\nOsimertinib, epidermal b\u00fcy\u00fcme fakt\u00f6r\u00fc resept\u00f6r\u00fc (EGFR) mutasyonlu ileri evre k\u00fc\u00e7\u00fck h\u00fccreli d\u0131\u015f\u0131 akci\u011fer kanseri (KHDAK) tedavisinde kullan\u0131lan, \u00fc\u00e7\u00fcnc\u00fc nesil, oral bir tirozin kinaz inhibit\u00f6r\u00fc (TK\u0130)<\/strong> ve son derece g\u00fc\u00e7l\u00fc bir k\u00fc\u00e7\u00fck molek\u00fcl ila\u00e7<\/strong>t\u0131r. \u00d6zellikle T790M diren\u00e7 mutasyonuna sahip hastalarda, birinci ve ikinci nesil EGFR inhibit\u00f6rlerine g\u00f6re \u00e7ok daha se\u00e7ici ve etkili bir tedavi imk\u00e2n\u0131 sunar (doi:10.1056\/NEJMoa1513137).\n<\/p>\n \nOsimertinib\u2019in molek\u00fcler tasar\u0131m\u0131, hem klasik aktivasyon mutasyonlar\u0131na (Exon 19 delesyonu, L858R) hem de tedavi s\u0131ras\u0131nda geli\u015fen T790M diren\u00e7 mutasyonuna y\u00fcksek afiniteli ve kovalent ba\u011flanma<\/strong> kapasitesine dayan\u0131r (doi:10.1016\/j.jtho.2016.03.010). Bu sayede sadece t\u00fcm\u00f6r kontrol\u00fcn\u00fc art\u0131rmakla kalmaz, ayn\u0131 zamanda sa\u011fkal\u0131m\u0131 uzatarak akci\u011fer kanseri tedavisinde ger\u00e7ek anlamda bir sessiz devrim<\/strong> yarat\u0131r.\n<\/p>\n \nOsimertinib, k\u00fc\u00e7\u00fck molek\u00fcl ila\u00e7 tasar\u0131m\u0131nda \u201chedefe kilitlenen\u201d yakla\u015f\u0131m\u0131n en ba\u015far\u0131l\u0131 \u00f6rneklerinden biridir. Yap\u0131-temelli ila\u00e7 tasar\u0131m\u0131 ile geli\u015ftirilen bu molek\u00fcl, mutant EGFR kinaz domenine, wild-type (normal) EGFR\u2019ye k\u0131yasla \u00e7ok daha y\u00fcksek se\u00e7icilik g\u00f6sterir (doi:10.1016\/j.ejca.2016.02.028).\n<\/p>\n \nBu se\u00e7icilik, iki \u00f6nemli avantaj sa\u011flar:\n<\/p>\n \nKovalent ba\u011flanma stratejisi, \u00f6zellikle T790M gibi \u201ckap\u0131 bek\u00e7isi\u201d mutasyonlara kar\u015f\u0131 kal\u0131c\u0131 inhibisyon sa\u011flayarak diren\u00e7 geli\u015fimini geciktirir<\/strong>. B\u00f6ylece osimertinib, yaln\u0131zca bir kinaz\u0131 bloke eden s\u0131radan bir TK\u0130 de\u011fil; diren\u00e7 mimarisini \u00f6ng\u00f6rerek tasarlanm\u0131\u015f, yeni nesil bir ak\u0131ll\u0131 k\u00fc\u00e7\u00fck molek\u00fcl<\/strong> olarak \u00f6ne \u00e7\u0131kar.\n<\/p>\n \nFaz III FLAURA<\/strong> \u00e7al\u0131\u015fmas\u0131, EGFR mutasyonlu ileri evre KHDAK hastalar\u0131nda birinci basamakta osimertinib kullan\u0131m\u0131n\u0131n, erlotinib veya gefitinib ile kar\u015f\u0131la\u015ft\u0131r\u0131ld\u0131\u011f\u0131nda progresyonsuz sa\u011fkal\u0131m\u0131 ve genel sa\u011fkal\u0131m\u0131 anlaml\u0131 bi\u00e7imde uzatt\u0131\u011f\u0131n\u0131<\/strong> g\u00f6sterdi (doi:10.1056\/NEJMoa1713137). \u00d6zellikle:\n<\/p>\n \nFaz III AURA3<\/strong> \u00e7al\u0131\u015fmas\u0131 ise, T790M pozitif ve \u00f6nceki nesil EGFR-TK\u0130\u2019ye diren\u00e7 geli\u015ftirmi\u015f hastalarda, osimertinib\u2019in platin bazl\u0131 kemoterapiye \u00fcst\u00fcn oldu\u011funu ortaya koydu (doi:10.1056\/NEJMoa1612674). Bu sonu\u00e7lar, osimertinib\u2019i sadece \u201ckurtarma tedavisi\u201d olmaktan \u00e7\u0131kar\u0131p, birinci basamak standart tedavi se\u00e7eneklerinden biri<\/strong> haline getirdi.\n<\/p>\n \nEGFR mutasyonlu KHDAK hastalar\u0131nda beyin metastazlar\u0131 olduk\u00e7a s\u0131k g\u00f6r\u00fcl\u00fcr ve bir\u00e7ok TK\u0130 kan-beyin bariyerini yeterince ge\u00e7emez. Osimertinib burada da fark yarat\u0131r: preklinik ve klinik veriler, ilac\u0131n merkezi sinir sistemine anlaml\u0131 d\u00fczeyde penetre oldu\u011funu ve beyin metastazlar\u0131 olan hastalarda belirgin klinik fayda<\/strong> sa\u011flad\u0131\u011f\u0131n\u0131 g\u00f6stermektedir (doi:10.1093\/annonc\/mdx806).\n<\/p>\n \nBu \u00f6zellik, osimertinib\u2019i sadece akci\u011ferde de\u011fil, beyinde de t\u00fcm\u00f6r kontrol\u00fc sa\u011flayabilen<\/strong> stratejik bir k\u00fc\u00e7\u00fck molek\u00fcl haline getirir. B\u00f6ylece radyoterapi ihtiyac\u0131n\u0131 geciktirebilir veya azaltabilir, ya\u015fam kalitesini olumlu etkileyebilir.\n<\/p>\n \nOsimertinib tedavisinde g\u00f6r\u00fclen yan etkiler \u00e7o\u011funlukla hafif-orta \u015fiddettedir ve uygun doz ayarlamalar\u0131 ile y\u00f6netilebilir. En s\u0131k bildirilen yan etkiler \u015funlard\u0131r (doi:10.1007\/s00280-018-3667-8):\n<\/p>\n \nNadir de olsa interstisyel akci\u011fer hastal\u0131\u011f\u0131 ve kardiyak etkiler g\u00f6r\u00fclebilece\u011fi i\u00e7in, uzun d\u00f6nem tedavide d\u00fczenli kardiyak ve pulmoner izlem<\/strong> \u00f6nerilir. Bununla birlikte, ileri evre akci\u011fer kanseri ba\u011flam\u0131nda genel fayda-risk dengesi son derece olumludur<\/strong> (doi:10.1056\/NEJMoa1713137).\n<\/p>\n \nOsimertinib, tirozin kinaz inhibit\u00f6r\u00fc<\/strong> s\u0131n\u0131f\u0131nda k\u00fc\u00e7\u00fck molek\u00fcl ila\u00e7 tasar\u0131m\u0131n\u0131n geldi\u011fi noktay\u0131 \u00e7arp\u0131c\u0131 bi\u00e7imde g\u00f6steriyor. Bu molek\u00fclden \u00f6\u011frendiklerimiz, onkolojide yeni nesil ila\u00e7 geli\u015ftirme stratejilerinin temelini olu\u015fturuyor:\n<\/p>\n \nBu yakla\u015f\u0131m, yaln\u0131zca EGFR de\u011fil; ALK, ROS1, MET, KRAS<\/strong> gibi di\u011fer onkojenik s\u00fcr\u00fcc\u00fcler i\u00e7in de yeni nesil k\u00fc\u00e7\u00fck molek\u00fcl tasar\u0131m\u0131n\u0131n kap\u0131s\u0131n\u0131 aral\u0131yor (doi:10.1038\/s41571-018-0050-6). K\u0131sacas\u0131, osimertinib bug\u00fcn akci\u011fer kanseri tedavisinde sessiz bir devrim yarat\u0131rken, yar\u0131n\u0131n hedefe y\u00f6nelik k\u00fc\u00e7\u00fck molek\u00fcl ila\u00e7lar\u0131n\u0131n da yol haritas\u0131n\u0131 \u00e7iziyor.\n<\/p>\n \nOsimertinib, EGFR aktivasyon mutasyonu (Exon 19 delesyonu veya L858R) ta\u015f\u0131yan ileri evre KHDAK hastalar\u0131nda birinci basamak tedavi olarak; ayr\u0131ca T790M pozitif, \u00f6nceki nesil EGFR-TK\u0130\u2019ye diren\u00e7 geli\u015ftirmi\u015f hastalarda ikinci basamakta veya daha sonra kullan\u0131lmak \u00fczere geli\u015ftirilmi\u015ftir (doi:10.1056\/NEJMoa1713137; doi:10.1056\/NEJMoa1612674).\n<\/p>\n \nEvet. Klinik \u00e7al\u0131\u015fmalar ve ger\u00e7ek ya\u015fam verileri, beyin metastaz\u0131 olan EGFR mutasyonlu hastalarda anlaml\u0131 intrakraniyal yan\u0131t oranlar\u0131 ve uzam\u0131\u015f progresyonsuz sa\u011fkal\u0131m bildirmektedir. Osimertinib, kan-beyin bariyerini ge\u00e7ebilen yap\u0131s\u0131 sayesinde beyin metastazlar\u0131nda g\u00fc\u00e7l\u00fc bir se\u00e7enektir (doi:10.1093\/annonc\/mdx806).\n<\/p>\n \nEn s\u0131k g\u00f6r\u00fclen yan etkiler cilt d\u00f6k\u00fcnt\u00fcs\u00fc, ishal, paroni\u015fi, hafif QT uzamas\u0131 ve nadiren interstisyel akci\u011fer hastal\u0131\u011f\u0131d\u0131r. \u00c7o\u011fu yan etki, doz azalt\u0131m\u0131, ge\u00e7ici tedavi aras\u0131 verme veya destek tedavilerle y\u00f6netilebilir (doi:10.1007\/s00280-018-3667-8).\n<\/p>\n \nEvet. Uzun s\u00fcreli kullan\u0131mda C797S gibi yeni EGFR mutasyonlar\u0131, MET amplifikasyonu veya fenotipik d\u00f6n\u00fc\u015f\u00fcm (\u00f6rne\u011fin k\u00fc\u00e7\u00fck h\u00fccreli d\u00f6n\u00fc\u015f\u00fcm) arac\u0131l\u0131\u011f\u0131yla diren\u00e7 geli\u015febilir. Bu nedenle, kombinasyon tedavileri ve daha ileri nesil k\u00fc\u00e7\u00fck molek\u00fcller \u00fczerinde yo\u011fun ara\u015ft\u0131rmalar s\u00fcrmektedir (doi:10.1038\/s41571-018-0050-6).\n<\/p>\n \nGenellikle hastal\u0131k progresyonu veya tolere edilemeyen toksisite geli\u015fene kadar s\u00fcrekli oral tedavi<\/strong> \u015feklinde kullan\u0131l\u0131r. Tedavi s\u00fcresi; t\u00fcm\u00f6r yan\u0131t\u0131, yan etki profili ve hastan\u0131n genel durumu gibi fakt\u00f6rlere g\u00f6re ki\u015fiselle\u015ftirilir (doi:10.1056\/NEJMoa1713137; doi:10.1056\/NEJMoa1513137).\n<\/p>\n Osimertinib, EGFR mutasyonlu ileri evre k\u00fc\u00e7\u00fck h\u00fccreli d\u0131\u015f\u0131 akci\u011fer kanserinde kullan\u0131lan \u00fc\u00e7\u00fcnc\u00fc nesil, se\u00e7ici ve kovalent bir tirozin kinaz inhibit\u00f6r\u00fcd\u00fcr. T790M diren\u00e7 mutasyonuna kar\u015f\u0131 etkinli\u011fi, FLAURA ve AURA \u00e7al\u0131\u015fmalar\u0131yla kan\u0131tlanm\u0131\u015f olup progresyonsuz ve genel sa\u011fkal\u0131m\u0131 anlaml\u0131 \u015fekilde uzat\u0131r.<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[122],"tags":[804,799,803,800,805,798,801,802],"class_list":["post-10240","post","type-post","status-publish","format-standard","hentry","category-molekul","tag-aura3-calismasi","tag-egfr-mutasyonu","tag-flaura-calismasi","tag-kucuk-hucreli-disi-akciger-kanseri","tag-kucuk-molekul-ilac-tasarimi","tag-osimertinib","tag-t790m","tag-tirozin-kinaz-inhibitoru"],"acf":[],"_links":{"self":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/10240","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=10240"}],"version-history":[{"count":1,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/10240\/revisions"}],"predecessor-version":[{"id":10241,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/10240\/revisions\/10241"}],"wp:attachment":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=10240"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=10240"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=10240"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}K\u00fc\u00e7\u00fck Molek\u00fcl Tasar\u0131m\u0131: Se\u00e7icilik, Diren\u00e7 ve Ak\u0131ll\u0131 Kimya<\/h2>\n
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FLAURA ve AURA \u00c7al\u0131\u015fmalar\u0131: Klinik Veriler Ne S\u00f6yl\u00fcyor?<\/h2>\n
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Kan-Beyin Bariyerini A\u015fan K\u00fc\u00e7\u00fck Molek\u00fcl: Beyin Metastazlar\u0131nda Osimertinib<\/h2>\n
Yan Etkiler ve G\u00fcvenlik: Y\u00f6netilebilir Toksisite Profili<\/h2>\n
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K\u00fc\u00e7\u00fck Molek\u00fcl \u0130la\u00e7lar\u0131n Gelece\u011fi: Osimertinib Bize Ne \u00d6\u011fretiyor?<\/h2>\n
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S\u0131k Sorulan Sorular (SSS)<\/h2>\n
1. Osimertinib hangi akci\u011fer kanseri hastalar\u0131 i\u00e7in uygundur?<\/h3>\n
2. Osimertinib beyin metastazlar\u0131nda ger\u00e7ekten etkili mi?<\/h3>\n
3. Osimertinib\u2019in en s\u0131k g\u00f6r\u00fclen yan etkileri nelerdir?<\/h3>\n
4. Osimertinib\u2019e kar\u015f\u0131 da zamanla diren\u00e7 geli\u015fir mi?<\/h3>\n
5. Osimertinib tedavisi ne kadar s\u00fcre devam eder?<\/h3>\n
Referanslar<\/h2>\n
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