Kolorektal saraton PD-1 / PD-L1 davolash

Colon cancer immunotherapy, rectal cancer immunotherapy, colorectal cancer immunotherapy, and colorectal cancer PD-1 / PD-L1 treatment.

Seventeen years ago, the number of drugs available for advanced colorectal cancer was very limited. There were only a few chemotherapeutic drugs and almost no targeted drugs. With the development of genomic testing and sophisticated cancer drugs, patients diagnosed with stage IV yo'g'on ichak saratoni have more and more treatment options. Some patients can achieve clinical cure, while others can obtain more targeted immunoterapiya options through genetic testing, resulting in longer survival time. At present, the survival time of advanced kolorektal saraton has increased from less than one year to 3 years, and 20% of patients can survive for 5 years or longer.

2020 yilda kolorektal saraton kasalligiga chalingan bemorlarni davolashning qanday yangi variantlari mavjud? Bozorga qanday yangi dorilar kirib kelmoqda, Global Onkolog Tarmoq Tibbiy Bo'limi sizning ma'lumotingiz uchun so'nggi ma'lumotlarni to'pladi.

Yo'g'on ichak saratoni uchun yaxlit dori davolash strategiyasi

1. Birinchi darajali davolash

Treatment options for advanced colorectal cancer include chemotherapy, targeted and immunotherapy. Before the treatment, genetic testing must be carried out, because the doctor will make a treatment plan based on the location of the original lesion, genetic mutations and biomarker detection.

Kolorektal saraton kimyosi odatda ko'p dori birikmasini tanlaydi. Shifokorlar bemorning haqiqiy holatiga qarab birlashadilar. Odatda ishlatiladigan dastlabki standart kombinatsiya sxemasi quyidagicha:

1. FOLFOX (LV / 5-florurasil + oksaliplatin)

2. CAPEOX (Xeloda (Capecitabine) + Oksaliplatin)

3. FOLFIRI (LV / 5-ftorurasil + irinotekan)

4. FOLFOXIRI (LV / 5-fluorourasil + irinotekan + oksaliplatin)

Ushbu muolajalar odatda Avastin® (bevacizumab) bilan birgalikda hayotni yaxshilash uchun, ayniqsa chap yo'g'on ichak saratonini davolash uchun ishlatiladi.

Bu haqda gapirganda, chap tomonda (pastga tushuvchi yo'g'on ichak, sigmasimon ichak, to'g'ri ichak) va o'ng tomonda (ko'tarilayotgan yo'g'on ichak, ko'ndalang yo'g'on ichak, ko'richak) yuzaga keladigan yo'g'on ichak saratoni o'smalarini davolash rejasi va prognozi butunlay boshqacha ekanligini hammaga eslatib o'tishimiz kerak. va chalkashmaslik kerak. Tashxisdan so'ng har bir kishi davolash rejasini tuzish uchun vakolatli mutaxassisni topishi kerak.

The specific plan for the left half of RAS / RAF wild-type patients is as follows. The recommended plan for Class I (preferred): FOLFOX / FOLFIRI ± Cetuximab Class II recommended plan: FOLFOX / CapeOx / FOLFIRI ± Bevacizumab; FOLFOXIRI ± Bevacizumab anti-

Yirtqich tipdagi RAS / RAF bemorlarining o'ng yarmi uchun maxsus reja quyidagicha. Tavsiya etilgan I daraja (afzal): FOLFOX / CapeOx / FOLFIRI ± bevacizumab; FOLFOXIRI ± bevacizumab. FOLFIRI + Avastin bilan taqqoslaganda, FOLFOXIRI + Avastinning 5 yillik umr ko'rish darajasi ikki baravarga oshgan. II sinf uchun tavsiya etilgan rejim: FOLFOX / FOLFIRI ± cetuximab.

2. Ikkinchi darajali davolash

Birinchi qatorda biz kimyoviy terapiya bilan birgalikda bevacizumabdan foydalanamiz. Agar davolash samarali bo'lmasa, biz kimyoviy terapiya rejimini o'zgartirib, bevatsizumabdan foydalanishni davom ettirishimiz mumkin. Albatta, kimyoviy terapiya rejimi bilan bir vaqtning o'zida boshqa maqsadli dori-darmonlarni o'zgartirish, aberseptga yoki ramucirumabga o'tish mumkin.

3. Uchinchi va orqa yo'nalishdagi davolanish

The choice of first-line and second-line drug options for colorectal cancer is usually some relatively standard chemotherapy drugs and targeted drugs. Starting from the third-line treatment is a back-line treatment. The back-line treatment plan can use some oral chemotherapeutic drugs that have just come out, including TAS-102, as well as S-1 (tegio), rifafine, or some immunotherapy, such as pembrolizumab (MSI-H).

Kolorektal saraton kasalligini aniq yo'naltirilgan davolashda yutuqlar

Kolorektal saraton kasalligini davolash bo'yicha ko'rsatmalarning 2017 yilgi versiyasida genetik tekshiruv bo'yicha tavsiyalar faqat KRAS, NRAS, dMMR va MSI-H ni o'z ichiga oladi va 2020 yildagi so'nggi davolash ko'rsatmalarida BRAF, HER2, NTRK va boshqalar kabi yangi maqsadlar mavjud. kolorektal saratonning ko'proq molekulyar ma'lumotlarini tushunish uchun genetik tekshiruv orqali yangi kiritilgan Point bizga ko'proq dori vositalarini topishda yordam beradi. Bemorlarning o'rtacha omon qolish darajasi 3 yildan ortiq, bu aniq tibbiyot tomonidan erishilgan katta yutuq.

1. Kolorektal saraton kasalligi uchun qaysi genlarni tekshirish kerak

Tashxis qo'yilgandan so'ng, shifokor kasallikning kichik guruhini aniqlash uchun metastatik kolorektal saraton (mCRC) bilan kasallangan har bir bemorni genetik tekshiruvdan o'tkazishi kerak, chunki bu ma'lumot davolash prognozini taxmin qilishi mumkin, masalan, HER2 amplifikatsiyasi anti-EGFRni taklif qiladi davolash Dori-darmonlarga qarshilik. Quyidagi genlar sinovdan o'tkazilishi kerak!

MSI, BRAF, KRAS, NRAS, RAS, HER2, NTRK.

2. Hozirgi vaqtda davolash mumkin bo'lgan maqsadlar va maqsadli dorilar

VEGF: Bevacizumab, Apsip

VEGFR: ramucirumab, rigofinib, frukintinib

EGFR: setuksimab, panitumumab

PD-1 / PDL-1: pamluzumab, nivolumab

CTLA-4: Ipilimumab

BRAF: Vimofinil, Konnefini

NTRK: Larotinib

Kolorektal saraton kasalligiga qarshi maqsadli va immunoterapiya dorilarining ro'yxati hozirgacha uyda va chet elda tasdiqlangan:

Kolorektal saratonga qaratilgan dorilar uchun ko'rsatmalar

Bevacizumab ko'rsatkichlari : metastatic colorectal cancer and advanced, metastatic or recurrent kichik hujayrali o'pka saratoni.

Trastuzumab uchun ko'rsatmalar : HER2-positive metastatic breast cancer, HER2-positive early breast cancer, HER2-positive metastatic gastric adenokarsinoma or gastroesophageal junction adenocarcinoma patients.

Pertuzumab uchun ko'rsatmalar : This product is suitable for combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with high-risk recurrence of HER2-positive early ko'krak saratoni.

Nivolumabning ko'rsatkichlari : epidermal growth factor receptor (EGFR) gene mutation negative and anaplastic limfoma kinase (ALK) negative, previous disease progression or intolerable locally advanced or metastatic after receiving platinum-based chemotherapy Adult patients with non-small cell lung cancer (NSCLC).

Regorafenib ko'rsatkichlari : patients with previously treated metastatic colorectal cancer. Durvalumab, Tremelimumab, Ipilimumab, and lapatini
b hali Xitoyda mavjud emas.

EGFR gen mutatsiyasi

Epidermik o'sish omil retseptorlari (EGFR) yo'g'on ichak saratonining taxminan 10 foizida, ko'pincha chap tomonda uchraydi.

Cetuximab va panitumumab FDA tomonidan 2004 va 2006 yillarda rivojlangan kolorektal saraton kasalligini davolash uchun rasman tasdiqlangan.

Dori nomi: panitumumab (Vectibix)

Maqsad: EGFR

Ishlab chiqaruvchi: Amgen (tashqarida)

Ko'rsatkichlar: EGFR ijobiy kolorektal saraton, KRAS kolorektal salbiy saraton

Dori nomi: Cetuximab (Erbitux)

Maqsad: EGFR

Ishlab chiqaruvchi: Merck (tashqarida)

Indications: advanced colorectal cancer, bosh va bo'yin saratoni

BRAF V600E gen mutatsiyasi

Yo'g'on ichak saratoni bilan kasallangan bemorlarning 7-10% BRAF V600E mutatsiyasiga ega. BRAF V600E mutatsiyasi BRAF faollashtiruvchi mutatsiyadir va BRAFning eng yuqori ulushiga ega variant hisoblanadi.

Noyob klinik xususiyatlarga ega:

Asosan o'ng yo'g'on ichakda paydo bo'ladi;

DMMR ulushi yuqori, 20% ga etadi;

BRAF V600E mutatsiyasining yomon prognozi;

Atipik uzatish rejimi;

BRAF mutant genlari bo'lgan bemorlar odatda yomon prognozga ega va ba'zi yangi aniq saratonga qarshi dorilar omon qolish vaqtini ikki baravar oshirgan.

Tadqiqot shuni ko'rsatdiki, FOLFOXIRI + bevacizumab BRAF mutatsiyasiga ega bemorlar uchun eng yaxshi davo bo'lishi mumkin.

V2 2019 versiyasi uchun NCCN ko'rsatmalarida BRAF V600E uchun metastatik kolorektal saraton kasalligini davolashning ikkinchi bosqichi tavsiya etiladi:

Verofenib + irinotekan + cetuximab / panitumumab

Dabarafenib + Trametinib + Cetuximab / Panitumumab

Encorafenib + Binimetinib + Cetux / Pan

The good news is that in the face of such a dangerous BRAF V600E mutant metastatic colorectal cancer, on April 8, 2020, Pfizer announced that the US FDA has approved Braftovi® (encorafenib, Cornefinil) and Erbitux® (cetuximab) , Cetuximab) combined drug regimen (Braftovi second drug regimen), used to treat patients with metastatic colorectal cancer (mCRC) carrying BRAF V600E mutation. These patients have already received one or two pre-treatments. This approval also makes the Braftovi second drug regimen the first targeted therapy approved by the FDA for patients with mCRC carrying BRAF mutations.

Kras genining mutatsiyasi

KRAS yovvoyi yo'tal yo'g'on ichak saratoni - bu maqsadli kombinatsiyalangan kimyoviy terapiyani davolashning birinchi bosqichi, shuning uchun qanday kimyoviy terapiyani tanlash kerak?

Muayyan maqsadli dori-darmonlarni tanlashda uzoqroq operatsion tizimga ega bo'lgan kimyoviy terapiya rejimini tanlash tavsiya etiladi, ya'ni ketuximab FOLFOX bilan, bevacizumab esa FOLFIRI bilan birlashtirilishi kerak. Rejaning aniq tanlovini klinik o'ziga xos tahlil bilan birlashtirish kerak:

Agar davolanishga umid bo'lsa, odatda kemoterapi bilan birga ketuximabga afzallik beriladi, chunki so'nggi vaqtlarda ketuximabning ob'ektiv samaradorligi bevacizumabdan yuqori;

Davolab bo'lmaydigan kasallikka chalingan bemorlar uchun birinchi qator sifatida kemoterapiya bilan birlashtirilgan bevacizumab, so'ngra ketuximab yoki panitumumab foydalanish mumkin.

Yo'g'on ichakning metastatik saratoniga chalingan bemorlar RAS mutatsion holatini, shu jumladan KRAS va NRASni tekshirishlari kerak. Hech bo'lmaganda KRAS exon 2 holati aniqlanishi kerak.

Agar shartlar ruxsat etilsa, KRAS exon 2 exon va NRAS mutatsion holatini aniqlashtirish kerak.

Ikki dorili kimyoterapiya bilan birgalikda Bevacizumab KRAS mutatsiyalari bo'lgan bemorlarga PFS (o'rtacha progressiv omon qolish) va OS (umumiy omon qolish) foyda keltirishi mumkin.

RAS mutatsiyasiga ega bemorlar uchun ketuximabdan foydalanish umumiy samaradorlikka salbiy ta'sir ko'rsatishi mumkin.

KRAS mutatsiyasiga yoki NRAS mutatsiyasiga ega bemorlar ketuximab yoki panitumumab dan foydalanmasliklari kerak.

HER2 kuchaytirish

Rivojlangan yoki metastatik kolorektal saraton kasalligiga chalingan bemorlarning 2% dan 2% gacha HER6 amplifikatsiyasi yoki haddan tashqari ekspression aniqlandi.

Pertuzumab and trastuzumab combine with different HER2 domains to produce synergistic inhibition on shish hujayralar.

My Pathway is the first clinical study to explore the efficacy of Pertuzumab + Trastuzumab therapy in patients with HER2 amplified metastatic colorectal cancer (regardless of KRAS mutation status). This study shows that HER2 dual-targeted therapy-Pertuzumab + Trastuzumab is well tolerated, or may be used as a treatment plan for patients with HER2 amplified metastatic colorectal cancer. Early genetic testing to identify HER2 mutations and consider early use of HER2 maqsadli terapiya may benefit patients.

NTRK genlarining birlashishi mutatsiyasi

Yo'g'on ichak saratoni bilan kasallangan bemorlarning 1-5 foizida NTRK sintezi rivojlanadi va NGS tekshiruvi tavsiya etiladi.

From January 23 to January 25, 2020, the American Society of Clinical Oncology Oshqozon-ichak shishi Symposium (ASCO-GI) specifically analyzed the clinical drug effects of patients with gastrointestinal tumors carrying NTRK fusion protein.

Sinov natijalari shuni ko'rsatdiki, oshqozon-ichak saratoni kichik guruhining remissiya darajasi 43% ni, yo'g'on ichak saratoni bilan kasallangan bemorlarning umumiy remissiya darajasi 50% ni tashkil etdi. Javobning davomiyligi juda o'zgarib turadi, 3.5 oydan 14.7 oygacha.

After a median follow-up period of 19 months, the median overall survival time was up to 33.4 months, nearly three years. The one-year overall survival rate (OS) is 69%. At the time of the data cutoff, four colon cancer patients and one pancreatic cancer patient were still alive and their condition did not deteriorate. And the safety and tolerability of larotinib is good. Most adverse reactions are grade 1 or 2.

Metastatik kolorektal saraton kasalligiga chalingan 75 yoshli ayol juda baxtli:

Birlamchi yo'g'on ichak shishi.

Peritoneal saraton.

Jigar metastazi.

Entratinib 1600 mg / m 2 haftasiga bir marta ketma-ket 4 kun davomida haftasiga bir marta (ya'ni 4 kun / 3 kun dam olish), ketma-ket uch hafta davomida har 28 kunda qabul qilindi. Sakkiz haftalik davolanishdan so'ng lezyon sezilarli darajada kamaydi.

Kolorektal saraton immunoterapiyasi va yangi kashfiyotlar

Prognostik tartib: MSI-H va BRAF yovvoyi turi> MSI-H va BRAF mutant> MSS va BRAF yovvoyi turi> MSS va BRAF mutant.

1. MSI-H / dMMR metastatik kolorektal saraton

Yuqori mikrosatellit beqarorligi (MSI-H) yaxshi prognostik omil bo'lib, MSI-H kolorektal saraton kasalligidagi BRAF mutatsiyasining darajasi taxminan 50% ni tashkil qiladi.

Immunitet tekshiruvi inhibitörleri MSI-H uchun samarali davolashdir. Hozirgi vaqtda MSI-H tipidagi mCRC bilan kasallangan bemorlarga qo'llaniladigan immunitet tekshiruvi inhibitörleri orasida pembrolizumab, nivolumab va ipilimumab mavjud.

Nivolumab / Ipilimumab kombinatsiyasi birinchi darajali davolashda kuchli faollikni ko'rsatadi

Nivolumab (Opdivo) va ipilimumab (Yervoy) ning oldingi qator birikmasi metastatik kolorektal saraton (mCRC) bilan og'rigan bemorlarda kuchli va uzoq muddatli klinik foydani ko'rsatdi va uning o'smasi mikrosatellit beqarorligi (MSI-H) / nomuvofiqlikni tiklash defekti (dMMR) -FACP Xaynts-Yozef Lenz, tibbiyot fanlari doktori, prognoz tarixi yomon odamlar.

II bosqich CheckMate-142 sinovida tadqiqotchilar MSI-H / dMMR mCRC (n = 45) bo'lgan bemorlar uchun birinchi darajali davolash sifatida nivolumab va past dozali ipilimumabning xavfsizligi va samaradorligini tekshirdilar. 2018 yilgi ESMO konferentsiyasida taqdim etilgan avvalgi natijalar shuni ko'rsatdiki, 45 bemorning umumiy javob darajasi (ORR) 60% ni, kasalliklarga qarshi kurash darajasi esa 84% ni tashkil etdi. 2019 ASCO yillik yig'ilishida sinovning klinik yangilanishi e'lon qilindi. 19.9 oylik o'rtacha kuzatuv vaqtida tergovchi tomonidan baholangan ORR ning kombinatsiyaga nisbati 64% gacha o'sdi va bemorlarning 84% ≥12 hafta davomida kasallik nazorati ostida edi.

2. MSS kolorektal saraton kasalligi

MSS kolorektal saraton kasalligida yangi yutuq: regorafen
ib (Stivarga) + nivolumab

Mikrosatellit stabilizatsiyasi (MSS) kasalligi bilan og'rigan bemor uchun taxminan 53 bemor [kombinatsiyalangan terapiya] olgan va 40% yuqori reaktsiyaga erishgan, bu esa refrakter bemorlarning bu qismida eshitilmagan.

Anti-VEGF terapiyasining PD-1 blokadasi bilan sinergetik ta'sir ko'rsatishi mumkinligi to'g'risida doimiy ma'lumotlar mavjud. Endi, bu MSS aholisi orasida birinchi marta. Ushbu ikkita davolash strategiyasini birlashtirib, biz juda ta'sirli natijalarni ko'rdik. Shuning uchun anti-VEGF strategiyasini immunitetni nazorat qilish punktini bostirish bilan birlashtirib, MSS kasalligi bo'lgan bemorlarda omon qolish uchun ko'proq foyda keltiradi.

Maqolaning xulosasi

Maqsadli terapiya davrida kolorektal saraton kasalligiga chalingan har bir bemor MSI aniqlash, RAS va BRAF mutatsion tahlilidan o'tishi va imkon qadar HER2 amplifikatsiyasi, NTRK va boshqa genlarni aniqlashni amalga oshirishi kerak. Genetik test (NGS) ko'pgina bemorlar uchun dastlabki tekshiruv standartiga kiritilgan. Endilikda mahalliy bemorlarni Global Onkologlar tarmog'i orqali tekshirish mumkin.

Biz kolorektal saraton kasalligini davolashning molekulyar inqilobida yashayapmiz. Biz yo'g'on ichak saratonining molekulyar genetikasi va uni klinik davolash qarorlariga qanday o'tkazish haqida ko'p narsalarni bilib oldik. Kelajakda yana ko'p narsalar bo'ladi. So'nggi tadqiqot natijalari va yo'g'on ichak saratoni bo'yicha eng yaxshi dori-darmon rejasiga kelsak, faqat uyda va chet elda eng yaxshi saraton mutaxassislari boy klinik tajribaga ega. Kolorektal saraton kasalligi davolashning eng yaxshi rejasini olish uchun Global Onkologlar Tarmog'i orqali nufuzli mutaxassislar bilan maslahatlashishga murojaat qilishi mumkin.