Identification

Summary

Pembrolizumab is a PD-1 blocking antibody used to treat various types of cancer, including metastatic melanoma, non small-cell lung cancer, cervical cancer, head and neck cancer, and Hodgkin's lymphoma.

Brand Names
Keytruda
Generic Name
Pembrolizumab
DrugBank Accession Number
DB09037
Background

Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptors. It was generated by grafting the variable sequences of a very high-affinity mouse antihuman PD-1 antibody onto a human IgG4-kappa isotype containing a stabilizing S228P Fc mutation.3 It contains 32 cysteine residues and the complete folded molecule includes 4 disulfide linkages as interchain bonds and 23 interchain bonds.9 It was developed by Merck & Co and first approved for the treatment of metastatic malignant melanoma by the FDA on September 4, 2014,6 becoming the first approved therapy against PD-1.2 In the time since its initial approval, pembrolizumab has been granted approval in the treatment of a wide variety of cancers.8

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db09037
Protein Chemical Formula
C6504H10004N1716O2036S46
Protein Average Weight
149000.0 Da
Sequences
>Heavy Chain Sequence
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF
NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG
NVFSCSVMHEALHNHYTQKSLSLSLGK
>Light Chain Sequence
EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES
GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
  • Lambrolizumab
  • Pembrolizumab
External IDs
  • Merck 3475
  • MK 3475
  • MK-3475
  • MK3475
  • Sch 900475
  • SCH-900475

Pharmacology

Indication

Pembrolizumab is indicated for the following conditions:8

Melanoma

  • for the treatment of patients with unresectable or metastatic melanoma
  • for the adjuvant treatment of adult and pediatric patients 12 years of age and older with Stage IIB, IIC, or III melanoma following complete resection

Non-Small Cell Lung Cancer (NSCLC)

  • in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK mutations
  • in combination with carboplatin and paclitaxel as a first-line treatment for patients with metastatic squamous NSCLC
  • as a monotherapy for the first-line treatment of NSCLC expressing PD-L1 with no EGFR or ALK mutations in patients with metastatic disease or stage III disease who are not candidates for surgery or chemoradiation
  • as a monotherapy for the treatment of NSCLC expressing PD-L1 with disease progression on or after platinum-based chemotherapy - this includes patients with EGFR or ALK mutations, providing they have experienced disease progression on prior FDA-approved therapy for these aberrations

Head and Neck Squamous Cell Cancer (HNSCC)

  • in combination with fluorouracil and platinum-based chemotherapy as a first-line treatment for patients with metastatic or recurrent, unresectable HNSCC
  • as a monotherapy for the first-line treatment of patients with metastatic or recurrent, unresectable HNSCC expressing PD-L1
  • as a monotherapy for the treatment of patients with metastatic or recurrent HNSCC with disease progression on or after platinum-based 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 following ≥2 lines of therapy

Primary Mediastinal Large B-cell Lymphoma (PMBCL)

  • for the treatment of adult and pediatric patients with refractory PMBCL, or PMBCL that has relapsed following ≥2 lines of therapy

Urothelial Carcinoma

  • for the treatment of locally advanced or metastatic urothelial carcinoma in patients ineligible for platinum-based chemotherapy
  • for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-based chemotherapy or within 12 months of adjuvant/neoadjuvant platinum-based chemotherapy
  • for the treatment of BCG vaccine-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with or without papillary tumors, who are are not candidates for cystectomy

Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer (dMMR)

  • as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment
  • for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer

Gastric Cancer

  • in combination with trastuzumab, with fluoropyrimidine- and platinum-containing chemotherapy, as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma
  • as a monotherapy for the treatment of patients with recurrent or locally advanced metastatic gastric or GEJ adenocarcinoma expressing PD-L1 who have experienced disease progression on or after ≥2 prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy

Esophageal Cancer

  • in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or GEJ carcinoma who are not candidates for surgery or definitive chemoradiation
  • as a monotherapy for the treatment of locally advanced or metastatic esophageal or GEJ carcinoma expressing PD-L1 in patients who are not candidates for surgery or definitive chemoradiation

Cervical Cancer

  • in combination with other chemotherapies, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer expressing PD-L1
  • as a monotherapy for the treatment of recurrent or metastatic cervical cancer expressing PD-L1 in patients who have experienced disease progression on or after previous chemotherapy

Hepatocellular Carcinoma (HCC)

  • as a monotherapy for the treatment of HCC in patients 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 MCC

Renal Cell Carcinoma (RCC)

  • in combination with either axitinib or lenvatinib as a first-line treatment for adult patients with advanced RCC
  • for the adjuvant treatment of patients with RCC who are at an intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions

Endometrial Carcinoma

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

Tumor Mutational Burden-High (TMB-H) Cancer

  • as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors that have progressed following prior treatment

Cutaneous Squamous Cell Carcinoma (cSCC)

  • for the treatment of patients with recurrent or metastatic sCC, or locally advanced sCC that is not curable with surgery or radiation therapy

Triple-Negative Breast Cancer (TNBC)

  • for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as a neoadjuvant treatment followed by continued use as a single adjuvant agent following surgery
  • in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC expressing PD-L1

For all approved adult indications, pembrolizumab may be used for an additional 6 weeks at 400mg weekly.8

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Pembrolizumab exerts its pharmacologic effects by releasing PD-1 pathway-mediated inhibition of the immune response, which in turn improves the anti-tumor immune response.8 Due to its relatively broad mechanism of action, it is useful in the treatment of a wide variety of cancers.

Pembrolizumab can cause immune-mediated adverse reactions - including hepatitis, nephritis, and pneumonitis - in any organ system or tissue. Careful monitoring of the patient (including laboratory evaluation of liver, kidney, and thyroid function) should occur at baseline and periodically throughout therapy to monitor for emerging immune-mediated reactions.8

Mechanism of action

Pembrolizumab binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and antagonizes its interaction with its known ligands PD-L1 and PD-L2.8 Under normal circumstances, the binding of the ligands of PD-1 to the receptor inhibits the TCR-mediated T-cell proliferation and cytokine production. This inhibitory signal appears to play a role in self-tolerance and collateral damage minimization after immune responses against a pathogen and maternal tolerance to fetal tissue.

The binding of pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response.8

TargetActionsOrganism
AProgrammed cell death protein 1
inhibitor
antibody
Humans
Absorption

Intravenously administered pembrolizumab is completely bioavailable. Steady-state is reached after approximately 16 weeks.8

Volume of distribution

The steady-state volume of distribution of pembrolizumab is approximately 6 liters.8

Protein binding

Pembrolizumab is not expected to bind to plasma proteins.3

Metabolism

Pembrolizumab is catalyzed into smaller peptides and amino acids via general protein degradation.3

Route of elimination

Not Available

Half-life

The terminal half-life of pembrolizumab is 22 days.8

Clearance

Clearance is moderately lower at steady-state (195 mL/day) than after the first dose (252 mL/day), although this decrease is not clinically significant.8

Adverse Effects
Adverseeffects
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Toxicity

There are no data regarding overdosage with pembrolizumab.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Pembrolizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Pembrolizumab.
AducanumabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Pembrolizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Alirocumab.
AmivantamabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Anifrolumab.
AnsuvimabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Anthrax immune globulin human.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Pembrolizumab is combined with Antilymphocyte immunoglobulin (horse).
Interactions
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Food Interactions
No interactions found.

Products

Products2
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dosage, form, labeller, route of administration, and marketing period.
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KeytrudaPowder, for solution50 mg / vialIntravenousMerck Ltd.2015-06-012019-12-04Canada flag
KeytrudaInjection, powder, for solution50 mgIntravenousMerck Sharp & Dohme B.V.2016-09-08Not applicableEU flag
KeytrudaInjection, solution25 mg/1mLIntravenousMerck Sharp & Dohme Corp.2015-01-15Not applicableUS flag
KeytrudaSolution25 mg / mLIntravenousMerck Ltd.2017-07-13Not applicableCanada flag
KeytrudaInjection, powder, lyophilized, for solution50 mg/2mLIntravenousMerck Sharp & Dohme Corp.2014-09-042015-12-21US flag
KeytrudaInjection, solution, concentrate25 mg/mlIntravenousMerck Sharp & Dohme B.V.2016-10-06Not applicableEU flag

Categories

ATC Codes
L01XC18 — Pembrolizumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DPT0O3T46P
CAS number
1374853-91-4

References

General References
  1. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15. [Article]
  2. Poole RM: Pembrolizumab: first global approval. Drugs. 2014 Oct;74(16):1973-81. doi: 10.1007/s40265-014-0314-5. [Article]
  3. Longoria TC, Tewari KS: Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol. 2016 Oct;12(10):1247-53. doi: 10.1080/17425255.2016.1216976. Epub 2016 Aug 16. [Article]
  4. Khoja L, Butler MO, Kang SP, Ebbinghaus S, Joshua AM: Pembrolizumab. J Immunother Cancer. 2015 Aug 18;3:36. doi: 10.1186/s40425-015-0078-9. eCollection 2015. [Article]
  5. Jazirehi AR, Lim A, Dinh T: PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab. Am J Cancer Res. 2016 Oct 1;6(10):2117-2128. eCollection 2016. [Article]
  6. FDA approval [Link]
  7. FDA news [Link]
  8. FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous injection [Link]
  9. Keytruda monograph [File]
  10. Keytruda official monograph [File]
KEGG Drug
D10574
PubChem Substance
347910395
RxNav
1547545
ChEMBL
CHEMBL3137343
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pembrolizumab
MSDS
Download (134 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentMelanoma / Non-Small Cell Lung Carcinoma (NSCLC)1
4RecruitingTreatmentMetastatic Non-Small Cell Lung Cancer1
4RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
4RecruitingTreatmentThymoma and Thymic Carcinoma1
4WithdrawnTreatmentMalignant Neoplasm of Pancreas1
3Active Not RecruitingTreatmentAbdominal wall neoplasm / Fallopian Tubes Cancer / Ovarian Cancer1
3Active Not RecruitingTreatmentAdenocarcinoma of the Stomach1
3Active Not RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Neoplasm, Gastric1
3Active Not RecruitingTreatmentBiliary Tract Carcinoma2
3Active Not RecruitingTreatmentBreast Neoplasms, Triple-Negative1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous
Injection, powder, for solutionIntravenous50 mg
Injection, powder, for solutionIntravenous; Parenteral50 MG
Injection, powder, lyophilized, for solutionIntravenous50 mg/2mL
Injection, solutionIntravenous25 mg/1mL
Injection, solutionIntravenous50 mg/1vial
Injection, solution, concentrateIntravenous25 MG/ML
Powder, for solutionIntravenous50 mg / vial
SolutionIntravenous25 mg / mL
Injection, solutionIntravenous
SolutionIntravenous25.0 mg/mL
SolutionIntravenous100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US2012135408No2012-03-292032-03-29US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility22.5-27.5 mg/ml (with histidine buffer)'Keytruda monograph'
isoelectric point6.8-6.9'Keytruda monograph'

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Signal transducer activity
Specific Function
Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. ...
Gene Name
PDCD1
Uniprot ID
Q15116
Uniprot Name
Programmed cell death protein 1
Molecular Weight
31646.635 Da
References
  1. McDermott J, Jimeno A: Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. Drugs Today (Barc). 2015 Jan;51(1):7-20. doi: 10.1358/dot.2015.51.1.2250387. [Article]
  2. FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous injection [Link]

Drug created at March 30, 2015 22:49 / Updated at January 27, 2022 17:28