Avapritinib preparatiga qaratilgan oshqozon-ichak tromal o'smasi

Avapritinib (Avapriny, Ayvakit, BLU-285) preparatiga yo'naltirilgan oshqozon-ichak tromal o'smasi USFDA tomonidan 9 yil 2020-yanvarda tasdiqlangan. Preparat ikkita ko'rsatmani o'z ichiga oladi: ishlamaydigan rezektsiya yoki trombotsitlardan kelib chiqqan o'sish retseptorlarini olib boruvchi metastatik GIST bo'lgan kattalar bemorlarini davolash uchun. alfa (PDGFRA) ekson 18 mutatsiyasi (shu jumladan PDGFRA D842V mutatsiyasi) va to'rt qatorli jarrohlik bo'lmagan yoki metastatik GIST kattalar bemorlari. 

ORR 86% ni tashkil qiladi, Avapritinib gastrointestinal stromal o'smalari bo'lgan bemorlarga yangi umid baxsh etadi

2019 yil noyabr oyida Birlashtiruvchi To'qimalar Onkologiya Jamiyatining (CTOS) yillik yig'ilishi PDGFRA exon 18 mutatsiyasida avapritinib bo'yicha NAVIGATOR I bosqich klinik tekshiruv natijalarini va to'rtinchi qator GISTni qabul qilgan bemorlarni e'lon qildi.

1. Tadqiqot tarixi

16 yil 2018-noyabr holatiga jami 121 ta to'rtinchi qator va undan yuqori bemorlar (asosan KIT mutatsiyalari) va PDGFRA exon 43 mutatsiyasiga ega 18 GIST bemorlari ro'yxatga olindi. Sinov sinovning dastlabki dozasini "kuniga bir marta 400 mg og'iz orqali" o'rganib chiqdi va keyinchalik toksikligi sababli tavsiya etilgan dozani "kuniga bir marta 300 mg og'iz" ga kamaytirdi. Bemor Avapritinibni kasallik avj olguncha yoki qabul qilinmaydigan toksikaga qadar qabul qildi.

2. Effektivlik to'g'risidagi ma'lumotlar

For patients with PDGFRA exon 18 mutation, there were 3 cases of complete remission (OR) and 34 cases of partial remission (PR), and the objective response rate (ORR) was 86%. The median duration of response (DOR) and median progression-free survival (PFS) were not reached. As of the data cut-off date (median follow-up time was 10.9 months), 78% of patients still responded.

To'rtinchi qator yoki undan yuqori bo'lgan GIST bemorlarining 111 nafari to'liq remissiya, 1 nafari qisman remissiya, ORR 23%, o'rtacha javob davomiyligi 22 oy, o'rtacha PFS 10.2 oy va o'rtacha kuzatuv vaqti 3.7 edi. oy.

Xavfsizlik nuqtai nazaridan, aksariyat noxush hodisalar (AE) asosan 1, 2 darajaga to'g'ri keladi va eng ko'p uchraydigan ko'ngil aynish, charchoq, anemiya, diareya, qusish va boshqalar; 3-4 daraja bilan bog'liq AE ≥ 2%, anemiya, charchoq, past fosfemiya, giperbilirubinemiya, neytropeniya va diareya. Bemorlarning 10% davolash bilan bog'liq bo'lgan AE tufayli davolanishni to'xtatdilar.

3. Klinik ahamiyati

Avapritinib is the first precision therapy approved for GIST patients with PDGFRA exon 18 mutation. It is an oral, potent and selective KIT and PDGFRα inhibitor. Avapritinib has shown extensive inhibition in oshqozon-ichak traktining stromal o'smalari (GIST) with KIT and PDGFRα mutations, including the D842V mutation of the PDGFRα gene and other primary or secondary resistance mutations.

Kalitsiz qulf-PDGFRA exon 18 mutant GIST

Oshqozon-ichak stromasi shish (GIST) is a rare mesenchymal tissue tumor, accounting for 0.1% to 3% of all gastrointestinal malignant tumors, with an incidence of 1 to 1.5 / 10 million. In people with oshqozon-ichak traktining stromal o'smalari, the most common sites are the stomach and small intestine, but they may also be found anywhere in or near the gastrointestinal tract. If the tumor cannot be completely removed by surgery or the tumor has metastasized, targeted therapy is a standard treatment.

Hozirgi vaqtda GIST o'smalarining 85% gacha PDGFRA va KIT ikkita gen mutatsiyasidan biriga ega. Ushbu mutatsiyalar saratonni qo'zg'atuvchi anormal KIT va PDGFRA oqsillarini ishlab chiqarishga olib keladi. Ushbu ikki oqsil odatda imatinib va ​​oqsil faolligini bloklaydigan shunga o'xshash dorilar tomonidan o'chirilishi mumkin. Ammo PDGFRA ekson 18 mutatsiyasi juda o'ziga xos bo'lib, u PDGFRA oqsilining shaklini o'zgartiradi va shu bilan preparatni unga bog'lanishiga yo'l qo'ymaydi. PDGFR [ekson 18] mutatsiyasi uchun oldingi "kalit" bu "qulf" uchun mos emas.

Avapritinib PDGFRA va KIT oqsillarini tanlab bog'laydi. Laboratoriya ishlarida preparat barcha tekshirilgan mutant PDGFRA oqsillari bilan bog'lanib, ularning saraton hujayralarida faolligini inhibe qilishi mumkin.

Hozirgi vaqtda gastrointestinal stromal o'smalar uchun to'rtta dori tasdiqlangan: Avapritinib, imatinib, sunitinib va ​​rifaginib. Avapritinib faqat hujayralardagi kinazalar (qizil doiralar) deb nomlangan o'ziga xos mutant fermentlar bilan bog'lanadi, shunga o'xshash dorilar esa ko'proq kinazalar bilan bog'lanadi. Rasm: Uyali signalizatsiya texnologiyasi.

Gastrointestinal stromal o'smalarning boshqa tadqiqotlari

Ripretinib

Ripretinib is a type II kinase inhibitor that can widely inhibit the activation loop mutations in KIT and PDGFRA. It is a kinase inhibitor with a “switch control” function, which can activate the activation loop (or activate the “switch”) into The active conformation, in turn, inhibits all tested KIT and PDGFRA mutants. Ripretinib’s effectiveness in preclinical cancer models and initial clinical trials also validated that Ripretinib can inhibit the universal KIT mutation in patients with drug-resistant GIST.

III bosqich tadqiqotlari (INVICTUS) ma'lumotlari shuni ko'rsatdiki, Ripretinib olgan bemorlarda o'smaning rivojlanishi yoki o'lim xavfi platsebo bilan solishtirganda 85% ga kam, meditsina operatsion tizimi 15.1 oy va platsebo guruhida 6.6 oy bo'lgan. Kechiktirilgan GIST to'rtinchi qatori yoki yuqoridagi davolash PFS va OS ning ikki tomonlama afzalliklarini keltirib chiqaradi va Ripretinib yaxshiroq tolerantlikni ko'rsatadi.

Larotrektnib

Dastlabki davolash uchun o'sma manbalarini ajratmaydigan dunyodagi birinchi maqsadli dori-Vitrakvi ® (larotrektinib, bundan keyin larotinib deb ataladi), 2018 yil noyabr oyida marketing uchun tasdiqlanganidan beri butun dunyo o'smalari hamjamiyati tomonidan ma'qullandi umidlar va tanlovlar.

The biggest attraction of the drug is that it is a new anti-cancer drug that targets specific gene mutations but not specific cancer types. The NTRK gene fusion solid tumors that it can treat include 17 types of cancers including breast cancer, colorectal cancer, lung cancer, and tiroid saratoni, and can be used for both adults and children. NTRK gene fusion exists in 0.7% ~ 3.6% of digestive tract tumors.

Therefore, if you do a genetic test, you can first see if there are any mutations that may bring a miracle of survival, you can call the medical department of the Global Oncologist Network to interpret the report.

I believe that with the advent of more and more targeted drugs, patients with gastrointestinal stroma
l o'smalar ko'proq davolash imkoniyatlari va uzoq umr ko'rishlari mumkin. Shuningdek, umid qilamanki, ushbu dorilar Xitoyda imkon qadar tezroq ro'yxatga kiritilishi va ko'proq bemorlarning manfaati uchun tibbiy sug'urtaga kiritilishi mumkin.