Pembrolizumab

Identification

Name
Pembrolizumab
Accession Number
DB09037
Description

Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptor. It was generated by grafting the variable sequences of a very high-affinity mouse antihuman PD-1 antibody onto a human IgG4-kappa isotype with the 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.8 It was developed by Merck & Co and firstly approved for the treatment of metastatic malignant melanoma. This is the first approved therapy against PD-1.2 It was approved firstly by the FDA on September 4, 2014.6 Its approval in melanoma was extended to several countries such as Australia, Israel, Korea, Macau, the European Union and the United Arab Emirates.4 On June 12, 2018, Pembrolizumab was approved for the treatment of cervical cancer under the status of accelerated approval.7

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
External IDs
  • Merck 3475
  • MK 3475
  • MK-3475
  • MK3475
  • Sch 900475
  • SCH-900475

Pharmacology

Indication

Pembrolizumab is indicated for the treatment of:

-Patients with unresectable or metastatic melanoma.Label

-As a single therapy, pembrolizumab is indicated for first-line treatment of patients with metastatic non-small cell lung cancer whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.9

-As a single therapy, pembrolizumab is indicated for first-line treatment of patients with metastatic non-small cell lung cancer 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 treatment.9

The following indications present the status of accelerated approval based on tumor response rate and durability of the response and thus, the approval of this indications are contingent upon verification and description of clinical benefit in confirmatory trials.

-Patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS > 1) as determined by an FDA-approved test.7

-In combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer.9

-Patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy.9

-Treatment of adults and pediatric patients with refractory classical Hodgkin lymphoma or who have relapsed after 3 or more prior lines of therapy.9

-Treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after 2 or more prior lines of therapy.9

-Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.9

-Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy.9

-Treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient with solid tumors that have progressed following previous treatment and colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.9

-Patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS >1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.9

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Pembrolizumab pharmacodynamic reports indicate that there are not effector functions by binding to C1q and CD64 not by cytokine release.3 On clinical trials, the objective response rate, defined as the proportion of patients with tumor size reduction of a predefined amount for a minimum time period, was assessed based on independent central review and a response duration. These studies performed for different classes of cancer showed a response either partial or complete in a range of 14.3-26% of the individuals. The response duration was estimated to be of 11 months and 45-91% of the patients had a response equal or greater than 6 months.7,3

In other clinical trials, it was reported the progression-free survival, defined as the time during and after the treatment that the patient lives with the disease without worsening. The administration of pembrolizumab improved the progression-free survival when compared to patients assigned to regular chemotherapy. The increase reached 34% of the individuals while chemotherapy reports only 16%.3

The results mentioned above have been so clear and consistent that in phase III clinical trials the trial was stopped early to allow patients to switch to the treatment with pembrolizumab.3

Mechanism of action

Pembrolizumab, as an IgG4 subclass antibody, is preferred over other subclasses as it only induces weakly the complement and cell activation due to low affinity to C1q and Fc receptors. It binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and it antagonizes its interaction with its known ligands PD-L1 and PD-L2. In 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 seems to be essential for self-tolerance, collateral damage minimizing after immune response against a pathogen and maternal tolerance to fetal tissue. Therefore, the binding of pembrolizumab to PD-1 prevents the inhibitory pathway causing a physiological shift to immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response.3

TargetActionsOrganism
AProgrammed cell death protein 1
inhibitor
antibody
Humans
Absorption

When administered intravenously, pembrolizumab is completely bioavailable. When administered in repeated doses every 3 weeks, the systemic accumulation accounts for a 2.2 fold increase.3 the reported time to reach steady-state is of 18 weeks.8 The absorption profile of pembrolizumab is proportionally increased with increases in the dosage.5

Volume of distribution

The volume of distribution at steady state of pembrolizumab is 7.5 L which indicated a limited extravascular distribution.8

Protein binding

Pembrolizumab is not expected to bind to plasma proteins in a specific manner.3

Metabolism

Pembrolizumab is catalyzed into small peptides and single amino acids via general protein degradation but it does not rely on metabolism for clearance.3

Route of elimination
Not Available
Half-life

The terminal half-life of pembrolizumab is 26 days.8

Clearance

Clearance is increased proportionally with the body weight and the mean clearance is registered to be 0.22 L/day. The renal clearance of pembrolizumab is not clinically modified in a significant manner by the presence of mild to moderate renal impairment.3

Adverse Effects
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Toxicity

Pembrolizumab seems to be very well tolerated for a cancer therapy and the rate of discontinuations is reported to be of 14%. The presence of side effects of grade 3-4 is 10-14%. Due to the mechanism of action, the immune response was highly managed with treatment interruption and corticosteroid treatment.3 even though fertility studies have not been performed, there are no notable effects in reproductive organs in not sexually mature animals.Label

Affected organisms
  • Humans and other mammals
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.
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.
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).
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Pembrolizumab.
Asfotase alfaThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Asfotase alfa.
AtezolizumabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Atezolizumab.
AvelumabThe risk or severity of adverse effects can be increased when Pembrolizumab is combined with Avelumab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KeytrudaInjection, powder, lyophilized, for solution50 mg/2mLIntravenousMerck Sharp & Dohme Corp.2014-09-042015-12-21US flag
KeytrudaSolution25 mgIntravenousMerck Ltd.2017-07-13Not applicableCanada flag
KeytrudaInjection, solution, concentrate25 mg/mlIntravenousMerck Sharp & Dohme B.V.2015-07-17Not applicableEU flag
KeytrudaPowder, for solution50 mgIntravenousMerck Ltd.2015-06-012019-12-04Canada flag
KeytrudaInjection, solution25 mg/1mLIntravenousMerck Sharp & Dohme Corp.2015-01-15Not applicableUS flag
KeytrudaInjection, powder, for solution50 mgIntravenousMerck Sharp & Dohme B.V.2015-07-17Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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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

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. [PubMed:25034862]
  2. Poole RM: Pembrolizumab: first global approval. Drugs. 2014 Oct;74(16):1973-81. doi: 10.1007/s40265-014-0314-5. [PubMed:25331768]
  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. [PubMed:27485741]
  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. [PubMed:26288737]
  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. [PubMed:27822406]
  6. FDA approval [Link]
  7. FDA news [Link]
  8. Keytruda monograph [File]
  9. 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
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (589 KB)
MSDS
Download (134 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentMetastatic Non-Small Cell Lung Carcinoma1
4RecruitingTreatmentAdvanced thymic carcinoma1
4RecruitingTreatmentMelanoma / Non-Small Cell Lung Carcinoma (NSCLC)1
4RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
4WithdrawnTreatmentMalignant Neoplasm of Pancreas1
3Active Not RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Gastric Adenocarcinoma1
3Active Not RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Neoplasm, Gastric1
3Active Not RecruitingTreatmentAdvanced BRAFV600 Wild-type Melanoma1
3Active Not RecruitingTreatmentCarcinoma, Colorectal1
3Active Not RecruitingTreatmentCervical Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous50 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg/2mL
Injection, solutionIntravenous25 mg/1mL
Injection, solution, concentrateIntravenous25 mg/ml
Injection, solution, concentrateIntravenous; Parenteral25 MG/ML
Powder, for solutionIntravenous50 mg
SolutionIntravenous25 mg
Injection, solutionIntravenous100 mg/4ml
Solution
SolutionIntravenous100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US2012135408No2012-03-292032-03-29US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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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

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. [PubMed:25685857]

Drug created on March 30, 2015 16:49 / Updated on September 25, 2020 15:13

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