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 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 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.