Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat
urothelial carcinoma
Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...
,
non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
(NSCLC),
triple-negative breast cancer
Triple-negative breast cancer (TNBC) is any breast cancer that lacks or show low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the tu ...
(TNBC),
small cell lung cancer
Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell ca ...
(SCLC),
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in th ...
, and
alveolar soft part sarcoma
Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown.
ASPS arises mainly in children and young adults and can migrate (metastasize) into other parts of the ...
.
It is a fully
humanized
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal a ...
, engineered
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
of
IgG1
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
isotype against the protein
programmed cell death-ligand 1
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the ''CD274'' gene.
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protei ...
(PD-L1).
[
The most common side effects when used on its own include tiredness, reduced appetite, nausea, vomiting, cough, difficulty breathing, diarrhea, rash, fever, pain in the back, joints, muscles and bones, weakness, itching and ]urinary tract infection
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...
. The most common side effects when used with other cancer medicines include peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
(nerve damage in the hands and feet), nausea, anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, ...
(low red blood cell counts), neutropenia
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
(low white blood cell counts), thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
(low platelet counts), rash, tiredness, constipation, reduced appetite, diarrhea, and cough.
Atezolizumab is the first PD-L1 inhibitor approved by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA).
Medical uses
In the European Union, atezolizumab is indicated for the treatment of urothelial carcinoma, NSCLC, SCLC, hepatocellular carcinoma, and breast cancer.
In the United States, atezolizumab is indicated for the treatment of NSCLC, TNBC, SCLC, hepatocellular carcinoma, and melanoma. Its indication for urothelial carcinoma was withdrawn in November 2022.
Adverse effects
The most common adverse effects in studies were fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, decreased appetite, nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, and infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable d ...
s. Urinary tract infection was the most common severe adverse effect.
Pharmacology
Mechanism of action
Atezolizumab blocks the interaction of PD-L1 with programmed cell death protein 1
Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein on the surface of T and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regula ...
(PD-1) and CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
receptors (B7-1Rs). PD-L1 can be highly expressed on certain tumors, which is thought to lead to reduced activation of immune cells (cytotoxic T-cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
in particular) that might otherwise recognize and attack the cancer. Inhibition of PD-L1 by atezolizumab can remove this inhibitor effect and thereby engender an anti-tumor response. It is one of several ways to block inhibitory signals related to T-cell activation, a more general strategy known as "immune checkpoint
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulat ...
inhibition."
For some cancers (notably bladder) the probability of benefit is related to PD-L1 expression, but most cancers with PD-L1 expression still do not respond, and many (about 15%) without PD-L1 expression do respond.
History
In 2015, it was in clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s as an immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
for several types of solid tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
. It was under investigation by Genentech
Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within ...
/Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX S ...
.[
In April 2016, Roche announced that atezolizumab had been granted ]fast track status
Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ne ...
for lung cancer by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA).
In May 2016, the FDA granted accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate en ...
to atezolizumab for locally advanced or metastatic urothelial carcinoma
Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...
treatment after failure of cisplatin-based chemotherapy.[ ] The confirmatory trial
A confirmatory trial is an adequately controlled trial where hypotheses are stated in advance and evaluated according to a protocol. This type of trial may be implemented when it is necessary to provide additional or firm evidence of efficacy or sa ...
(to convert the accelerated approval into a full approval) failed to achieve its primary endpoint
Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of disease, symptom, sign or laboratory abnormality constituting a target outcome in clinical research trials. The term may also refer to any disease or sign tha ...
of overall survival
Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be us ...
. In 2018, FDA altered the use of atezolizumab as a first-line treatment for metastatic bladder cancer in people who can't receive cisplatin-based chemotherapy and have high levels of PD-L1.
In May 2016, atezolizumab was approved by the FDA for the treatment of people with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within twelve months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[ In May 2017, atezolizumab failed a phase III trial for second line bladder cancer.
The safety and efficacy of atezolizumab were studied in people with urothelial carcinoma.][ ][ ] Tumors temporarily shrank in a minority of participants, with people being more likely to benefit if the tumor expressed PD-L1.[ The trial was conducted in the United States, Canada, Spain, France, Great Britain, Germany, Italy and the Netherlands.]
In October 2016, atezolizumab was approved by the FDA for the treatment of people with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. People with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab.[ ]
This approval was based on two international, randomized, open-label clinical trials (OAK and POPLAR) that demonstrated consistent results in efficacy and safety in a total of 1137 participants with NSCLC. Compared with docetaxel, treatment with atezolizumab in the intended participants population in the two trials resulted in a 4.2 and a 2.9 month improvement in overall survival (OS), respectively.
Atezolizumab was approved for medical use in the European Union in September 2017.[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.]
In May 2018, the use of atezolizumab in combination with bevacizumab
Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein ( intravenous) and used for colon cancer, ...
(Avastin) and standard chemotherapy for some people with lung cancer was granted priority review.
In August 2018, the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from people with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.
In September 2018, it was announced that atezolizumab prolongs survival in extensive stage SCLC treatment, according to study results presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.
In October 2018, a combined clinical trial of the drug with nab-paclitaxel
Protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel or nab-paclitaxel, is an injectable formulation of paclitaxel used to treat breast cancer, lung cancer and pancreatic cancer, among others. Paclitaxel kills cancer ...
on people with advanced TNBC concluded.
Atezolizumab, in combination with bevacizumab
Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein ( intravenous) and used for colon cancer, ...
, paclitaxel
Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical can ...
, and carboplatin
Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used ...
, was approved in the United States in December 2018, for the first-line treatment of people with metastatic non-squamous, non-small cell lung cancer (NSq NSCLC) with no EGFR or ALK genomic tumor aberrations.[ ] Approval was based on the IMpower150 trial (NCT02366143), an open-label, randomized (1:1:1), three-arm trial enrolling 1202 participants receiving first-line treatment for metastatic NSq NSCLC.
In March 2019, it was approved in the United States, in combination with paclitaxel protein-bound, for adults with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells Cof any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for atezolizumab.
Approval was based on IMpassion130 (NCT02425891), a multicenter, international, double-blinded, placebo-controlled, randomized trial that included 902 participants with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Participants were randomized (1:1) to receive either atezolizumab (840 mg) or placebo intravenous infusions on days 1 and 15 of every 28-day cycle, plus paclitaxel protein-bound (100 mg/m2) administered via intravenous infusion on days 1, 8, and 15 of every 28-day cycle.
In March 2019, it was approved in the United States, in combination with carboplatin and etoposide
Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).[ ]
Approval was based on IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 participants with ES-SCLC who received no prior chemotherapy for extensive stage disease and had ECOG performance status 0 or 1.
In December 2019, atezolizumab in combination with paclitaxel protein-bound and carboplatin was approved by the FDA for the first-line treatment of adults with metastatic non-squamous non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.[ ]
Efficacy was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in participants with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease, but could have received prior EGFR or ALK kinase inhibitor, if appropriate. The trial randomized 724 participants (ITT) to receive atezolizumab, paclitaxel protein-bound, and carboplatin, followed by single-agent atezolizumab or to receive paclitaxel protein-bound and carboplatin, followed by maintenance pemetrexed at the investigator's discretion (control).
In May 2020, the atezolizumab was approved by the FDA for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells C ≥ 50%or PD-L1 stained tumor-infiltrating immune cells Ccovering ≥ 10% of the tumor area C ≥ 10%, with no EGFR or ALK genomic tumor aberrations.[ ]
Efficacy was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in participants with stage IV NSCLC whose tumors express PD-L1 (TC ≥ 1% or IC ≥ 1%), who had received no prior chemotherapy for metastatic disease. Participants were randomized (1:1) to receive atezolizumab 1200 mg every three weeks until disease progression or unacceptable toxicity or platinum-based chemotherapy.
In May 2020, atezolizumab in combination with bevacizumab was approved by the FDA for people with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.[ ]
Efficacy was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in participants with locally advanced unresectable or metastatic hepatocellular carcinoma who had not received prior systemic therapy. A total of 501 participants were randomized (2:1) to receive either atezolizumab 1200 mg as an intravenous infusion (IV) followed by bevacizumab 15 mg/kg IV on the same day, every 3 weeks, or sorafenib orally twice daily.
In July 2020, it was approved in the United States, in combination with cobimetinib
Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma. Cobimetinib is a MEK inhibitor. Cotelli ...
and vemurafenib
Vemurafenib (INN, marketed as Zelboraf) is an inhibitor of the B-Raf enzyme developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma.; The name "vemurafenib" comes from V600E mutated BRAF i ...
, for the treatment of people with BRAF V600 mutation-positive unresectable or metastatic melanoma.[ ]
Efficacy in combination with cobimetinib and vemurafenib was evaluated in a double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150, NCT02908672) in 514 participants. After a 28-day cycle of cobimetinib and vemurafenib, participants received atezolizumab 840 mg intravenous infusion every 2 weeks in combination with cobimetinib 60 mg orally once daily and vemurafenib 720 mg orally twice daily, or placebo in combination with cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 960 mg orally twice daily.
IMpower110 randomized patients with stage IV NSCLC with PD-L1 expression ≥ 1% to atezolizumab single agent or to chemotherapy.[ Text was copied from this source, which is available under ]
Creative Commons Attribution 4.0 International License
The chemotherapy used was Cisplatin or Carboplatin, combined with gemcitabine for patient with squamous cell NSCLC, or pemetrexed for patients with nonsquamous disease. Atezolizumab was better tolerated than chemotherapy. In the subgroup of patients with EGFR and ALK wild-type tumors who had PD-L1 stained ≥ 50% of tumor cells (205 patients), the overall survival was 20.2 months with atezolizumab, and 13.1 months with chemotherapy. FDA approval is for patients with PD-L1 stained ≥ 50% of tumor cells, or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area, with no EGFR or ALK genomic tumor aberrations.
IMpower130 was an open-label, phase III trial that compared atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy, with chemotherapy alone as first-line treatment for metastatic non-squamous NSCLC. About half of the patients had PD-L1 negative tumors. Median overall survival was 18.6 months in the atezolizumab plus chemotherapy group and 13.9 months in the chemotherapy group; HR 0.79, p = 0.033. Subgroup analysis showed progression free survival benefit, and a trend toward overall survival benefit in all PD-L1 expression levels.
IMpower150 randomized patients with NSq NSCLC to treatment with chemotherapy plus bevacizumab, chemotherapy plus atezolizumab or chemotherapy plus bevacizumab and atezolizumab. The chemotherapy used was carboplatin and paclitaxel. Median overall survival was 19.8 and 14.9 months for patients treated with chemotherapy plus bevacizumab, with or without atezolizumab, respectively. Median OS with atezolizumab and chemotherapy alone was 19.5 months, raising question with regard to the added value of Bevacizumab to this combination for the general patients population. Importantly, patients with baseline liver metastases had an improved overall survival with atezolizumab, bevacizumab, and chemotherapy combination, compared to bevacizumab and chemotherapy alone, with a median OS of 13.3 and 9.4 months, respectively, HR 0.52. No improvement in overall survival was observed for patients with liver metastasis treated with chemotherapy and atezolizumab compared to patients treated with chemotherapy and bevacizumab. Recent report about safety and patient-reported outcomes of atezolizumab plus chemotherapy and bevacizumab shows that this drug combination seems tolerable and with manageable toxicities. For patients with NSq NSCLC with baseline liver metastases, the combination of chemotherapy, atezolizumab and bevacizumab could be an option to consider in the first line.
Society and culture
Drug cost controversy
Atezolizumab treatment costs on average per month in the United States, depending on the dosage schedule.
Despite updated data showing 30% more people with extensive stage small cell lung cancer
Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell ca ...
are alive at 24 months compared to those who received chemotherapy alone, Canadian regulator had rejected to fund atezolizumab for extensive stage small-cell lung cancer "as too costly" followed by United Kingdom also citing "drug's cost-effectiveness." However, U.K. reversed its previous decision and approved tecentriq for extensive stage small cell lung cancer after price re-think on May 27, 2020.
Research
, it is in clinical trials for colorectal cancer, melanoma, breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
, non-small-cell lung carcinoma
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
, bladder cancer
Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become ma ...
, renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, res ...
.
Promising results have been observed for melanoma and non-small-cell lung cancer, and bladder cancer.[
A phase I trial reported a 19% ]objective response rate
Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of disease, symptom, sign or laboratory abnormality constituting a target outcome in clinical research trials. The term may also refer to any disease or sign tha ...
in metastatic triple-negative breast cancer
Triple-negative breast cancer (TNBC) is any breast cancer that lacks or show low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the tu ...
.
As of 2019, atezolizumab is in trial for several types of cancer, such as pancreatic cancer
Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of panc ...
, gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Ly ...
and ovarian Cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
.
References
External links
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