I-Avapritinib (i-Avapriny, i-Ayvakit, i-BLU-285) yamathumbu emathunjini emathunjini ivunywa yi-USFDA ngomhla ka-9 Januwari, 2020. Lesi sidakamizwa sihlanganisa izinkomba ezimbili: ekwelapheni iziguli ezindala ezine-resection engasebenzi noma i-GIST ye-metastatic ethwele i-factor factor receptor platelet i-alpha (PDGFRA) exon 18 mutation (kufaka phakathi i-PDGFRA D842V mutation), Neziguli zabantu abadala ezingama-line ezingezona ezokuhlinzwa noma ze-metastatic.
I-ORR ifike ku-86%, i-Avapritinib iletha ithemba elisha ezigulini ezinamathumba aqinile emathunjini
NgoNovemba 2019, umhlangano waminyaka yonke we-Connective Tissue Oncology Society (CTOS) wamemezela imiphumela ye-NAVIGATOR Phase I yecala lomtholampilo ku-avapritinib e-PDGFRA exon 18 mutations and iziguli ezithola i-GIST yomugqa wesine.
1. Isizinda socwaningo
Kusukela ngoNovemba 16, 2018, kubhaliswe inani eliphelele leziguli eziyi-121 zomugqa wesine nangaphezulu (ikakhulukazi ukuguqulwa KIT) neziguli ezingama-43 ze-GIST ezine-PDGFRA exon 18. Isivivinyo sihlolisise umthamo wokuqala wesivivinyo njengo- "400 mg ngomlomo kanye ngosuku", futhi kamuva sinciphise umthamo onconyiwe waba “300 mg ngomlomo kanye ngosuku” ngenxa yobuthi. Isiguli sithole i-Avapritinib kuze kube ukuqhubekela phambili kwesifo noma ubuthi obungamukeleki.
2. Idatha yokusebenza
Ezigulini ezine-PDGFRA exon 18 mutation, bekunezigameko ezi-3 zokuxolelwa okuphelele (OR) kanye namacala angama-34 okuxolelwa okuyingxenye (PR), kanye nezinga lokuphendula lenhloso (ORR) lalingama-86%. Ubude besikhathi sokuphendula (DOR) kanye ne-median progression-free survival (PFS) abufinyelelwanga. Kusukela ngosuku lokunqanyulwa kwedatha (isikhathi sokulandelela esimaphakathi kwakuyizinyanga ezingu-10.9), ama-78% eziguli asaphendula.
Ezigulini eziyi-111 ze-GIST ezinolayini wesine noma ngaphezulu, i-1 ibinokuxolelwa okuphelele, i-23 inokuthethelelwa okuyingxenye, i-ORR ibingama-22%, ubude besikhathi sokuphendula obuphakathi bekuyizinyanga eziyi-10.2, i-median PFS bekuyizinyanga eziyi-3.7, kanti isikhathi sokulandelela semaphakathi bekungu-10.8. inyanga.
Mayelana nokuphepha, izehlakalo ezimbi kakhulu (ama-AEs) ikakhulu zinga-grade 1, 2 kanti ezivame kakhulu ukucanuzela kwenhliziyo, ukukhathala, i-anemia, uhudo, ukuhlanza, njll. Ibanga lesi-3-4 elihlobene ne-AE ≥ 2%, i-anemia, ukukhathala, i-Phosphaemia ephansi, i-hyperbilirubinemia, i-neutropenia nohudo. Iziguli eziyi-10% ziyeke ukwelashwa ngenxa yama-AE ahlobene nokwelashwa.
3. Inani lomtholampilo
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 izimila stromal emathunjini (GIST) with KIT and PDGFRα mutations, including the D842V mutation of the PDGFRα gene and other primary or secondary resistance mutations.
I-Keyless lock-PDGFRA exon 18 mutant GIST
Gastrointestinal stromal isisu (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 izimila stromal emathunjini, 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.
Njengamanje, kufika ku-85% wamathumba e-GIST anokuguqulwa kofuzo okukodwa kwe-PDGFRA ne-KIT. Lezi zinguquko ziholela ekukhiqizweni kwamaprotheni e-KIT ne-PDGFRA angajwayelekile, aqhuba umdlavuza. Lawa maprotheni amabili ngokuvamile angavalwa yi-imatinib nezidakamizwa ezifanayo ezivimba umsebenzi wephrotheni. Kodwa ukuguqulwa kwe-PDGFRA exon 18 kukhethekile kakhulu, kushintsha ukuma kwephrotheni ye-PDGFRA, ngaleyo ndlela kuvimbele umuthi ekubopheni kuwo. Ngokuguqulwa kwe-PDGFR [exon 18], "ukhiye" wangaphambilini awufaneleki "lokhiya".
I-Avapritinib ibopha ngokukhethekile amaprotheni e-PDGFRA ne-KIT. Ezifundweni zaselabhorethri, umuthi ungabopha kuwo wonke amaprotheni we-mutant PDGFRA ahlolwe futhi uvimbele umsebenzi wawo kumaseli womdlavuza.
Izidakamizwa ezine njengamanje zivunyelwe izicubu zomzimba zesisu: Avapritinib, imatinib, sunitinib, ne-rifaginib. I-Avapritinib ibopha kuphela kuma-enzyme athile we-mutant abizwa ngama-kinase (imibuthano ebomvu) kumaseli, kanti izidakamizwa ezifanayo zibopha kuma-kinase amaningi. Isithombe: Ubuchwepheshe Bokusayina Kwamaseli.
| Isidakamizwa esihlosiwe samukelwe isimila esiswini samathumbu (GIST) | Ezinye izinkomba zomdlavuza | Uhlu lwasekhaya |
| Gleevec | I-Imatinib | I-acute lymphocytic leukemia (Philadelphia chromosome positive), chronic eosinophilic leukemia, Philadelphia chromosome positive chronic myeloid leukemia, dermatofibrosarcoma protuberans, myeloproliferative tumor | Kubhalwe ohlwini futhi kwafakwa kumshwalense wezokwelapha |
| I-Regorafenib | I-Stivarga | Liver cancer, umdlavuza colorectal | Kubhalwe ohlwini futhi kwafakwa kumshwalense wezokwelapha |
| Sutent | I-Sunitinib | Xixianai, umdlavuza wezinso | Kubhalwe ohlwini futhi kwafakwa kumshwalense wezokwelapha |
| I-Avapritinib (Ayvakit) | cha | Kubhalwe ohlwini |
Enye inqubekela phambili yocwaningo yamathumba e-stromal yamathumbu
I-Ripretinib
I-Ripretinib iwuhlobo lwe-II kinase inhibitor engavimbela kabanzi ukuguqulwa kwe-loop yokuvula ku-KIT naku-PDGFRA. Kuyi-kinase inhibitor enomsebenzi "wokulawula ukushintsha", engenza kusebenze iluphu yokuvula (noma yenze kusebenze "ukushintsha") ku-Conformation esebenzayo, futhi, ivimbela zonke izinguquko ezihloliwe ze-KIT ne-PDGFRA. Ukusebenza kwe-Ripretinib kumamodeli womdlavuza we-preclinical kanye nokuhlolwa komtholampilo kokuqala kuphinde kwaqinisekisa ukuthi i-Ripretinib ingavimbela ukuguqulwa kwendawo yonke kwe-KIT ezigulini ezine-GIST engazweli emthini.
Imininingwane evela ocwaningweni lweSigaba III (INVICTUS) ikhombise ukuthi iziguli ezithola i-Ripretinib zazinengozi engama-85% ephansi yokwanda kwesimila noma yokufa uma kuqhathaniswa ne-placebo, ene-median OS yezinyanga eziyi-15.1, nezinyanga eziyi-6.6 eqenjini le-placebo. Ukwelashwa emuva kwesikhathi kwe-GIST ulayini wesine noma ngaphezulu kuletha izinzuzo ezimbili ze-PFS ne-OS, kanti iRipretinib ikhombisa ukubekezelelana okungcono.
I-Larotrectnib
Isidakamizwa sokuqala esibhekiswe emhlabeni esingahlukanisi imithombo yesimila ekwelashweni kokuqala-i-Vitrakvi ® (larotrectinib, ngemuva kwalokhu ebizwa nge-larotinib), sivunyiwe ngumphakathi wesimila somhlaba wonke selokhu savunyelwa ukumaketha ngoNovemba 2018 Odokotela neziguli balethe okusha amathemba nokukhetha.
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 umdlavuza we-thyroid, and can be used for both adults and children. NTRK gene fusion exists in 0.7% ~ 3.6% of digestive tract tumors.
Ngakho-ke, uma wenza ukuhlolwa kofuzo, ungabona kuqala ukuthi kukhona yini ukuguqulwa okungaletha isimangaliso sokusinda, ungashayela umnyango wezokwelapha we-Global Oncologist Network ukuze uhumushe umbiko.
Ngikholelwa ukuthi ngokufika kwezidakamizwa ezihlosiwe kakhulu, iziguli ezine-stroma yamathumbu
l amathumba angathola izinketho zokwelashwa ezengeziwe kanye nezinzuzo zokuphila isikhathi eside. Ngiyethemba futhi ukuthi le mithi ingafakwa ohlwini e-China ngokushesha ngangokunokwenzeka futhi ifakwe kumshwalense wezokwelapha ukuze kuzuze iziguli ezengeziwe.
