Crizotinib

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Crizotinib
Crizotinib fix.svg
Clinical data
Trade names Xalkori, others
Other namesPF-02341066
1066
AHFS/Drugs.com Monograph
MedlinePlus a612018
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 43%
Protein binding 91%
Metabolism Liver (CYP3A4/CYP3A5-mediated)
Elimination half-life 42 hours
Excretion Faeces (63%), urine (22%)
Identifiers
  • 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.166.440 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H22Cl2FN5O
Molar mass 450.34 g·mol−1
3D model (JSmol)
  • C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl
  • InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 Yes check.svgY
  • Key:KTEIFNKAUNYNJU-GFCCVEGCSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). [1] [2] [3] [4] It acts as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor. [5] [6] [7]

Contents

Medical uses

Crizotinib is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) or relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. [1] [2]

It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT). [1] [8]

Mechanism of action

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2 2xp2.png
Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. [10] The kinase activity of the fusion protein is inhibited by crizotinib. [10] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene. [10] [11] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide. [12] [13]

ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children. [14]

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms. [15]

Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. [15] [16] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors. [17]

Society and culture

In August 2011, the US Food and Drug Administration (FDA) approved crizotinib to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. [3] Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the FDA approved crizotinib in ROS1-positive non-small cell lung cancer. [18]

In October 2012, the European Medicines Agency (EMA) approved the use of crizotinib to treat non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. [2] [19]

Research

Lung cancer

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene. [11] [12] Tumors shrank at least 30% in 57% of people treated. [12] [20] Most had adenocarcinoma, and had never smoked or were former smokers. [11] They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy. [11] [21] They were given 250 mg crizotinib twice daily for a median duration of six months. [11] Approximately 50% of these patients had at least one side effect, such as nausea, vomiting, or diarrhea. [21] Some responses to crizotinib have lasted up to 15 months. [21]

A Phase III trial, PROFILE 1007, [22] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC. [23] [13] [24] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy. [13]

In February 2016, the J-ALEX phase III study comparing alectinib with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed that progression-free survival was longer with alectinib. [25] These results were confirmed in a 2017 analysis. [26]

Lymphomas

In people affected by relapsed or refractory ALK+ anaplastic large cell lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60–75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present. [27] [28] [29]

Other cancers

Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma. [30]

Related Research Articles

<span class="mw-page-title-main">Anaplastic large-cell lymphoma</span> Medical condition

Anaplastic large-cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large-cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However, the four types have very different clinical presentations, gene abnormalities, prognoses, and/or treatments.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Non-small-cell lung cancer</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

<span class="mw-page-title-main">Anaplastic lymphoma kinase</span> Protein-coding gene in the species Homo sapiens

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.

<span class="mw-page-title-main">ROS1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.

<span class="mw-page-title-main">Adenocarcinoma of the lung</span> Medical condition

Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.

<span class="mw-page-title-main">ALK inhibitor</span>

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion, although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC. For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.

<span class="mw-page-title-main">ALK positive lung cancer</span> Medical condition

ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein, most frequently, the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. Less frequently, there will be novel translocation partners for the ALK gene, in place of EML4. This abnormal gene fusion leads to the production of a protein that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.

<span class="mw-page-title-main">Brigatinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

<span class="mw-page-title-main">Inflammatory myofibroblastic tumour</span> Medical condition

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of the mesodermal cells that form the connective tissues which support virtually all of the organs and tissues of the body. IMT was formerly termed inflammatory pseudotumor. Currently, however, inflammatory pseudotumor designates a large and heterogeneous group of soft tissue tumors that includes inflammatory myofibroblastic tumor, plasma cell granuloma, xanthomatous pseudotumor, solitary mast cell granuloma, inflammatory fibrosarcoma, pseudosarcomatous myofibroblastic proliferation, myofibroblastoma, inflammatory myofibrohistiocytic proliferation, and other tumors that develop from connective tissue cells. Inflammatory pseudotumour is a generic term applied to various neoplastic and non-neoplastic tissue lesions which share a common microscopic appearance consisting of spindle cells and a prominent presence of the white blood cells that populate chronic or, less commonly, acute inflamed tissues.

Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.

<span class="mw-page-title-main">Ceritinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Ceritinib is a prescription-only drug used for the treatment of non-small cell lung cancer (NSCLC). It was developed by Novartis and received FDA approval for use in April 2014..Ceritinib is also sold under the brand name Spexib in few countries by Novartis.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Alectinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Alectinib (INN,), sold under the brand name Alecensa, is an anticancer medication that is used to treat non-small-cell lung cancer (NSCLC). It blocks the activity of anaplastic lymphoma kinase (ALK). It is taken by mouth. It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group.

<span class="mw-page-title-main">Entrectinib</span> TKI inhibitor used for cancer treatment

Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

<span class="mw-page-title-main">Lorlatinib</span> Kinase inhibitor for treatment of non-small-cell lung cancer

Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play a role in the development of cancer.

<span class="mw-page-title-main">Selpercatinib</span> Chemical compound

Selpercatinib, sold under the brand name Retevmo among others, is a medication for the treatment of cancers in people whose tumors have an alteration in a specific gene. It is taken by mouth.

<span class="mw-page-title-main">Repotrectinib</span> Medication

Repotrectinib, sold under the brand name Augtyro, is an anti-cancer medication used for the treatment of non-small cell lung cancer. It is taken by mouth. Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC.

References

  1. 1 2 3 4 "Xalkori- crizotinib capsule". DailyMed. Archived from the original on 9 October 2021. Retrieved 18 April 2021.
  2. 1 2 3 4 "Xalkori EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 19 April 2021. Retrieved 18 April 2021.
  3. 1 2 "Drug Approval Package: Xalkori Capsules (crizotinib) NDA #202570". U.S. Food and Drug Administration (FDA). 27 September 2011. Archived from the original on 7 April 2021. Retrieved 18 April 2021.
  4. ↑ "Summary Review for Regulatory Action" (PDF). U.S. Food and Drug Administration (FDA). 26 August 2011. Archived (PDF) from the original on 6 April 2021. Retrieved 19 April 2021.
  5. ↑ Forde PM, Rudin CM (June 2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opinion on Pharmacotherapy. 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID   22594847. S2CID   23715951.
  6. ↑ Roberts PJ (2013). "Clinical use of crizotinib for the treatment of non-small cell lung cancer". Biologics: Targets and Therapy. 7: 91–101. doi: 10.2147/BTT.S29026 . PMC   3643289 . PMID   23671386.
  7. ↑ Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (April 2013). "Crizotinib: A comprehensive review". South Asian Journal of Cancer. 2 (2): 91–7. doi: 10.4103/2278-330X.110506 . PMC   3876666 . PMID   24455567.
  8. ↑ "FDA approves crizotinib for ALK-positive inflammatory myofibroblastic tumor". U.S. Food and Drug Administration (FDA) (Press release). 14 July 2022. Archived from the original on 14 July 2022. Retrieved 14 July 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. ↑ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al. (September 2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". Journal of Medicinal Chemistry. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID   21812414.
  10. 1 2 3 "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 12 May 2010. Archived from the original on 6 December 2012. Retrieved 7 June 2010.
  11. 1 2 3 4 5 "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 5 June 2010. Archived from the original on 6 April 2020. Retrieved 7 June 2010.
  12. 1 2 3 Winslow R (7 June 2010). "Advances Come in War on Cancer". The Wall Street Journal. Archived from the original on 9 October 2021. Retrieved 7 June 2010.
  13. 1 2 3 "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (PDF) (Press release). Pfizer Oncology. 20 May 2010. Archived from the original (PDF) on 12 June 2010. Retrieved 7 June 2010.
  14. ↑ Janoueix-Lerosey I, Schleiermacher G, Delattre O (March 2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi: 10.1038/onc.2009.518 . PMID   20101209.
  15. 1 2 Clinical trial number NCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" at ClinicalTrials.gov
  16. ↑ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, et al. (December 2007). "Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma". Molecular Cancer Therapeutics. 6 (12 Pt 1): 3314–22. doi: 10.1158/1535-7163.MCT-07-0365 . PMID   18089725.
  17. ↑ Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, et al. (May 2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms". Cancer Research. 67 (9): 4408–17. doi: 10.1158/0008-5472.CAN-06-4443 . PMID   17483355.
  18. ↑ "NICE backs Pfizer's Xalkori after squeezing out a new discount – FiercePharma". 18 August 2016. Archived from the original on 8 August 2020. Retrieved 18 August 2016.
  19. ↑ "Xalkori - EMEA/H/C/002489 - T/0059" (PDF). European Medicines Agency. 2012. Archived (PDF) from the original on 4 October 2018. Retrieved 22 October 2018.
  20. ↑ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". Archived from the original on 28 January 2011. NB Fig 1.
  21. 1 2 3 "Gene-based lung cancer drug shows promise". NBC News. 7 May 2010. Retrieved 7 June 2010.
  22. ↑ "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer. Archived (PDF) from the original on 3 March 2016. Retrieved 16 August 2014.
  23. ↑ Clinical trial number NCT00932451 for "An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
  24. ↑ Clinical trial number NCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
  25. ↑ "Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit" (PDF). Roche. February 2016. Archived (PDF) from the original on 18 April 2016. Retrieved 8 December 2017.
  26. ↑ "FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer". Healio. November 2017. Archived from the original on 9 December 2017. Retrieved 8 December 2017.
  27. ↑ Gambacorti-Passerini C, et al. (2010). "Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients". Annual Meeting of the American Society of Hematology. Orlando, Florida.
  28. ↑ Gambacorti-Passerini C, Messa C, Pogliani EM (February 2011). "Crizotinib in anaplastic large-cell lymphoma". The New England Journal of Medicine. 364 (8): 775–6. doi: 10.1056/NEJMc1013224 . PMID   21345110.
  29. ↑ Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, et al. (February 2014). "Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients". Journal of the National Cancer Institute. 106 (2): djt378. doi: 10.1093/jnci/djt378 . PMID   24491302.
  30. ↑ Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP (2009). "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066". J Clin Oncol. 27 (15s. suppl, abstr 10008b): 10008b. doi:10.1200/jco.2009.27.15_suppl.10008b. Archived from the original on 16 August 2014.
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