What to do about drug resistance of non-small cell lung cancer targeted drugs, you want to know here
Lung cancer is the cancer with the highest morbidity and mortality in China. About 1.6 million people die of this disease each year worldwide, and about 85% of these cases are non-small cell lung cancer (NSCLC). At present, many cancer-targeting drugs have been developed for advanced kichik hujayrali o'pka saratoni in the world. These new therapeutic drugs have increased the median survival time of patients to 35 months, which not only significantly prolonged their life span, but also achieved Personalized treatment. However, most patients will develop secondary drug resistance 8 to 14 months after receiving EGFR-TKI (standard first-line treatment for patients with sensitive mutations in the EGFR gene). How to solve the problem of drug resistance has become a hot research topic. Will continue to answer for everyone.
1. Nima uchun kichik hujayrali bo'lmagan o'pka saratoni uchun mo'ljallangan terapiya chidamli?
Maqsadli dori qarshiligi odatda birlamchi qarshilik va ikkilamchi qarshilikka bo'linadi.
1. Birlamchi dorilarga qarshilik: bemorning o'ziga xos EGFR maqsadli mutatsiyalariga ishora qiladi, ammo KRAS gen mutatsiyasining tabiiy mavjudligi tufayli gefitinib va erlotinib gidroxlorid tabletkalari va boshqa maqsadli dorilar samarasiz, 3 oylik foydalanishdan keyin dori-darmonlarga qarshilik paydo bo'ladi.
2. Ikkilamchi dori qarshiligi: In the course of targeted drug treatment, because the target signal pathway continues to be inhibited by drugs, the shish produces other gene mutations in order to escape the drug, inhibiting the therapeutic effect of the targeted drug on the EGFR target, thereby Lead to drug resistance. The effective time of medication is usually more than 3 months.
2. Kichkina hujayrali bo'lmagan o'pka saratoni uchun maqsadli terapiyaning dori-darmonlarga chidamliligi mexanizmi
There are currently three specific mechanisms for non-small cell o'pka saratoni drug resistance. First, drug resistance is generated through genetic mutation. About 40% of the genes in patients with positive genetic tests will generate new genes from the original genes, which will cause insensitivity to the original drugs, resulting in drug resistance. Secondly, the cunning cancer cells will usually “repair the dark path of the plank road” and take a detour. This situation accounts for about 20% of patients with drug resistance. In addition to the above two drug resistance pathways, the drug resistance mechanism of the remaining 30% of patients is not yet clear.
3. Kichkina hujayrali bo'lmagan o'pka saratoni bilan og'rigan bemorlarning dori-darmonlarga chidamliligini qanday baholash mumkin?
1. Usually, when the drug is resistant, the targeted drug cannot control the growth of the tumor, which will cause the tumor to grow or metastasize far away. At this time, the patient will have certain symptoms, such as no cough before, but recently started coughing, or after brain metastasis The patient will have dizziness, headache, vomiting without cause, and patients with bone metastasis will experience pain, nerve compression and other symptoms. At this time, the patient needs to be vigilant.
2. Dori-darmonlarga chidamliligini oshirishi mumkin bo'lgan bemorlar uchun eng yaxshi usul kasalxonaga muntazam tekshiruvdan o'tish. Maqsadli dori o'simta markerlari va tasvirni tekshirish orqali chidamli ekanligini aniqlang.
4. Bemorda giyohvandlikka chidamliligi paydo bo'lgandan so'ng, shifokor odatda ikkinchi biopsiyani tavsiya qiladi, bu nimani anglatadi
Umuman aytganda, o'pka saratoniga chalingan, EGFR-TRI preparatlarini qabul qiladigan va kasallik avj olgan barcha bemorlar ikkinchi marta biopsiyadan o'tishlari kerak.
1. Yangi boshlang'ich saraton yoki saraton kasalligining qaytalanishini aniqlash uchun patologik tashxisni yana bir bor tozalang.
2. Carry out the second genetic test to determine whether it is drug resistance caused by the mutation of the gene again, and detect whether there is a new targeted treatment plan.
The second biopsy can promptly detect disease progression, reveal drug resistance mechanisms, and formulate appropriate follow-up treatment plans. The second biopsy is mainly divided into tissue biopsy and liquid biopsy. Tissue biopsy is mainly divided into thoracotomy biopsy, bronchoscopy biopsy and percutaneous lung biopsy. For patients who cannot obtain tumor tissue, liquid biopsy based on blood NGS gene sequencing technology can be selected to obtain further treatment opportunities.
5. Kichkina hujayrali bo'lmagan o'pka saratonining birinchi avlod TKI maqsadli terapiyasidan so'ng, agar preparatning qarshiligi paydo bo'lsa, nima qilishim kerak?
EGFR-TKI ning birinchi avlodi gefitinib, erlotinib va ikotinibni o'z ichiga oladi.
NCCN ko'rsatmalariga binoan T790M mutatsion sinovi birinchi navbatda EGFR-TKI qarshiligining birinchi avlodidan keyin tavsiya etiladi. Bemorda simptomlar mavjudmi, miya metastazi bormi, mahalliy rivojlanishmi yoki ko'p sonli rivojlanishmi, shunga qarab turli xil strategiyalar qabul qilinadi.
1. T790M musbat bemorlar uchun: first recommendation is Osimertinib treatment, continue TKI treatment for patients with slow progression, and local treatment for patients with local progression, including radiotherapy for brain metastasis, local radiotherapy for single lesion To take chemotherapy for patients with extensive progress.
2. T790M manfiy bemorlar uchun: kimyoterapiya berilishi mumkin, yoki immunoterapiya may be selected based on the PD-L1 expression of the patient.
3. Dori-darmonlarga qarshilik ko'rsatgandan keyin asemptomatik bo'lgan bemorlar uchun: mahalliy davolash TKI davosi uchun qabul qilinishi yoki davom ettirilishi mumkin. Faqatgina miya metastazlari bo'lgan bemorlar uchun mahalliy davolashni ko'rib chiqish mumkin va EGFR-TKI ning birinchi avlodidan foydalanishda davom etish mumkin.
6. Osimertinibni qabul qilganidan keyin qancha vaqt o'tgach, preparatga qarshilik paydo bo'ladi?
Osimertinib uchinchi avlod EGFR-TKI maqsadli dori-darmon bo'lib, o'rtacha 11 oylik dori-darmonlarga qarshilik ko'rsatadi. Ammo, klinik qo'llanmalarda, ko'plab bemorlarda osimertinibni qabul qilganidan keyin ikki yoki uch yil o'tgach qarshilik mutatsiyalari paydo bo'ladi, shuning uchun oksitinibga qarshilik ko'rsatish vaqtining o'ziga xos holati odamda farq qiladi.
7. Osimertinibning dorilarga chidamliligi mexanizmi qanday?
Osimertinibning dori-darmonlarga chidamliligi mexanizmi juda murakkab, jumladan C797S mutatsiyasi, MET amplifikatsiyasi / RETni qayta tashkil etish / ROS-1ni qayta tashkil etish, HER-2ni kuchaytirish, BRAF mutatsiyasi, RAS mutatsiyasi, FGFR1 mutatsiyasi, kichik hujayrali o'pka saratoniga aylanish, Genetik mavjud emas mutatsiyalar va boshqalar, va keyinchalik dori-darmonlarga qarshi turlicha mexanizmlar uchun keyingi dori sxemalari har xil.
1. EGFR gen mutatsiyalari yana: EGFR796 va 797 mutatsiyalari 24.7% ni, EGFR 792 mutatsiyalari 10.8% ni, EGFR 718 va 719 mutatsiyalari 9.7% -EGFR genini, qayta chidamli mutatsiyalarni tashkil etdi, bu mamlakatning yarmiga yaqin barcha bemorlarning 45 foizini tashkil qiladi.
2. Boshqa gen mutatsiyalari: shu jumladan PIK3CA, BRAF, MET, RET, KRAS va boshqalar. O'pka saratoniga olib keladigan keng tarqalgan va kam uchraydigan genlarning turli xil genlari ishtirok etadi va ular tarqalib ketgan.
3. Kichik hujayrali o'pka saratoniga aylandi.
8. Oxitinib dori-darmonlarga chidamliligi bo'yicha maqsadli terapiyadan so'ng nima qilish kerak?
Turli xil qarshilik genlari uchun dastlabki eritma quyidagicha:
1. Uch karra mutatsiyaga uchragan holda (C797S / T790M / 19-del) bugatinibni tanlash samarasi osimertinib / gefitinibga qaraganda yaxshiroq va ta'sirga C797S va T790M fazoviy joylashuvi ta'sir qilmaydi. (1) Bugatinib anti-EGFR klassi bilan birgalikda (cetuximab / panitumumab) uch mutatsiyaning terapevtik ta'sirini kuchaytirishi mumkin va ikkita preparatning kombinatsiyasi sinergetik ta'sir ko'rsatishi mumkin; (2) Bugatinib Selumetinib (Simetinib) bilan qo'shilib, C797S mutatsiyasidan kelib chiqqan osimertinib qarshiligini engib chiqishi mumkin.
2. EGFR C797S trans-kelishuvi uchun gefitinib / erlotinib bilan birlashtirilgan osimertinib kabi uchinchi avlod maqsadli dorilar bilan birlashtirilgan birinchi avlod maqsadli dori-darmonlarni ko'rib chiqing. Cis-hizalama uchun siz qilishingiz mumkin
Bugatinib + VEGF maqsadli dorilarni tanlang.
3. Agar faqat C79CS mutatsiyasi bo'lsa, siz gefitinib, erlotinib, ikotinib kabi birinchi avlod EGFR inhibitoridan foydalanishingiz mumkin.
4. MET amplifikatsiyasi shuni ko'rsatadiki, osimertinib MET ingibitorlari bilan birlashtirilgan (kamatinib, krizotinib, Savolitinib va boshqalar). BRAF mutatsiyasiga ko'ra osimertinib BRAF inhibitörleri (dalafinib + trametinib) bilan birlashtirilgan. RET mutatsiyasi Osimertinibni Kabotinib bilan birlashtirishni taklif qildi va albatta Osimertinibni BLU-667 bilan birlashtirdi.
Oksetinib qarshiligidan keyin yana genetik tekshiruvni o'tkazib, davolanishga yaxshiroq yordam berish uchun mutatsion maqsadga muvofiq mos dori vositasini tanlash tavsiya etiladi. Maqsadli dori-darmonlarni kombinatsiyalashgan terapiyasi uchun professional shifokorga murojaat qilish yaxshiroqdir.
9. Kichkina hujayrali bo'lmagan o'pka saratoni uchun mo'ljallangan dorilarning yon ta'siri
Molekulyar maqsadli dorilarning maqsadi aniq, ammo bu klinik nojo'ya reaktsiyalar paydo bo'lmaydi degani emas. Diareya, proteinuriya, yuqori qon bosimi, husnbuzar kabi toshmalar va yurak kasalliklari kabi maqsadli dorilarning nojo'ya reaktsiyalari ma'lum. Maqsadli dorilar an'anaviy sitotoksik dorilarga qaraganda pastroq bo'lishiga qaramay, ularni hali ham esdan chiqarmaslik kerak. Ba'zi kam uchraydigan nojo'ya reaktsiyalarni klinik diagnostika tufayli aniqlash qiyin, ko'pincha bu jiddiy oqibatlarga olib keladi.
Masalan, erlotinibni davolash asemptomatik jigar transaminazasining ko'tarilishiga olib kelishi mumkin va oshqozon-ichakdan qon ketish kamdan-kam hollarda qayd etiladi, gefitinib esa kichik molekulali anti-EGFR maqsadli terapiyasidir, garchi uning metabolizmi asosan jigar bo'lsa, taxminan 4% buyraklar tomonidan prototip shaklida tozalanadi. va metabolitlar va klinik buyrak etishmovchiligiga moyil bo'lib, bu preparatni bekor qilgandan keyin yaxshilanadi. Maqsadli dori terapiyasida iloji boricha og'ir va hatto o'limga olib keladigan salbiy reaktsiyalardan saqlanish kerak. Noqulay reaktsiyalar bemorning davolanishga bo'lgan ishonchiga ta'sir qiladi. Jiddiy salbiy reaktsiyalar davolash jarayonini to'xtatishi mumkin.
