Pembrolizumab

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.¹³ 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.^8,9

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

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

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Pharmacology

Indication

Pembrolizumab is indicated for the following conditions:^12,11,10

Melanoma

for the treatment of patients with unresectable or metastatic melanoma (adult patients in the US⁸ and patients ≥12 years old in the EU)¹⁰
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
in combination with platinum-based chemotherapy for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery

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 not candidates for cystectomy
for the treatment of locally advanced or metastatic urothelial carcinoma in combination with enfortumab vedotin in adult patients ineligible for platinum-based chemotherapy under the accelerated approval from the FDA

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, 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 whose tumors express PD -L1 (CPS ≥1) as determined by an FDA-approved test
in combination with fluoropyrimidine - and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma

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
in combination with chemoradiotherapy for the treatment of patients with FIGO 2014 Stage III -IVA cervical cancer

Hepatocellular Carcinoma (HCC)

as a monotherapy for the treatment of HCC in patients who have been previously treated with sorafenib

Biliary Tract Cancer (BTC)

in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer

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
as a monotherapy for the treatment of patients with advanced endometrial carcinoma that is 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

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Advanced endometrial cancer	Regimen in combination with: Lenvatinib (DB09078)	••••••••••••		••••••• ••••••••••• ••••• ••••••••••••• ••• • ••••••••• ••• •••••••• ••••••• •• •••••••••	•••••••••• ••••••••
Used in combination to treat	Advanced renal cell carcinoma (arcc)	Regimen in combination with: Lenvatinib (DB09078)	••••••••••••	•••••		•••••••••• ••••••••
Used in combination to treat	Advanced renal cell carcinoma (arcc)	Regimen in combination with: Axitinib (DB06626)	••••••••••••	•••••		•••••••••• ••••••••
Adjunct therapy in treatment of	Figo 2014 stage iii-iva cervical cancer		••••••••••••			•••••••••• ••••••••
Treatment of	Hepatocellular carcinoma		••••••••••••		•••••••••• ••••••• •••• •••••••••	•••••••••• ••••••••

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
AProgrammed cell death protein 1	inhibitor antibody	Humans
UProgrammed cell death 1 ligand 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

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Toxicity

There are no data regarding overdosage with pembrolizumab.

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Pembrolizumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Pembrolizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Pembrolizumab is combined with Aducanumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Pembrolizumab.
Alirocumab	The risk or severity of adverse effects can be increased when Pembrolizumab is combined with Alirocumab.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Keytruda	Solution	25 mg / mL	Intravenous	Merck Ltd.	2017-07-13	Not applicable
Keytruda	Injection, powder, lyophilized, for solution	50 mg/2mL	Intravenous	Merck Sharp & Dohme LLC	2014-09-04	2015-12-21
Keytruda	Injection, solution, concentrate	25 mg/ml	Intravenous	Merck Sharp & Dohme B.V.	2016-10-06	Not applicable
Keytruda	Powder, for solution	50 mg / vial	Intravenous	Merck Ltd.	2015-06-01	2019-12-04
Keytruda	Injection, powder, for solution	50 mg	Intravenous	Merck Sharp & Dohme B.V.	2016-09-08	Not applicable

Chemical Identifiers

UNII: DPT0O3T46P
CAS number: 1374853-91-4

References

General References

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]
Poole RM: Pembrolizumab: first global approval. Drugs. 2014 Oct;74(16):1973-81. doi: 10.1007/s40265-014-0314-5. [Article]
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]
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]
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]
FDA approval [Link]
FDA news [Link]
FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous injection [Link]
Health Canada Approved Drug Products: KEYTRUDA (pembrolizumab) solution for intravenous infusion [Link]
EMA Summary of Product Characteristics: Keytruda (pembrolizumab) concentrate for solution for infusion (December 2023) [Link]
FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous injection (January 2024) [Link]
FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous administration (Oct 2023) [Link]
Keytruda monograph [File]
Keytruda official monograph [File]

External Links

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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Melanoma / Non-Small Cell Lung Carcinoma	1
4	Active Not Recruiting	Treatment	Squamous Cell Carcinoma of the Head and Neck (SCCHN)	1
4	Not Yet Recruiting	Treatment	Infusion related reaction / Oncology	1
4	Recruiting	Treatment	Metastatic Non-Small Cell Lung Cancer	2
4	Recruiting	Treatment	Newly diagnosed Glioblastoma Multiforme (GBM)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous
Injection, powder, for solution	Intravenous	50 mg
Injection, powder, for solution	Intravenous; Parenteral	50 MG
Injection, powder, lyophilized, for solution	Intravenous	50 mg/2mL
Injection, solution	Intravenous	25 mg/1mL
Injection, solution	Intravenous	50 mg/1vial
Injection, solution, concentrate	Intravenous	25 MG/ML
Powder, for solution	Intravenous	50 mg / vial
Solution	Intravenous	100.000 mg
Solution	Intravenous	25 mg / mL
Injection, solution	Intravenous	100 mg/4ml
Solution	Intravenous	25.0 mg/mL
Solution	Intravenous	100 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US2012135408	No	2012-03-29	2032-03-29

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	22.5-27.5 mg/ml (with histidine buffer)	'Keytruda monograph'
isoelectric point	6.8-6.9	'Keytruda monograph'

Targets

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insights and accelerate drug research.

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Details1. Programmed cell death protein 1

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

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]
Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A: Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel). 2021 Mar 5;7(3). pii: jof7030186. doi: 10.3390/jof7030186. [Article]
FDA Approved Drug Products: Keytruda (pembrolizumab) solution for intravenous injection [Link]

Details2. Programmed cell death 1 ligand 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Antibody

General Function: Not Available
Specific Function: Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell ...
Gene Name: CD274
Uniprot ID: Q9NZQ7
Uniprot Name: Programmed cell death 1 ligand 1
Molecular Weight: 33275.095 Da

References

Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A: Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel). 2021 Mar 5;7(3). pii: jof7030186. doi: 10.3390/jof7030186. [Article]

Drug created at March 30, 2015 22:49 / Updated at January 24, 2024 05:40

Pembrolizumab

Identification

Pharmacology

Melanoma

Non-Small Cell Lung Cancer (NSCLC)

Head and Neck Squamous Cell Cancer (HNSCC)

Classical Hodgkin Lymphoma (cHL)

Primary Mediastinal Large B-cell Lymphoma (PMBCL)

Urothelial Carcinoma

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

Gastric Cancer

Esophageal Cancer

Cervical Cancer

Hepatocellular Carcinoma (HCC)

Biliary Tract Cancer (BTC)

Merkel Cell Carcinoma (MCC)

Renal Cell Carcinoma (RCC)

Endometrial Carcinoma

Tumor Mutational Burden-High (TMB-H) Cancer

Cutaneous Squamous Cell Carcinoma (cSCC)

Triple-Negative Breast Cancer (TNBC)

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References