Lub zog muaj zog KIT inhibitor Ayvakit tau thov rau qhov kev ntsuas qhov tshiab hauv Asmeskas, thiab CStone Cov Tshuaj Kho Mob tau tsim nws hauv Suav Teb!

Blueprint Cov Tshuaj Kho Mob, tus khub ntawm CStone, yog lub tuam txhab ua lag luam tshuaj muaj lub zog tshwj xeeb rau kev mob caj ces, mob tsis tshua muaj thiab tshuaj tua kab mob cancer. Tsis ntev los no, lub tuam txhab tau tshaj tawm tias nws tau xa daim ntawv thov cov tshuaj ntxiv tshiab (sNDA) rau lub hom phiaj tshuaj anticancer Ayvakit (avapritinib) rau Asmeskas Chaw Tswj Xyuas Khoom Noj thiab Tshuaj (FDA) rau kev kho mob rau qib mauj mastocytosis (SM) hauv cov neeg laus. Ayvakit yog cov muaj zog thiab xaiv cov tshuaj tiv thaiv ntawm D816V hloov pauv KIT (tus tsav tseem ceeb ntawm SM) thiab tam sim no tau tsim kho rau kev kho ntawm kev txawj ntse thiab tsis tau paub tshaj SM.

Blueprint tau thov kom muaj kev rov saib xyuas feem ntawm sNDA, thiab yog tias pom zoo, nws txoj kev txheeb xyuas kev cia siab yuav tsum luv rau 6 lub hlis. FDA muaj 60-hnub ua ntawv tshuaj xyuas lub sijhawm los txiav txim seb sNDA puas ua tiav thiab siv tau rau kev thov. Yav dhau los, FDA tau tso cai rau Ayvakit kev tsim cov tshuaj uas tsis raug cai (BTD) rau kev kho mob siab kawg ntawm SM, suav nrog: txhoj puab SM (ASM), SM nrog kev cuam tshuam txog cov qog ntshav (SM-AHN) thiab mast cell leukemia (MCL).

Blueprint R& D Thawj Tswj Hwm Fouad Namouni, MD, hais tias:" Niaj hnub no' daim ntawv thov yog ib kauj ruam tseem ceeb rau peb lub hom phiaj. Peb lub hom phiaj yog nqa Ayvakit rau cov neeg mob uas muaj tus kab mob siab heev SM, uas yog ib qho kev ua tsis muaj zog thiab muaj kev phom sij rau lub neej. Cov. Peb daim ntawv thov yog saib raws li cov ntaub ntawv tsis muaj kev soj ntsuam tau teev nyob rau thaj tsam ntawm tus kabmob SM, uas qhia tau tias cov neeg mob tau kho nrog Ayvakit tau tau txais cov lus qhia tau zoo tag nrho (ORR) thiab ua tiav cov lus teb (CR), thiab kev muaj sia nyob ntev. Peb tos ntsoov yuav ua haujlwm zoo nrog US FDA thaum lub sijhawm tshuaj xyuas kom pib thawj qhov kev kho mob rau qhov ua rau SM."

SM yog qhov tsis tshua muaj kab thiab debilitating tus kab mob. Yuav luag txhua tus neeg mob tshwm sim los ntawm KIT D816V hloov chaw. Kev tswj tsis tau ntawm kev nthuav tawm thiab ua kom muaj mast hlwb tuaj yeem ua rau kom muaj kev phom sij txog lub neej. Ntawm cov qib siab kawg SM subtypes, qhov nruab nrab zuag qhia tag nrho kev ciaj sia (OS) ntawm kev txhoj puab heev SM (ASM) yog kwv yees li 3.5 xyoo, thiab qhov nruab nrab ntawm OS ntawm SM nrog kev cuam tshuam cov qog hematological hlav (SM-AHN) yog li 2 xyoo. Mast cell Qhov nruab nrab OS rau cov mob leukemia (MCL) yog tsawg dua 6 lub hlis. Ayvakit yog kev kho qhov tseeb rau SM, thiab nws tsuas yog qhov muaj zog heev KIT D816V inhibitor uas tau muab pov thawj hauv tsev kho mob SM.

Tam sim no, tsis muaj kev pom zoo kho uas tau xaiv qhov kev cuam tshuam KIT D816V kev hloov pauv. Qhov ntau-kinase inhibitor midostaurin tau txais kev pom zoo rau kev kho mob siab heev SM. Raws li IWG tus qauv, ORR yog 28%. ORR txhais tau tias yog kev zam txim tag nrho, kho ib feem lossis txhim kho kho mob.

Lub Cuaj Hlis xyoo no, Blueprint tau tshaj tawm cov txiaj ntsig zoo saum toj kawg nkaus ntawm Theem I EXPLORER thiab Theem II PATHFINDER cov chaw kuaj mob ntsuas Ayvakit hauv cov neeg mob uas muaj SM. Raws li cov kev qhia tas los ntawm EXPLORER mus sib hais, nws hais txog qhov hloov pauv hloov los ntawm Ayvakit: cov neeg mob lub mast cell lub nra yog qhov txo qis, uas qhia qhov feem ntau ntawm cov lus teb rov qab (ORR: 75%) thiab ua tiav tus lej teb (CR), tag nrho ciaj sia Lub sijhawm (OS) yog lub sij hawm ntev dua li ntawm cov txiaj ntsig hauv keeb kwm. Hauv qhov kev tshawb fawb no, Ayvakit feem ntau pom zoo ua tau zoo, thiab kev nyab xeeb ntawm 200 mg ib hnub ib zaug (QD) qhia txog kev txhim kho.

EXPLORER thiab PIONEER cov ntaub ntawv xeem:

Hauv ob qhov kev sim no, 85 tus neeg mob tau soj ntsuam rau qhov ua tau zoo raws li IWG-MRT-ECNM tus qauv hloov (IWG tus qauv), suav nrog 44 tus neeg mob tau kho nrog pib 200 mg ib zaug ib hnub (QD). Hnub kawg rau kev tshaj tawm cov txiaj ntsig ntawm sab saum toj: Kev sim kev hais plaub yog Lub Tsib Hlis 27, 2020, PHTHFINDER kev sim yog Lub Rau Hli 23, 2020, thiab kev soj ntsuam kev txo qis los ntawm lub chaw yuav ua tiav nyob rau lub Cuaj hli 2020. Cov ntawv sau npe kawg yog ua raws cov kev txheeb xyuas ntawm qhov tus lej teb (ORR) thiab lub sijhawm teb (DOR). ORR txhais tau tias yog kev kho mob tag nrho, kho qee yam lossis kho kev kho mob ntawm kev ua tiav lossis ib feem ntawm kev rov qab los ntawm cov ntshav (CR / CRh). Txhua daim ntawv qhia ntawm cov chaw kuaj mob tau lees paub.

Hauv kev soj ntsuam EXPLORER, 53 cov neeg mob tuaj yeem raug ntsuas rau kev zam txim, kev soj qab taug qab nruab nrab yog 27.3 hlis, ORR yog 76% (95% CI: 62%, 86%), thiab 36% ntawm cov neeg mob tiav CR / CRh. Qhov nruab nrab DOR yog 38.3 hli (95% CI: 21.7 lub hlis, NE). Qhov nruab nrab OS tsis tuaj yeem kwv yees (95% CI: 46.9 hli, NE).

Kev tshuaj xyuas ua ntej ntawm kev soj ntsuam PHTHFINDER pom tias 32 tus neeg mob tuaj yeem txheeb xyuas tau kev kho mob, nrog rau kev soj qab taug qab nruab nrab ntawm 10.4 lub hlis, ib qho ORR ntawm 75% (95% CI: 57%, 89%), thiab 19 % cov neeg mob tiav CR / CRh. Tsis tas li ntawd, cov ntaub ntawv tau hais tias cov kev pab cuam txuas ntxiv mus tob zuj zus ntxiv, nyob ntawm tus nqi sib xws nrog EXPLORER mus sib hais. Qhov nruab nrab DOR tsis tau kwv yees (95% CI: NE, NE), thiab OS tsis raug tshuaj xyuas vim lub sijhawm sau npe ntawm cov neeg mob hauv PHTHFINDER kev sim. Cov ntsiab lus saum toj kawg nkaus ntawm PHTHFINDER kev sim siab yog ua raws cov kev npaj ua ntej kom ntsuas tau qhov zoo tshaj ntawm Ayvakit thiab yav dhau los tshaj tawm hais txog ORR (28%) ntawm ntau cov kinase inhibitor midostaurin raws li IWG cov qauv. Qhov txheeb xyuas lub sij hawm ib ntus tau mus txog qhov kawg qhov kawg (p=0.0000000016).

Hauv kev tso tawm qhov kev cuam tshuam ntawm 200mg QD koob tshuaj pab pawg, 44 tus neeg mob tuaj yeem raug soj ntsuam rau qhov ua tau Cov sijhawm nruab nrab rov qab mus kuaj yog 10.4 hli. Hauv pawg no, ORR yog 68%, thiab 18% ntawm cov neeg mob ua tiav CR / CRh.

Cov ntaub ntawv kev nyab xeeb zoo ib yam nrog cov txiaj ntsig yav dhau los, thiab tsis muaj lub cim tshiab. Ayvakit feem ntau ua siab ntev, thiab feem ntau cov xwm txheej tsis zoo (AE) yog qhia raws li qeb 1 lossis 2. Hauv kev kuaj mob EXPLORER thiab PHTHFINDER, Ayvakit pom tias piv nrog txhua koob, qhov tiv thaiv tau zoo tuaj ntawm pib 200 mg QD. Hauv ob qhov kev sim no, 8.1% ntawm cov neeg mob txuas mus ntxiv ntawm Ayvakit vim yog kev kho mob ntsig txog qhov tshwm sim tsis zoo (TRAE).

Cov txiaj ntsig ntawm kev sim dhau los piav qhia EXPLORER tau qhia tias kev muaj mob ua ntej thrombocytopenia (raws li Blueprint Cov Tshuaj Kho Mob kwv yees, tshwm sim hauv kwv yees li 10% -15% ntawm cov neeg mob uas muaj SM) thiab qhov pib ntawm 300 mg QD lossis siab dua yog intracranial hemorrhage ( ICB) Muaj feem cuam tshuam. Raws li cov ntaub ntawv no, Blueprint Cov Tshuaj Txhim Kho tau siv cov txheej txheem tswj kev kho mob hauv EXPLORER thiab PATHFINDER cov kev sim, suav nrog cov qauv tshwj tseg rau kev muaj mob ua kom tsis txhob mob plab, soj ntsuam platelet ib txwm, thiab cov lus qhia thaum muaj xwm ceev los cuam tshuam kev mob loj ntawm thrombocytopenia. Ntawm 76 EXPLORER thiab PATHFINDER kev sim cov neeg mob yam tsis muaj kev mob siab ua ntej muaj mob loj, 2 tus neeg mob (2.6%) muaj qhov xwm txheej ICB. Ob qhov xwm txheej tsis zoo yog ob Qeb 1 thiab asymptomatic. Cov ntaub ntawv kev nyab xeeb no tau txheeb xyuas qhov kev cuam tshuam hauv chaw soj ntsuam ntawm txoj cai tswj kev kho mob.

Cov tshuaj nquag ua haujlwm ntawm Ayvakit yog avapritinib, uas tuaj yeem xaiv thiab muaj zog inhibit KIT thiab PDGFRA mutant kinases. Cov tshuaj yog ib hom kuv inhibitor tsim los tsom rau kev ua si lub zog kinase conformation; tag nrho oncogenic kinases teeb liab los ntawm qhov kev hloov pauv no. Avapritinib tau pom tias muaj kev cuam tshuam dav dav rau GIST-cuam tshuam rau KIT thiab PDGFRA kev hloov pauv, suav nrog kev ua haujlwm muaj zog tiv thaiv kev voj kev hloov pauv cuam tshuam nrog kev tawm tsam kev kho tam sim no tau pom zoo.

Piv nrog kev pom zoo multi-kinase inhibitors, avapritinib yog qhov kev xaiv ntau rau KIT thiab PDGFRA dua li lwm cov kinases. Ib qho ntxiv, avapritinib yog qhov tsim tshwj xeeb los xaiv khi thiab khi D816 hloov pauv KIT, uas yog ib tus neeg tsav tsheb muaj kabmob feem ntau kwv yees li ntawm 95% ntawm cov neeg mob uas muaj kab mob mastocytosis (SM). Kev tshawb nrhiav pom tau pom tias avapritinib tuaj yeem cuam tshuam KIT D816V nrog cov sub-nanomolar potency thiab muaj qhov tsawg ntawm kev ua haujlwm.

Ayvakit tau pom zoo los ntawm Asmeskas FDA thaum Lub Ib Hlis 2020 rau kev kho mob tsis muaj kev tiv thaiv lossis metastatic GIST cov neeg laus nrog kev hloov pauv hauv exon 18 ntawm platelet-derived kev loj hlob tau txais alpha (PDGFRA) noob (suav nrog PDGFRA D842V hloov). Nws tsim nyog teev tias Ayvakit yog thawj qhov kev kho kom raug pom zoo rau GIST thiab thawj cov tshuaj nrog cov haujlwm siab tiv thaiv GIST nrog kev hloov pauv hauv exon 18 ntawm PDGFRA noob.

CStone Cov Khoom Siv Tshuaj tau mus txog kev sib koom tes tshwj xeeb thiab kev pom zoo nrog Blueprint Medicines, thiab tau txais txoj kev txhim kho thiab kev ua lag luam ntawm peb txoj cai siv tshuaj suav nrog Ayvakit hauv Greater Suav. Hauv lub Peb Hlis ntawm lub xyoo no, CStone Cov Tshuaj Kho Mob tau tshaj tawm qhov kev xa daim ntawv thov tshuaj tshiab rau avapritinib hauv Taiwan, Suav. Lub Plaub Hlis xyoo no, CStone Cov Tshuaj Kho Mob tshaj tawm tias National Medical khoom Administration (NMPA) yuav lees txais cov ntawv thov tshuaj tshiab rau avapritinib, suav txog 2 qhov ntsuas, uas yog: (1) Rau kev kho mob platelet-derived kev loj hlob factor receptor alpha (PDGFRA ) Cov neeg mob loj uas tsis tuaj yeem tiv thaiv lossis metastatic GIST nrog kev hloov pauv hauv exon 18 (suav nrog PDGFRA D842V kev hloov pauv); (2) Cov neeg laus nrog cov plaub-kab tsis tuaj yeem pom lossis metastatic GIST. Nov yog CStone' s thawj cov npe tshuaj tshiab tau lees txais los ntawm NMPA, khij ib kauj ruam tseem ceeb hauv tuam txhab' s kev hloov pauv kev lag luam.