Durvalumab

Immunotherapy: mechanism of action for Durvalumab, Pembrolizumab, Ipilimumab, Atezolizumab . Adapted from: First line Immunotherapy for Non-Small Cell Lung Cancer. Nasser NJ, Gorenberg M, Agbarya A. Pharmaceuticals 2020, 13(11), 373 https://doi.org/10.3390/ph13110373

Durvalumab

Antigen-binding fragment of durvalumab (pale green) in complex with PD-L1 (pink). PDB: 5X8M​.
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	CD274
Clinical data
Trade names	Imfinzi
Other names	MEDI4736, MEDI-4736
AHFS/Drugs.com	Monograph
MedlinePlus	a617030
License data	US DailyMed: Durvalumab
Pregnancy category	AU: D[1]
Routes of administration	Intravenous
ATC code	L01FF03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only [2] EU: Rx-only [3]
Identifiers
CAS Number	1428935-60-7
PubChem CID	249565666
IUPHAR/BPS	7985
DrugBank	DB11714
ChemSpider	none
UNII	28X28X9OKV
KEGG	D10808 Y
Chemical and physical data
Formula	C6502H10018N1742O2024S42
Molar mass	146322.36 g·mol−1

Durvalumab^[4] (trade name Imfinzi) is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca.^[5] It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279).

Durvalumab is known as a checkpoint inhibitor drug.^[6]

Medical uses[]

The US Food and Drug Administration (FDA) has approved durvalumab for certain types of bladder and lung cancer:^[2]

• Adults with locally advanced or metastatic urothelial carcinoma who either have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Adults with unresectable, Stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
• In combination with etoposide and either carboplatin or cisplatin, as first-line treatment for adults with extensive-stage small cell lung cancer.

Clinical trials[]

A phase IB clinical trial of durvalumab and tremelimumab showed some activity in non-small cell lung cancer (NSCLC).^[7] Phase 1 data in advanced metastatic urothelial bladder (Study 1108) has led to FDA breakthrough therapy designation.^[6][8] Early results of a phase I trial combining durvalumab and gefitinib in lung cancer patients "showed promise".^[9] A phase I clinical trial is currently underway using durvalumab with a TLR 7/8 agonist (MEDI 9197) for solid tumors.^[10] A Phase 1b/2a trial is underway combining durvalumab with an HPV DNA vaccine (MEDI 0457) in patients with HPV-associated recurrent/metastatic head and neck cancer.^[11]

MYSTIC[]

In July 2017, AstraZeneca announced that a phase III trial of durvalumab with tremelimumab as a first-line treatment of non-small cell lung cancer failed to meet its primary endpoint of progression-free survival.^[12]

PACIFIC[]

In November 2017, the double-blinded phase III AstraZeneca PACIFIC clinical trial demonstrated the efficacy of durvalumab in the treatment of stage III non-small cell lung cancer.^[13] 709 patients with stage III NSCLC who did not have disease progression after two or more cycles of a platinum-based chemotherapy were randomly assigned to receive durvalumab or a placebo as consolidation therapy for their lung cancer. Durvalumab increased the median progression-free survival from 5.6 months (placebo) to 16.8 months (durvalumab); the 12 month progression-free survival rate was increased from 35.3% (placebo) to 55.9% (durvalumab), and the 18 month progression-free survival rate was increased from 27.0% (placebo) to 44.2% (durvalumab).^[6] The median time to death or distant metastases was also increased from 14.6 months (placebo) to 23.2 months (durvalumab). Extreme side effects were also increased from 26.1% of patients (placebo) to 29.9% of patients (durvalumab).

CASPIAN[]

In March 2021, the open-label, sponsor-blind (AstraZeneca), randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide (CASPIAN) demonstrated the efficacy of durvalumab in combination with platinum-based chemotherapy in the treatment of small cell lung cancer.^[14] Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]).^[15]

References[]

External links[]

• "Durvalumab". Drug Information Portal. U.S. National Library of Medicine.
• "Durvalumab". NCI Drug Dictionary. National Cancer Institute.</ref>
• "Durvalumab". National Cancer Institute. 5 May 2017.