Tyrosine kinase inhibitor

Tyrosine kinase inhibitors are inhibitors that inhibit various enzymes from the group of tyrosine kinases . Some tyrosine kinase inhibitors are drugs - active ingredients that have so far been used primarily for tumor diseases . In the medical sense, it is understood to mean chemical substances that have been specially designed and optimized for the inhibition of certain tyrosine kinases (so-called designer drugs ). There are also monoclonal antibodies against receptor tyrosine kinases . However, these are generally not referred to as “tyrosine kinase inhibitors”. Tyrosine kinase inhibitors are among the protein kinase inhibitors . Some tyrosine kinase inhibitors are Src inhibitors .

It has been known since around the 1990s that dysregulated tyrosine kinases often play a key role in the development of tumor diseases. So the concept was developed to specifically inhibit these tyrosine kinases with inhibitors in order to treat the tumor disease. Chronic myeloid leukemia (CML) showed convincingly that this is actually possible . In CML, the permanently activated and dysregulated ABL tyrosine kinase is the cause of the disease. The use of the newly developed tyrosine kinase inhibitor imatinib resulted in very good treatment successes. Today imatinib is considered the standard in the treatment of CML.

This success has given a great boost to research into specific tyrosine kinase inhibitors, and a large number of such substances are now in preclinical testing or already in clinical use. Tyrosine kinase inhibitors have a much more specific effect and usually have a lower spectrum of side effects than conventional cytostatics .

Commercially available tyrosine kinase inhibitors

Tyrosine kinase inhibitor	Trade name	Manufacturer	Inhibition of tyrosine kinases	Field of application (indication)	Date of first approval
Afatinib	Giotrif (Europe), Gilotrif (USA)	Boehringer Ingelheim	ErbB family, d. H. EGFR1 / HER1 (ErbB-1) , HER2 / c-neu (ErbB-2) , HER3 (ErbB-3) and HER4 (ErbB-4)	Non-small cell lung cancer (NSCLC)	USA: Jul 12, 2013. Europe: Sept 25, 2013.
Alectinib	Alcensa	Roche	ALK	Non-small cell lung cancer with an ALK mutation	USA: Dec 11, 2015 Europe: Feb 21, 2017.
Axitinib	Inlyta	Pfizer	VEGFR , PDGFRA / B , KIT , ...	Renal cell carcinoma (RCC)	USA: Europe:
Bosutinib	Bosulif	Pfizer	ABL , SRC , ...	Chronic myeloid leukemia (CML)	USA: Sep 4 2012 Europe: March 27, 2013
Cabozantinib	Cometriq (MTC) Cabometyx (RCC)	Exelixis	RET , MET , VEGFR2 , ...	Thyroid cancer (MTC) Renal cell carcinoma (RCC) Liver cell cancer	USA: Nov 29, 2012 USA: Dec 19, 2017 Europe: Mar 21, 2014 Europe: Sep 9. 2016 Europe: November 2018
Crizotinib	Xalkori	Pfizer	ALK , ROS1 , MET	ALK -positive non-small cell lung cancer (NSCLC)	USA: Aug 26, 2011 Europe: Oct 23, 2012
Dasatinib	Sprycel	Bristol-Myers Squibb	ABL , ...	Chronic myeloid leukemia (CML) BCR-ABL -positive acute lymphoblastic leukemia (ALL)	USA: Jun 28, 2006 Europe: Dec 23, 2005.
Erlotinib	Tarceva	Hoffmann-La Roche	EGFR1 , ...	Non-small cell lung cancer pancreatic cancer	USA: Nov. 18, 2004 USA: Nov. 2, 2005 Europe: Sep. 19 2005
Gefitinib	Iressa	AstraZeneca	EGFR , ...	Non-small cell lung cancer with activating EGFR mutations	USA: May 2, 2003, severely restricted Jun. 17, 2005 Europe: Jun. 24, 2009
Gilteritinib	Xospata	Astellas	FLT3 / AXL	Acute myeloid leukemia	USA: NN Europe: October 25, 2019
Ibrutinib	Imbruvica	Pharmacyclics Janssen	BTK	Mantle cell lymphoma Chronic lymphatic leukemia	USA: Nov 13, 2013 Europe: Oct 20, 2014
Imatinib	Glivec (Europe) Gleevec (USA)	Novartis	ABL , KIT , PDGFRA , PDGFRB , ...	Chronic myeloid leukemia (CML) GIST BCR-ABL -positive acute lymphoblastic leukemia Dermatofibrosarcoma protuberans special cases of myeloproliferative neoplasias or hypereosinophilic syndromes / eosinophilic leukemia	USA: Apr. 18, 2003 Europe: Nov. 7, 2001 (extended Nov. 7, 2006)
Lapatinib	Tykerb (USA) Tyverb (Europe)	GlaxoSmithKline	ERBB2 , ...	Breast cancer ( HER2 / new +)	USA: Mar 13, 2007 Europe: Jun 10, 2008.
Lenvatinib	Lenvima	Eisai	VEGF	Thyroid cancer, hepatocellular carcinoma, renal cell carcinoma	USA: Feb 16, 2015 Europe: Jun 1, 2015
Midostaurin	Rydapt	Novartis	MS-like tyrosine kinase 3 mutation-positive (FLT3 +)	Acute myeloid leukemia mastocytosis	USA: Apr 28, 2017
Neratinib	Nerlynx	Pierre Fabre	ERBB1 , ERBB2 and ERBB4	Breast cancer ( HER2 / new +)	USA: July 17, 2017 Europe: August 31, 2018
Nilotinib	Tasigna	Novartis	ABL , KIT , PDGFRA , PDGFRB , ....	Chronic myeloid leukemia	USA: Oct 29, 2007 Europe: Nov 19, 2007
Nintedanib	Vargatef, Ofev	Boehringer Ingelheim	VEGF , FGF , PDGF , ....	Bronchial carcinoma and pulmonary fibrosis .	USA: NN Europe: NN
Pazopanib	Votrient	Novartis	VEGFR , PDGFR , KIT	Renal cell carcinoma certain types of soft tissue sarcoma	USA: Oct 19, 2009 Europe: Jun 14, 2010
Ponatinib	Iclusig	Ariad	ABL , SRC , FLT3 , FGFR , VEGFR , ...	Chronic myeloid leukemia, BCR-ABL- positive acute lymphoblastic leukemia	USA: Dec. 14, 2012 from Oct. 31 to Dec. 20, 2013 removed from the market by the FDA Europe: Jul
Regorafenib	Stivarga	Bayer	VEGFR2 , ...	Colorectal carcinoma , gastrointestinal stromal tumor (GIST), hepatocellular carcinoma	USA: Sep 27 2012 Europe: Aug 26, 2013.
Ruxolitinib	Jakafi (USA) Jakavi (EU)	Incyte Novartis	JAK2 , ...	Myelofibrosis Chronic neutrophil leukemia	USA: Europe:
Sorafenib	Nexavar	Bayer	VEGFR2 , VEGFR3 , ...	Renal cell carcinoma, hepatic cell carcinoma , thyroid carcinoma	USA: Dec. 20, 2005 and Nov. 19, 2007 Europe: Jul. 19, 2006
Sunitinib	Sutent	Pfizer	VEGFR1-3 , PDGFRA , PDGFRB , KIT , FLT3	Renal cell carcinoma, GIST, pancreatic neuroendocrine tumors	USA: Feb. 2, 2007, Europe: Jul. 19, 2006
Tofacitinib	Xeljanz	Pfizer	JAK3 , ...	Rheumatoid arthritis Ulcerative colitis	USA: Europe:
Vandetanib	Caprelsa	Genzyme	RET , VEGFR , ...	Thyroid cancer	USA: Europe:

Other partially approved tyrosine kinase inhibitors are e.g. B. bafetinib , masitinib and nintedanib .

Commercially available veterinary tyrosine kinase inhibitors

Tyrosine kinase inhibitor	Trade name	Manufacturer	Inhibition of tyrosine kinases	Field of application (indication)
Masitinib	Masivet	AB Science	KIT	Canine mast cell tumor
Toceranib	Palladia	Pfizer	KIT , VEGFR , PDGFR	Canine mast cell tumor

Individual evidence

^ Doriano Fabbro, Frank McCormick: Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Cancer Drug Discovery and Development. Springer Science & Business Media, 2007. ISBN 978-1-59259-962-2 . P. 1ff.
↑ ^a ^b ^c Summary of the EPAR for the public (German)
↑ FDA approves new treatment for a type of late-stage lung cancer , PM FDA of July 12, 2013
↑ European public assessment report , EPAR (English); s. Authorization details.
↑ FDA approves new oral therapy to treat ALK-positive lung cancer. FDA, December 11, 2015, accessed September 22, 2017 .
↑ Media release: Roche receives EU approval of Alecensa (alectinib) for people with previously treated ALK-positive non-small cell lung cancer. Roche, February 21, 2017, accessed on September 22, 2017 .
↑ Approval by the FDA for chronic myeloid leukemia in the case of intolerance or ineffectiveness of other therapies
↑ Appendix 1: Summary and Characteristics of the Medicinal Product. (PDF; 520 kB) EMA, accessed on May 29, 2013 (Approval for the treatment of CML if at least one tyrosine dinate inhibitor has already been tried and if imatinib, nilotinib and dasatinib are not considered useful. Approval was granted only conditionally and has to be be renewed annually).
↑ FDA: Cometriq. Retrieved May 7, 2015 .
↑ FDA: Cabometyx. Retrieved April 6, 2018 .
↑ EMA: Cometriq. Retrieved September 27, 2015 .
↑ EMA: Cabometyx. Retrieved April 6, 2018 .
↑ Cabozantinib (Cabometyx) for advanced liver cell cancer. Retrieved June 6, 2019 .
↑ FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. Retrieved July 7, 2013 .
↑ Xalkori: crizotinib. Retrieved July 7, 2013 .
↑ Approval by the FDA for CML and ALL in the event of failure or intolerance of a previous imatinib-containing therapy ( FDA approves dasatinib (Sprycel) ( Memento of November 7, 2008 in the Internet Archive ) )
↑ Approval as orphan drug for the CML and BCR-ABL -positive ALL statement of the European Medicines Agency (pdf) .
↑ Approval by the FDA for locally advanced or metastatic non-small cell lung cancer after failure of at least one previous chemotherapy ( FDA News ( Memento of May 13, 2009 in the Internet Archive ))
↑ Approval by the FDA for the combination therapy with gemcitabine for inoperable or metastatic pancreatic cancer ( FDA Approval for Erlotinib Hydrochloride, National Cancer Institute Drug Information ( Memento of December 22, 2010 in the Internet Archive ))
↑ Approval by the European Medicines Agency for patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one previous chemotherapy and in patients with metastatic pancreatic cancer in combination with gemcitabine ( approval information from the European Medicines Agency (pdf) )
↑ Approval letter from the FDA for Iressa ^® ( Memento of May 13, 2009 in the Internet Archive ) (PDF; 25 kB).
↑ After the INTACT1 and INTACT2 studies showed no life extension with Iressa versus placebo ( FDA statement on Iressa December 17, 2004 ( Memento of March 9, 2008 in the Internet Archive )), the FDA restricted approval to patients who Iressa had already received and, in the opinion of the treating physicians, benefited from it ( FDA statement ( Memento of May 28, 2009 in the Internet Archive ))

↑ Iressa approval text of the EMEA (pdf) .

↑ European Commission Approves Astellas' XOSPATA ™ (gilteritinib) as a Monotherapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation , PM Astellas, October 25, 2019, accessed October 29, 2019.

↑ FDA approves Imbruvica for rare blood cancer .

↑ with rearrangement of the gene for the platelet factor receptor beta PDGFRB

↑ with the fusion gene FIP1L1-PDGFRA

↑ FDA infopage Gleevec (Imatinib Mesylate) , especially Regulatory history including approval letters and reviews from Drugs @ FDA

↑ European Public Assessment Report (EPAR) Glivec (pdf) of the European Medicines Agency.

↑ Approval for combination therapy with capecitabine (Xeloda ^® ) in patients with HER2 / neu-positive breast cancer who have already had previous therapy with anthracyclines , taxanes and trastuzumab (Herceptin ^® ) ( FDA Approves Tykerb for Advanced Breast Cancer Patients )

↑ Regulatory information from the European Medicines Agency .

↑ US FDA APPROVES ANTICANCER AGENT LENVIMA ™ (LENVATINIB MESYLATE) AS TREATMENT FOR RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER , Eisai PM on February 16, 2015.

↑ EISAI RECEIVES EUROPEAN COMMISSION APPROVAL OF ANTICANCER AGENT LENVIMA® FOR TREATMENT OF ADVANCED THYROID CANCER REFRACTORY TO RADIOACTIVE IODINE , PM Eisai from June 1, 2015.

↑ Novartis receives FDA approval for Rydapt® in newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and three types of systemic mastocytosis (SM) , PM Novartis April 28, 2017, accessed May 11, 2017.

↑ FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer , PM FDA, accessed October 27, 2019.

↑ Summary of Product Characteristics , EMA EPAR, accessed on October 27, 2019.

↑ Approval by the FDA for CML in chronic or accelerated phase and imatinib intolerance or ineffectiveness, FDA Grants Accelerated Approval to Nilotinib (Tasigna) to Treat Leukemia ( Memento from March 1, 2009 in the Internet Archive )

↑ Authorization by the European Medicines Agency for Imatinib intolerance or ineffectiveness as an orphan medicinal product , European Public Assessment Report (EPAR) Tasigna (pdf; 60 kB).

↑ Approval by the FDA for advanced renal cell carcinoma

↑ Approval for advanced renal cell carcinoma that has not been treated or has been pretreated with cytokines .

↑ FDA approval for ponatinib for patients with chronic myeloid leukemia or BCR-ABL-positive acute lymphoblastic leukemia, in whom other tyrosine kinase inhibitors are ineffective or incompatible.

↑ FDA.gov .

↑ FDA approval for regorafenib for the treatment of patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy based on fluoropyrimidines, oxaliplatin or irinotecan, anti-VEGF therapy or, in the case of non-mutated (wild-type) KRAS gene who were treated with anti-EGFR therapy.

↑ EMA: Stivarga (regorafenib) - authorization details .

↑ FDA Approves New Treatment for Advanced Kidney Cancer ( February 22, 2009 memento on the Internet Archive ) , FDA News, accessed July 3, 2008.

↑ FDA Approves Nexavar for Patients with Inoperable Liver Cancer , FDA News, accessed July 3, 2008.

↑ Authorization by the European Medicines Agency for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma if treatment with interferon- α / interleukin-2 was unsuccessful or not possible ( Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Nexavar )

↑ FDA converts approval from accelerated to regular for sunitinib malate (Sutent) for the treatment of advanced renal cell carcinoma ( Memento from March 1, 2009 in the Internet Archive )

↑ Registration information from the European Medicines Agency (pdf) .

[1] Doriano Fabbro, Frank McCormick: Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Cancer Drug Discovery and Development. Springer Science & Business Media, 2007. ISBN 978-1-59259-962-2 . P. 1ff.

[EPAR_dt-2] Summary of the EPAR for the public (German)

[3] FDA approves new treatment for a type of late-stage lung cancer , PM FDA of July 12, 2013

[4] European public assessment report , EPAR (English); s. Authorization details.

[5] FDA approves new oral therapy to treat ALK-positive lung cancer. FDA, December 11, 2015, accessed September 22, 2017 .

[6] Media release: Roche receives EU approval of Alecensa (alectinib) for people with previously treated ALK-positive non-small cell lung cancer. Roche, February 21, 2017, accessed on September 22, 2017 .

[7] Approval by the FDA for chronic myeloid leukemia in the case of intolerance or ineffectiveness of other therapies

[8] Appendix 1: Summary and Characteristics of the Medicinal Product. (PDF; 520 kB) EMA, accessed on May 29, 2013 (Approval for the treatment of CML if at least one tyrosine dinate inhibitor has already been tried and if imatinib, nilotinib and dasatinib are not considered useful. Approval was granted only conditionally and has to be be renewed annually).

[9] FDA: Cometriq. Retrieved May 7, 2015 .

[10] FDA: Cabometyx. Retrieved April 6, 2018 .

[11] EMA: Cometriq. Retrieved September 27, 2015 .

[12] EMA: Cabometyx. Retrieved April 6, 2018 .

[13] Cabozantinib (Cabometyx) for advanced liver cell cancer. Retrieved June 6, 2019 .

[14] FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. Retrieved July 7, 2013 .

[15] Xalkori: crizotinib. Retrieved July 7, 2013 .

[16] Approval by the FDA for CML and ALL in the event of failure or intolerance of a previous imatinib-containing therapy ( FDA approves dasatinib (Sprycel) ( Memento of November 7, 2008 in the Internet Archive ) )

[17] Approval as orphan drug for the CML and BCR-ABL -positive ALL statement of the European Medicines Agency (pdf) .

[18] Approval by the FDA for locally advanced or metastatic non-small cell lung cancer after failure of at least one previous chemotherapy ( FDA News ( Memento of May 13, 2009 in the Internet Archive ))

[19] Approval by the FDA for the combination therapy with gemcitabine for inoperable or metastatic pancreatic cancer ( FDA Approval for Erlotinib Hydrochloride, National Cancer Institute Drug Information ( Memento of December 22, 2010 in the Internet Archive ))

[20] Approval by the European Medicines Agency for patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one previous chemotherapy and in patients with metastatic pancreatic cancer in combination with gemcitabine ( approval information from the European Medicines Agency (pdf) )

[21] Approval letter from the FDA for Iressa ^® ( Memento of May 13, 2009 in the Internet Archive ) (PDF; 25 kB).

[22] After the INTACT1 and INTACT2 studies showed no life extension with Iressa versus placebo ( FDA statement on Iressa December 17, 2004 ( Memento of March 9, 2008 in the Internet Archive )), the FDA restricted approval to patients who Iressa had already received and, in the opinion of the treating physicians, benefited from it ( FDA statement ( Memento of May 28, 2009 in the Internet Archive ))

[23] Iressa approval text of the EMEA (pdf) .

[24] European Commission Approves Astellas' XOSPATA ™ (gilteritinib) as a Monotherapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation , PM Astellas, October 25, 2019, accessed October 29, 2019.

[25] FDA approves Imbruvica for rare blood cancer .

[26] with rearrangement of the gene for the platelet factor receptor beta PDGFRB

[27] with the fusion gene FIP1L1-PDGFRA

[28] FDA infopage Gleevec (Imatinib Mesylate) , especially Regulatory history including approval letters and reviews from Drugs @ FDA

[29] European Public Assessment Report (EPAR) Glivec (pdf) of the European Medicines Agency.

[30] Approval for combination therapy with capecitabine (Xeloda ^® ) in patients with HER2 / neu-positive breast cancer who have already had previous therapy with anthracyclines , taxanes and trastuzumab (Herceptin ^® ) ( FDA Approves Tykerb for Advanced Breast Cancer Patients )

[31] Regulatory information from the European Medicines Agency .

[32] US FDA APPROVES ANTICANCER AGENT LENVIMA ™ (LENVATINIB MESYLATE) AS TREATMENT FOR RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER , Eisai PM on February 16, 2015.

[33] EISAI RECEIVES EUROPEAN COMMISSION APPROVAL OF ANTICANCER AGENT LENVIMA® FOR TREATMENT OF ADVANCED THYROID CANCER REFRACTORY TO RADIOACTIVE IODINE , PM Eisai from June 1, 2015.

[34] Novartis receives FDA approval for Rydapt® in newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and three types of systemic mastocytosis (SM) , PM Novartis April 28, 2017, accessed May 11, 2017.

[35] FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer , PM FDA, accessed October 27, 2019.

[36] Summary of Product Characteristics , EMA EPAR, accessed on October 27, 2019.

[37] Approval by the FDA for CML in chronic or accelerated phase and imatinib intolerance or ineffectiveness, FDA Grants Accelerated Approval to Nilotinib (Tasigna) to Treat Leukemia ( Memento from March 1, 2009 in the Internet Archive )

[38] Authorization by the European Medicines Agency for Imatinib intolerance or ineffectiveness as an orphan medicinal product , European Public Assessment Report (EPAR) Tasigna (pdf; 60 kB).

[39] Approval by the FDA for advanced renal cell carcinoma

[40] Approval for advanced renal cell carcinoma that has not been treated or has been pretreated with cytokines .

[41] FDA approval for ponatinib for patients with chronic myeloid leukemia or BCR-ABL-positive acute lymphoblastic leukemia, in whom other tyrosine kinase inhibitors are ineffective or incompatible.

[42] FDA.gov .

[43] FDA approval for regorafenib for the treatment of patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy based on fluoropyrimidines, oxaliplatin or irinotecan, anti-VEGF therapy or, in the case of non-mutated (wild-type) KRAS gene who were treated with anti-EGFR therapy.

[44] EMA: Stivarga (regorafenib) - authorization details .

[45] FDA Approves New Treatment for Advanced Kidney Cancer ( February 22, 2009 memento on the Internet Archive ) , FDA News, accessed July 3, 2008.

[46] FDA Approves Nexavar for Patients with Inoperable Liver Cancer , FDA News, accessed July 3, 2008.

[47] Authorization by the European Medicines Agency for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma if treatment with interferon- α / interleukin-2 was unsuccessful or not possible ( Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Nexavar )

[48] FDA converts approval from accelerated to regular for sunitinib malate (Sutent) for the treatment of advanced renal cell carcinoma ( Memento from March 1, 2009 in the Internet Archive )

[49] Registration information from the European Medicines Agency (pdf) .