Osimertinib is used to treat locally advanced or metastaticnon-small-cell lung cancer (NSCLC), if the cancer cells are positive for theT790M mutation in the gene coding forEGFR or for activating EGFR mutations.[4][11] The T790M mutation may bede novo or acquired following first-line treatment with other EGFR tyrosine kinase inhibitors, such asgefitinib,erlotinib, andafatinib.[12]
In the US, EGFR exon 19 deletions, exon 21 L858R mutations, or the T790M status of the patient before treatment with osimertinib must be detected by a companion diagnostic test.[4] The Food and Drug Administration (FDA) has approved multiple tests, includingFoundationOne 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]
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]
Osimertinib is metabolized byCYP3A4 andCYP3A5, so substances that strongly inhibit either enzyme, like macrolide antibiotics, antifungals, and antivirals may increase exposure to osimertinib, and substances likerifampicin that activate either enzyme may decrease the effectiveness of osimertinib.[4][20]
Osimertinib preferentially binds irreversibly to mutatedepidermal 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 linearpharmacokinetics; the median time toCmax 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]
Osimertinib is provided as themesylate; 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]
Thedrug 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]
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 grantedpriority review,fast track,breakthrough therapy, andorphan drug designations.
At launch, in the United States,AstraZeneca priced the drug atUS$12,750 per month.[24]: 59 A cost effective generic medicine can be found in many countries, i.e.,Bangladesh. Bangladesh has a reputation of manufacturing and exporting quality medicine around the world by some renowned pharmaceutical companies, under the brand names Tagrix, Osimert, and Osicent.[25]
^"Proposed INN: List 113"(PDF).International Nonproprietary Names for Pharmaceutical Substances.29 (2): 285. 2015.Archived(PDF) from the original on 28 April 2017. Retrieved16 November 2015.
^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.PMID28526474.
^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.PMID27840244.
^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.PMID34079087.
^abc"UK label". UK Electronic Medicines Compendium. 26 January 2017.Archived from the original on 27 February 2017. Retrieved27 February 2017.
^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.PMID28565936.
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