Pemigatinib

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Pemigatinib
Pemigatinib.svg
Clinical data
Trade names Pemazyre
Other namesINCB054828
AHFS/Drugs.com Monograph
MedlinePlus a620028
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(morpholin4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C24H27F2N5O4
Molar mass 487.508 g·mol−1
3D model (JSmol)
  • CCN1C2=C3C=C(NC3=NC=C2CN(C1=O)C4=C(C(=CC(=C4F)OC)OC)F)CN5CCOCC5
  • InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)
  • Key:HCDMJFOHIXMBOV-UHFFFAOYSA-N

Pemigatinib, sold under the brand name Pemazyre, is an anti-cancer medication used for the treatment of bile duct cancer (cholangiocarcinoma). [5] [6] [8] [9] Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading. [8]

Contents

Pemigatinib belongs to a group of medicines called protein kinase inhibitors. [10] It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs). [10] FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells. [10] By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer. [10]

The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin. [8] [9] Ocular (eye) toxicity is also a risk of pemigatinib. [8] [9] Additional common adverse reactions include rash, anemia, epistaxis, serous retinal detachment, extremity pain, dyspepsia, blurred vision, peripheral edema, and dizziness. [11]

Medical uses

Pemigatinib is indicated for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy. [5] [6] [8] In the United States it is also indicated for the treatment of relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement. [11]

Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine. [8] Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2). [8]

History

Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection. [8] [9] [12]

The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment. [8] [9] [13] The trial was conducted at 67 sites in the United States, Europe, and Asia. [13] During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects. [8] [9] [13] To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks. [8] The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate). [8] The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response. [8] Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer. [8] [9]

The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority review, breakthrough therapy and orphan drug designations. [8] [9] [14] [15] The FDA granted approval of Pemazyre to Incyte Corporation. [8]

On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer. [10] On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2. [16] On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Pemazyre, intended for the second-line treatment of advanced or metastatic cholangiocarcinoma characterized by fusion or rearrangements of fibroblast growth factor receptor 2. [17] The applicant for this medicinal product is Incyte Biosciences Distribution B.V. [17] Pemigatinib was approved for medical use in the European Union in March 2021. [6]

Efficacy was evaluated in FIGHT-203 (NCT03011372), a multicenter open-label, single-arm trial that included 28 participants with relapsed or refractory MLNs with FGFR1 rearrangement. [11] Eligible participants were either not candidates for or have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy (e.g., chemotherapy). [11] Pemigatinib was administered until disease progression, unacceptable toxicity, or until participants were able to receive allo-HSCT. [11]

Society and culture

Names

Pemigatinib is the international nonproprietary name (INN). [18]

Related Research Articles

<span class="mw-page-title-main">Cholangiocarcinoma</span> Bile duct adenocarcinoma

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.

<span class="mw-page-title-main">Fibroblast growth factor receptor 2</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 is a protein that in humans is encoded by the FGFR2 gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor.

<span class="mw-page-title-main">Fibroblast growth factor receptor 1</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.

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

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

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

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

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

Nintedanib, sold under the brand names Ofev and Vargatef, is an oral medication used for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer.

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

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

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

<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">Erdafitinib</span> Chemical compound

Erdafitinib, sold under the brand name Balversa, is an anti-cancer medication. It is a small molecule inhibitor of fibroblast growth factor receptor (FGFR) used for the treatment of cancer. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival. Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.

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

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

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

Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Avapritinib is a kinase inhibitor.

<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.

Pralsetinib, sold under the brand name Gavreto, is a medication approved for RET mutation-positive medullary thyroid cancer (MTC) and RET fusion-positive differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) therapy. Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.

Amivantamab, sold under the brand name Rybrevant, is a bispecific monoclonal antibody used to treat non-small cell lung cancer. Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

Infigratinib, sold under the brand name Truseltiq, is an anti-cancer medication used to treat cholangiocarcinoma.

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

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References

  1. 1 2 "Pemazyre". Therapeutic Goods Administration (TGA). 27 September 2022. Retrieved 29 April 2023.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "Pemazyre (Specialised Therapeutics Alim Pty Ltd)". Therapeutic Goods Administration (TGA). 7 October 2022. Archived from the original on 27 March 2023. Retrieved 9 April 2023.
  4. ↑ "Summary Basis of Decision (SBD) for Pemazyre". Health Canada. 23 October 2014. Archived from the original on 30 August 2022. Retrieved 29 May 2022.
  5. 1 2 3 "Pemazyre- pemigatinib tablet". DailyMed. Archived from the original on 6 February 2021. Retrieved 1 February 2021.
  6. 1 2 3 4 "Pemazyre EPAR". European Medicines Agency (EMA). 25 January 2021. Archived from the original on 2 September 2021. Retrieved 1 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ↑ "Pemazyre Product information". Union Register of medicinal products. Archived from the original on 5 March 2023. Retrieved 3 March 2023.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "FDA Approves First Targeted Treatment for Patients with Cholangiocarcinoma, a Cancer of Bile Ducts". U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Archived from the original on 18 April 2020. Retrieved 17 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. 1 2 3 4 5 6 7 8 "FDA grants accelerated approval to pemigatinib for cholangiocarcinoma". U.S. Food and Drug Administration (FDA). 17 April 2020. Archived from the original on 21 April 2020. Retrieved 20 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 3 4 5 "EU/3/18/2066". European Medicines Agency (EMA). 19 December 2018. Archived from the original on 24 October 2020. Retrieved 20 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. 1 2 3 4 5 "FDA approves pemigatinib for relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement". U.S. Food and Drug Administration (FDA). 29 August 2022. Archived from the original on 30 August 2022. Retrieved 29 August 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. ↑ "Pemazyre: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 19 September 2020. Retrieved 21 April 2020.
  13. 1 2 3 "Drug Trials Snapshot: Pemazyre". U.S. Food and Drug Administration (FDA). 17 April 2020. Archived from the original on 4 August 2020. Retrieved 5 May 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  14. ↑ "Pemigatinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 28 February 2021. Retrieved 19 April 2020.
  15. ↑ "Pemigatinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 28 February 2021. Retrieved 19 April 2020.
  16. ↑ "EU/3/19/2216". European Medicines Agency (EMA). 23 January 2020. Archived from the original on 28 November 2020. Retrieved 19 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  17. 1 2 "Pemazyre: Pending EC decision". European Medicines Agency (EMA). 29 January 2021. Archived from the original on 1 February 2021. Retrieved 2 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  18. ↑ World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80". WHO Drug Information. 32 (3): 479. hdl: 10665/330907 .

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