Osimertinib

Last updated

Osimertinib
Osimertinib.svg
Clinical data
Trade names Tagrisso, others
Other namesAZD9291, mereletinib, osimertinib mesilate (JAN JP), osimertinib mesylate (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a616005
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Probably high [4]
Metabolism Oxidation (CYP3A)
Elimination half-life 48 hours
Excretion Feces (68%), urine (14%)
Identifiers
  • N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H33N7O2
Molar mass 499.619 g·mol−1
3D model (JSmol)
  • C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
  • InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
  • Key:DUYJMQONPNNFPI-UHFFFAOYSA-N

Osimertinib, sold under the brand name Tagrisso, [6] is a medication used to treat non-small-cell lung carcinomas with specific mutations. [7] [8] It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Contents

The most common side effects include diarrhea, rash, musculoskeletal pain, dry skin, skin inflammation around nails, sore mouth, fatigue and cough. [9]

Osimertinib was approved for medical use in the United States in November 2015, [10] and in the European Union in February 2016. [5]

Medical uses

Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), if the cancer cells are positive for the T790M mutation in the gene coding for EGFR or for activating EGFR mutations. [4] [11] The T790M mutation may be de novo or acquired following first-line treatment with other EGFR tyrosine kinase inhibitors, such as gefitinib, erlotinib, and afatinib. [12]

In the US, EGFR exon 19 deletions, exon 21 L858R mutations or the T790M status of the patient prior to treatment with osimertinib must be detected by a companion diagnostic test. [4] The Food and Drug Administration (FDA) has approved multiple tests, including FoundationOne CDx for this purpose. [13] In Europe and elsewhere, activating EGFR mutations or T790M mutations may be determined by a validated test. [14]

In February 2024, the FDA approved osimertinib, in combination with platinum-based chemotherapy, for people with locally advanced or metastatic non-small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. [15]

In people treated with osimertinib, resistance usually develops within approximately ten months. [16] Resistance mediated by an exon 20 C797S mutation accounts for the majority of resistance cases, [17] which has resulted in multiple attempts with non-ATP competitive or allosteric inhibitors to try and offset this acquired resistance by targeting other regions of the RTK kinase domain. [18]

In September 2024, the FDA approved osimertinib for adults with locally advanced, unresectable (stage III) non-small cell lung cancer (NSCLC) whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. [19]

Adverse effects

Very common (greater than 10% of clinical trial subjects) adverse effects include diarrhea, stomatitis, rashes, dry or itchy skin, infections where finger or toenails abut skin, low platelet counts, low leukocyte counts, and low neutrophil counts. [20]

Common (between 1% and 10% of clinical trial subjects) adverse effects include interstitial lung disease. [20]

It can cause fetal harm. [4] [21]

Interactions

Osimertinib is metabolized by CYP3A4 and CYP3A5, so substances that strongly inhibit either enzyme, like macrolide antibiotics, antifungals, and antivirals may increase exposure to osimertinib, and substances like rifampicin that activate either enzyme may decrease the effectiveness of osimertinib. [4] [20]

Pharmacology

Osimertinib preferentially binds irreversibly to mutated epidermal growth factor receptor proteins, particularly those with more common mutations in lung cancer such as L858R mutation or an exon 19 deletion. [4]

It exhibits linear pharmacokinetics; the median time to Cmax is 6 hours (range 3–24 hours). The estimated mean half-life is 48 hours, and oral clearance (CL/F) is 14.3 (L/h). [4] 68% of elimination is by feces and 14% by urine. [4]

Chemistry

Osimertinib is provided as the mesylate; the chemical formula is C28H33N7O2·CH4O3S, and the molecular weight is 596 g/mol. The chemical name is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt. [4]

History

The drug discovery program that led to osimertinib started in 2009 and yielded the drug by 2012; the process was structure-driven and aimed to find a third generation EGFR inhibitor that would selectively target the T790M form of the EGFR receptor. [22]

Osimertinib was designated as a breakthrough therapy in April 2014, based on phase I trial results, [22] and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015. [23] [10]

In February 2016, the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program. [22] [5]

In February 2024, the FDA approved osimertinib, in combination with platinum-based chemotherapy, for people with locally advanced or metastatic non-small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. [15] Efficacy was evaluated in FLAURA 2 (NCT04035486), an open-label, randomized trial of 557 participants with EGFR exon 19 deletion or exon 21 L858R mutation-positive la/mNSCLC and no prior systemic therapy for advanced disease. [15] Participants were randomized 1:1 to receive either osimertinib with platinum-based chemotherapy or osimertinib monotherapy. [15] The application was granted priority review, fast track, breakthrough therapy, and orphan drug designations.

Society and culture

Economics

At launch, in the United States, AstraZeneca priced the drug at US$12,750 per month. [24] : 59 

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Gefitinib</span> Medication used for cancer

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

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

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<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">Afatinib</span> Chemical compound

Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

Spectrum Pharmaceuticals, Inc. is an American biopharmaceutical company located in Boston, MA. It develops and markets drugs for treatments in hematology and oncology.

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.

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

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). 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. It also acts as an ALK and ROS1 inhibitor.

<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">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">Icotinib</span> Chemical compound

Icotinib is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use in China as first-line monotherapy in patients with non-small-cell lung cancer with somatic EGFR mutations.

T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid; methionine is a larger nonpolar amino acid. Rather than directly blocking inhibitor binding to the active site, T790M increases the affinity for ATP so that the inhibitors are outcompeted; irreversible covalent inhibitors such as osimertinib can overcome this resistance.

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

Olmutinib (INN) is an investigational anti-cancer drug. It acts by covalently bonding to a cysteine residue near the kinase domain of epidermal growth factor receptor (EGFR).

<span class="mw-page-title-main">Mobocertinib</span> Small molecule tyrosine kinase inhibitor

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.

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.

<span class="mw-page-title-main">Aumolertinib</span> Drug for treatment of cancer

Aumolertinib is a pharmaceutical drug for the treatment of cancer. It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).

<span class="mw-page-title-main">Sunvozertinib</span> Pharmaceutical drug

Sunvozertinib is a pharmaceutical drug for the treatment of non-small-cell lung cancer (NSCLC). It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.

<span class="mw-page-title-main">Lazertinib</span> Anti-cancer medication

Lazertinib, sold under the brand name Lazcluze and Leclaza, is an anti-cancer medication used for the treatment of non-small cell lung cancer. It is a kinase inhibitor of epidermal growth factor receptor.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
  3. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  4. 1 2 3 4 5 6 7 8 9 10 "Tagrisso- osimertinib tablet, film coated". DailyMed. 5 June 2020. Retrieved 16 October 2020.
  5. 1 2 3 "Tagrisso EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 16 October 2020.
  6. ↑ "Proposed INN: List 113" (PDF). International Nonproprietary Names for Pharmaceutical Substances (INN). 29 (2): 285. 2015. Archived (PDF) from the original on 28 April 2017. Retrieved 16 November 2015.
  7. ↑ Ayeni D, Politi K, Goldberg SB (September 2015). "Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer". Clinical Cancer Research. 21 (17): 3818–20. doi:10.1158/1078-0432.CCR-15-1211. PMC   4720502 . PMID   26169963.
  8. ↑ Tan CS, Gilligan D, Pacey S (September 2015). "Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer". The Lancet. Oncology. 16 (9): e447–e459. doi:10.1016/S1470-2045(15)00246-6. PMID   26370354.
  9. ↑ "FDA Approves First Adjuvant Therapy for Most Common Type of Lung Cancer". U.S. Food and Drug Administration (FDA) (Press release). 18 December 2020. Retrieved 20 December 2020.
  10. 1 2 "Tagrisso (osimertinib) tablets". U.S. Food and Drug Administration (FDA). 22 December 2015. Retrieved 16 October 2020.
  11. ↑ Gijtenbeek RG, Damhuis RA, van der Wekken AJ, Hendriks LE, Groen HJ, van Geffen WH (April 2023). "Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study". The Lancet Regional Health. Europe. 27: 100592. doi:10.1016/j.lanepe.2023.100592. PMC   9932646 . PMID   36817181.
  12. ↑ Xu M, Xie Y, Ni S, Liu H (May 2015). "The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)". Annals of Translational Medicine. 3 (7): 96. doi:10.3978/j.issn.2305-5839.2015.03.60. PMC   4430733 . PMID   26015938.
  13. ↑ Center for Devices and Radiological Health. "In Vitro Diagnostics - List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)". www.fda.gov. Archived from the original on 25 January 2018. Retrieved 17 January 2018.
  14. ↑ "European Tagrisso information" (PDF). European Medicines Agency. Archived (PDF) from the original on 17 January 2018. Retrieved 17 January 2018.
  15. 1 2 3 4 "FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer". U.S. Food and Drug Administration. 16 February 2024. Retrieved 27 February 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. ↑ Patel H, Pawara R, Ansari A, Surana S (December 2017). "Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance". European Journal of Medicinal Chemistry. 142: 32–47. doi:10.1016/j.ejmech.2017.05.027. PMID   28526474.
  17. ↑ Wang S, Song Y, Liu D (January 2017). "EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance". Cancer Letters. 385: 51–54. doi:10.1016/j.canlet.2016.11.008. PMID   27840244.
  18. ↑ Saraon P, Pathmanathan S, Snider J, Lyakisheva A, Wong V, Stagljar I (June 2021). "Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches". Oncogene. 40 (24): 4079–4093. doi:10.1038/s41388-021-01841-2. PMID   34079087. S2CID   235307318.
  19. ↑ "FDA approves osimertinib for non-small cell lung cancer". U.S. Food and Drug Administration. 25 September 2024. Retrieved 27 September 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  20. 1 2 3 "UK label". UK Electronic Medicines Compendium. 26 January 2017. Archived from the original on 27 February 2017. Retrieved 27 February 2017.
  21. ↑ Bollinger MK, Agnew AS, Mascara GP (July 2018). "Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation". Journal of Oncology Pharmacy Practice. 24 (5): 379–388. doi:10.1177/1078155217712401. PMID   28565936. S2CID   206671000.
  22. 1 2 3 Yver A (June 2016). "Osimertinib (AZD9291)-a science-driven, collaborative approach to rapid drug design and development". Annals of Oncology. 27 (6): 1165–70. doi: 10.1093/annonc/mdw129 . PMID   26961148.
  23. ↑ "Approved Drugs - Osimertinib". U.S. Food and Drug Administration (FDA). 13 November 2015. Archived from the original on 27 February 2017. Retrieved 27 February 2017.
  24. ↑ "AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report Priority Area 02: Cancer" (PDF). AHRQ. December 2015. Archived from the original (PDF) on 30 April 2017. Retrieved 27 February 2017.
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