thyroid gland, or other parts of the body. Talk with the doctor.
• If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
• Check your blood sugar as you have been told by your doctor.
• Tell your doctor if you have signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Call your doctor right away if you have signs of thyroid, pituitary, or adrenal gland problems. Some signs may be change in mood or the way you act, change in weight, constipation, deeper voice, dizziness, fainting, feeling cold, feeling very tired, hair loss, headache that lasts or is very bad, or lowered interest in sex.
• Infusion reactions have happened with pembrolizumab. Sometimes, these could be very bad or life-threatening. Talk with the doctor.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• If you have had an organ transplant, talk with your doctor. This medicine may raise the chance of organ transplant rejection.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• If you are a female, use birth control that you can trust to prevent pregnancy while taking this medicine and for 4 months after your last dose.
• If you get pregnant while taking pembrolizumab or within 4 months after your last dose, call your doctor right away.

For lymphoma:

• If you are having a stem cell transplant, talk with your doctor. Some problems with stem cell transplants using stem cells from someone else (allogeneic) have happened after treatment with this medicine. These problems can be very bad and can lead to death.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about pembrolizumab, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about pembrolizumab. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using pembrolizumab.

Review Date: October 4, 2017

(pem broe LIZ ue mab)

Merkel cell carcinoma (advanced)

Data from a small noncontrolled phase II study supports the use of pembrolizumab in the treatment of advanced merkel cell carcinoma [Nghiem 2016]. Additional trials may be necessary to further define the role of pembrolizumab in this condition.

Withhold treatment for any of the following (may resume upon recovery to grade 0 or 1 toxicity):

Colitis, moderate (grade 2) or severe (grade 3); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Dermatologic toxicity: Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

Endocrinopathies:

Hyperglycemia, severe; also administer antihyperglycemics.

Hyperthyroidism, severe (grade 3) or life threatening (grade 4); manage with thionamides and beta-blockers as appropriate.

Hypophysitis, grade 2 (symptomatic); also administer corticosteroids (followed by a taper) and hormone replacement therapy if appropriate.

Hematologic toxicity, grade 4 (in patients with classical Hodgkin lymphoma)

Nephritis, grade 2; also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Pneumonitis, moderate (grade 2); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Other treatment-related toxicity, severe or grade 3; may require corticosteroids (based on severity). Upon improvement to grade 0 or 1, initiate corticosteroid taper and continue to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at grade 0 or 1 following corticosteroid taper. May consider other systemic immunosuppressants if not controlled by corticosteroids (based on limited data).

Withhold (may resume upon recovery to grade 0 or 1 toxicity) or discontinue for:

Hyperthyroidism, severe (grade 3) or life-threatening (grade 4); manage with thionamides and beta-blockers as appropriate.

Hypophysitis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids and hormone replacement as appropriate.

Permanently discontinue for:

Adverse reactions that are life-threatening (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity [in patients with classical Hodgkin lymphoma]), persistent grade 2 or 3 adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy) that does not recover to grade 0 or 1 within 12 weeks after the last pembrolizumab dose, or any recurrent severe or grade 3 treatment-related adverse reaction. Also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Colitis, life-threatening (grade 4); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Dermatologic toxicity: Grade 4 severe skin reactions or confirmed SJS or TEN.

Immune mediated adverse reactions: Discontinue permanently if unable to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks.

Infusion-related reaction, grade 3 or 4.

Nephritis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Pneumonitis, severe (grade 3), life-threatening (grade 4), or moderate (grade 2) that recurs; also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

There are no known significant interactions.

200 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Comments:
-When administering this drug in combination with chemotherapy, it should be administered prior to chemotherapy when given on the same day.

Uses:
-As a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] 50% or greater) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations
-As a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1% or greater) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving this drug
-In combination with pemetrexed and carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC

200 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Use: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy

200 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Uses: For the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

200 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Uses: For the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

See DOSE ADJUSTMENTS.