KEYTRUDA® (pembrolizumab)

KEYTRUDA® (pembrolizumab) injection

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KEYTRUDA® (pembrolizumab)

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

Indications and usage

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:

Melanoma

  • for the treatment of patients with unresectable or metastatic melanoma.
  • for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer (NSCLC)

  • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.
  • in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC.
  • as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic
  • as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) 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 KEYTRUDA.

Head and Neck Squamous Cell Cancer (HNSCC)

  • in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC.
  • as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
  • as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma (cHL)

  • for the treatment of adult patients with relapsed or refractory cHL.
  • for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

  • for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy.
  • Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

  • for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
  • for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy.
  • for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

  • for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.
  • Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC)

  • for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC)

Gastric Cancer

  • in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
  • as a single agent for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy

Esophageal Cancer

  • for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or; as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test

Cervical Cancer

  • for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

Hepatocellular Carcinoma (HCC)

  • for the treatment of patients with HCC who have been previously treated with sorafenib.

Merkel Cell Carcinoma (MCC)

  • for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma

Renal Cell Carcinoma (RCC)

  • in combination with axitinib, for the first-line treatment of patients with advanced RCC.

Endometrial Carcinoma

  • in combination with lenvatinib, for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High (TMB-H) Cancer

  • for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options
  • Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established

Cutaneous Squamous Cell Carcinoma (cSCC)

  • for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation.
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Triple-Negative Breast Cancer (TNBC)

  • for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
  • in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA approved test.

Adult Indications: Additional Dosing Regimen of 400 mg Every 6 Weeks

  • for use at an additional recommended dosage of 400 mg every 6 weeks for all approved adult indications

Dosage and administration

  • Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
  • Urothelial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
  • MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • HCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
  • RCC: 200 mg every 3 weeks or 400 mg every 6 weeks with axitinib 5 mg orally twice daily.
  • Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily.
  • TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
  • cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
  • TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.

Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth

Pharmacodynamics

Based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data from an interim analysis of 41 patients with melanoma treated with pembrolizumab 400 mg every 6 weeks, there are no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.

Warnings and precautions

Immune-Mediated Adverse Reactions

  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immunemediated colitis, immune-mediated hepatitis, immunemediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection.
  • Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
  • Withhold or permanently discontinue based on severity and type of reaction.

Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue KEYTRUDA based on the severity of reaction.

Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.

Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception.

Adverse effects

Most common adverse reactions (reported in ≥20% of patients) were:

  • KEYTRUDA as a single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
  • KEYTRUDA in combination with chemotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
  • KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
  • KEYTRUDA in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia and rash.

Use in specific populations

Pregnancy: Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.

Lactation: There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use: The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with cHL, PMBCL, MCC, MSI-H cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patient.

Storage

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

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