Durvalumab

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Identification

Summary

Durvalumab is an antineoplastic monoclonal antibody used to treat urothelial carcinoma and locally advanced, unresectable non-small cell lung cancer.

Brand Names

Imfinzi

Generic Name

Durvalumab

DrugBank Accession Number

DB11714

Background

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody and a novel immune-checkpoint inhibitor for cancer treatment.² Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture,⁷ durvalumab is a programmed death-ligand 1 (PD-L1) blocking antibody that works to promote normal immune responses that attack tumour cells.^7,9

Durvalumab is marketed under the brand name Imfinzi, which is available for intravenous injections. It was granted accelerated approval by the FDA in May 2017 ⁵ for the treatment of selected patients with locally advanced or metastatic urothelial carcinoma.⁷ In September 2018, durvalumab was approved by the EMA for the treatment of adult patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), only if PD-L1 is expressed in ≥ 1% of tumour cells and there was no observable disease progression following platinum-based chemoradiation therapy.^2,9 On March 27, 2020, durvalumab was approved by the FDA for use in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).⁸

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

C₆₅₀₂H₁₀₀₁₈N₁₇₄₂O₂₀₂₄S₄₂

Protein Average Weight

146300.0 Da

Sequences

>Durvalumab heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY
VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRE
EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

>Durvalumab light chain
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

KEGG DRUG: Durvalumab [Link]

Download FASTA Format

Synonyms

Durvalumab

External IDs

MEDI 4736
MEDI-4736
MEDI4736

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Pharmacology

Indication

Durvalumab is indicated for the treatment of adults with the following conditions:

unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.¹²
metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumour aberrations, in combination with tremelimumab and platinum-based chemotherapy.^12,13
extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin as first-line therapy.⁸
locally advanced or metastatic biliary tract cancer (BTC) in combination with gemcitabine and cisplatin.¹⁰
unresectable hepatocellular carcinoma (uHCC) alone or in combination with tremelimumab.^9,11,13
in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumours≥ 4 cm and/or node-positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.¹⁴
in combination with carboplatin and paclitaxel is indicated for the first-line treatment of adults with primary advanced or recurrent endometrial cancer who are candidates for systemic therapy. This is followed by maintenance treatment with either durvalumab as monotherapy or in combination with olaparib in endometrial cancer that is mismatch repair deficient (dMMR).⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group
Used in combination to treat	Advanced hepatocellular carcinoma (hcc)	Regimen in combination with: Tremelimumab (DB11771)	••••••••••••	•••••
Treatment of	Advanced hepatocellular carcinoma (hcc)		••••••••••••	•••••
Used in combination to treat	Extensive-stage small cell lung cancer (sclc)	Regimen in combination with: Cisplatin (DB00515), Etoposide (DB00773)	••••••••••••	•••••
Used in combination to treat	Extensive-stage small cell lung cancer (sclc)	Regimen in combination with: Carboplatin (DB00958), Etoposide (DB00773)	••••••••••••	•••••
Used in combination to treat	Locally advanced biliary tract cancer	Regimen in combination with: Cisplatin (DB00515), Gemcitabine (DB00441)	••••••••••••	•••••

Associated Therapies

Contraindications & Blackbox Warnings

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Pharmacodynamics

Durvalumab is an anticancer antibody that works to promote the antitumour responses mediated by immune cells. By blocking the action of PD-L1, durvalumab exerts its anticancer effects by increasing T-cell activation, enhancing detection and ablation of tumour cells.⁷ In in vitro assays, durvalumab inhibited the activity of PD-L1 in a concentration-dependent manner.⁵ In co-engrafted human tumor and immune cell xenograft mouse models, durvalumab was effective in decreasing tumour size. Durvalumab does not mediate antibody-dependent cell-mediated cytotoxicity (ADCC).⁷

Mechanism of action

Because cancer cells express antigens that are recognized and taken up by antigen-presenting cells (APCs), the immune responses prime and activate cytotoxic T cells, and allow them to travel to the site of the tumour to destroy cancer cells. However, tumours often evade T cell-mediated immune responses to enhance their survival.⁴ Inflammatory mediators, such as IFN-gamma, induce the expression of programmed cell death ligand-1 (PD-L1), which is a type 1 transmembrane protein expressed on tumour cells and tumour-associated immune cells in the tumour microenvironment.^2,7 PD-L1 acts as an immune checkpoint to regulate immune responses. PD-L1 is a ligand to PD-1, which is a cell surface receptor expressed on activated T cells in peripheral tissues following antigen exposure.^2,3 Both PD-L1 and PD-1 are co-inhibitory molecules involved in blocking T cell-mediated immune responses. PD-L1 also interacts with CD-80, which is a receptor constitutively expressed by T cells and is upregulated early after T cell activation.⁶

The expression of PD-L1 is an adaptive immune response by tumour cells, resulting in the over-expression of the molecule in some cancers.³ PD-L1 interacts with PD-1 and CD80, which leads to blocked cytotoxic T cell activation, T cell proliferation, and cytokine production.⁷ By binding to PD-L1 and preventing its association with PD-1 and CD80, durvalumab activates the immune responses mediated by cytotoxic T cells that attack tumour cells.⁷ Durvalumab displays selective and high affinity toward PD-L1 but not PD-L2, which is a regulatory ligand expressed in tumour cells to a lesser extent and involved in regulating inflammation and differentiation of T cells.²

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

Absorption

Durvalumab exhibits a dose-proportional pharmacokinetic profile that is non-linear at doses <3 mg/kg and linear at doses ≥3 mg/kg. Following intravenous administration in patients with solid tumours, the steady-state plasma concentrations were reached at approximately 16 weeks.⁷

Volume of distribution

In patients receiving the dose range of ≥ 10 mg/kg every 2 weeks, the mean steady state volume of distribution (Vss) was 5.64 L.^7,9

Protein binding

There is limited information on the serum protein binding profile of durvalumab.

Metabolism

Durvalumab is subject to protein catabolism via reticuloedothelial system or target-mediated disposition.⁹

Route of elimination

Durvalumab is primarily eliminated by protein catabolism.⁹

Half-life

Based on baseline clearance rate, the geometric mean terminal half-life is 18 days.^7,9

Clearance

Clearance of durvalumab decreases over time, resulting in a mean steady-state clearance (CLss) of 8.2 mL/h following 365 days of initial drug administration. However, the decrease in CLss is not considered clinically relevant.^7,9

Adverse Effects

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Toxicity

There is limited information about the overdose profile and LD₅₀ of durvalumab. In case of overdose, the patient should be closely monitored for drug-related adverse events, and appropriate symptomatic treatment should be immediately initiated.⁹ Based on the findings of clinical studies, durvalumab had a risk of causing immune-mediated reactions, such as pneumonitis, hepatitis, and other serious infections. In animal reproductive studies, durvalumab caused fetal harm and this fetal toxicity may be possible in humans.⁷

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.

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

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Imfinzi	Injection, solution, concentrate	50 mg/ml	Intravenous	Astra Zeneca Ab	2021-01-12	Not applicable
Imfinzi	Injection, solution	120 mg/2.4mL	Intravenous	AstraZeneca Pharmaceuticals LP	2017-05-01	Not applicable
Imfinzi	Solution	50 mg / mL	Intravenous	Astra Zeneca	2017-11-20	Not applicable
Imfinzi	Injection, solution, concentrate	50 mg/ml	Intravenous	Astra Zeneca Ab	2021-01-12	Not applicable
Imfinzi	Injection, solution	500 mg/10mL	Intravenous	AstraZeneca Pharmaceuticals LP	2017-05-01	Not applicable

Chemical Identifiers

UNII: 28X28X9OKV
CAS number: 1428935-60-7

References

General References

Keizer RJ, Huitema AD, Schellens JH, Beijnen JH: Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Aug;49(8):493-507. doi: 10.2165/11531280-000000000-00000. [Article]
Botticella A, Mezquita L, Le Pechoux C, Planchard D: Durvalumab for stage III non-small-cell lung cancer patients: clinical evidence and real-world experience. Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466619885530. doi: 10.1177/1753466619885530. [Article]
Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ, Ryu SE, Shin W, Heo YS: Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep. 2017 Jul 17;7(1):5532. doi: 10.1038/s41598-017-06002-8. [Article]
Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A: Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018 Jan 23;12:209-215. doi: 10.2147/DDDT.S141491. eCollection 2018. [Article]
Syed YY: Durvalumab: First Global Approval. Drugs. 2017 Aug;77(12):1369-1376. doi: 10.1007/s40265-017-0782-5. [Article]
Ni X, Song Q, Cassady K, Deng R, Jin H, Zhang M, Dong H, Forman S, Martin PJ, Chen YZ, Wang J, Zeng D: PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Invest. 2017 May 1;127(5):1960-1977. doi: 10.1172/JCI91138. Epub 2017 Apr 17. [Article]
FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use [Link]
FDA.gov Resources for Information: FDA approves durvalumab for extensive-stage small cell lung cancer [Link]
European Medicines Agency: IMFINZI (durvalumab) Summary of Product Characteristics [Link]
FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use (September 2022) [Link]
FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use (October 2022) [Link]
FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use (November 2022) [Link]
EMA Approved Drug Products: IMJUDO (tremelimumab) Intravenous Infusion [Link]
FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use (August 2024) [Link]

External Links

KEGG Drug: D10808
PubChem Substance: 347911229
RxNav: 1919503
Drugs.com: Drugs.com Drug Page
Wikipedia: Durvalumab

FDA label

Download (576 KB)

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Active Not Recruiting	Not Available	Small Cell Lung Cancer (SCLC)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Treatment	Non-Small Cell Lung Carcinoma	1	somestatus	stop reason	just information to hide
Not Available	Not Yet Recruiting	Treatment	Non-Small Cell Lung Carcinoma	1	somestatus	stop reason	just information to hide
Not Available	Recruiting	Not Available	Immune Related Adverse Events / Immunotherapy / Interstitial Pneumonitis	1	somestatus	stop reason	just information to hide
Not Available	Recruiting	Not Available	Unresectable Hepatocellular Carcinoma (HCC)	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	120 mg/2.4mL
Injection, solution	Intravenous	500 mg/10mL
Injection, solution, concentrate	Intravenous	120 mg/2.4ml
Injection, solution, concentrate	Intravenous	50 mg/ml
Injection, solution, concentrate	Intravenous	50 mg/1ml
Injection, solution, concentrate	Intravenous; Parenteral	50 MG/ML
Solution	Intravenous	50 mg / mL
Injection, solution, concentrate		120 mg/2.4ml
Injection, solution, concentrate		500 mg/10ml
Solution	Intravenous	50 mg/ml
Injection, solution	Intravenous	50 MG/ML
Solution, concentrate	Intravenous	50 mg
Solution	Intravenous	500.000 mg

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Programmed cell death 1 ligand 1

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

General Function: Plays a critical role in induction and maintenance of immune tolerance to self (PubMed:11015443, PubMed:28813410, PubMed:28813417, PubMed:31399419). As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response (PubMed:11015443, PubMed:28813410, PubMed:28813417, PubMed:36727298). Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10) (PubMed:10581077). Can also act as a transcription coactivator: in response to hypoxia, translocates into the nucleus via its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis (PubMed:32929201)
Specific Function: Receptor ligand activity
Gene Name: CD274
Uniprot ID: Q9NZQ7
Uniprot Name: Programmed cell death 1 ligand 1
Molecular Weight: 33275.095 Da

References

Bellmunt J, Powles T, Vogelzang NJ: A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 2017 Mar;54:58-67. doi: 10.1016/j.ctrv.2017.01.007. Epub 2017 Feb 2. [Article]
Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A: Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018 Jan 23;12:209-215. doi: 10.2147/DDDT.S141491. eCollection 2018. [Article]
Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ, Ryu SE, Shin W, Heo YS: Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep. 2017 Jul 17;7(1):5532. doi: 10.1038/s41598-017-06002-8. [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]

Details2. Programmed cell death protein 1

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

General Function: Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self (PubMed:21276005). Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2 (PubMed:21276005). Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). Suppresses T-cell activation through the recruitment of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated within the ITSM motif, leading to the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta (By similarity)
Specific Function: Signaling receptor activity
Gene Name: PDCD1
Uniprot ID: Q15116
Uniprot Name: Programmed cell death protein 1
Molecular Weight: 31646.635 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 October 20, 2016 20:41 / Updated at August 30, 2024 01:02

Durvalumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Targets

References

References