KEYTRUDA-Pembrolizumab Immunotherapy for Solid Tumors: Mechanism of Action, Indication, Side Effects

KEYTRUDA a-k-a 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) Indications

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

Melanoma-for the treatment of patients with unresectable or metastatic melanoma

Non-Small Cell Lung Cancer (NSCLC)

Small Cell Lung Cancer (SCLC)-for the treatment of patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy

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

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

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

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)

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC)-for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer

Gastric Cancer-for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction 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

Cervical Cancerfor 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 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

Cutaneous Squamous Cell Carcinoma (cSCC) -for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation

Triple-Negative Breast Cancer (TNBC)- 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  

Formulation

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. 12 


Mechanism of Action of Pembrolizumab- Immune checkpoint inhibitor

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. 

Pharmacokinetics: 

The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. 

Side Effects of Pembrolizumab (Keytruda)

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, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. 

Infusion-related reactions:

Other most common adverse reactions are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 

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