Ayvakit Qhia Tau Zoo Siv Hauv Kev Kho Mob Ua Ntej SM: Cov Tag Nrho Tag Nrho Yog 75%!

Blueprint Cov Tshuaj Kho Mob, tus khub ntawm CStone, yog lub tuam txhab ua lag luam tshuaj muaj lub zog tshwj xeeb rau kev kho mob hauv caj ces, mob tsis tshua muaj thiab kev siv tshuaj kho mob cancer. Tsis ntev los no, lub tuam txhab tshaj tawm cov txiaj ntsig zoo saum toj kawg nkaus ntawm Theem I EXPLORER thiab Theem II PATHFINDER cov chaw soj ntsuam kev tshuaj ntsuam xyuas lub hom phiaj tshuaj anticancer Ayvakit (avapritinib) rau kev kho mob ntawm cov neeg mob uas muaj kab mob mastocytosis (SM).

Raws li cov txiaj ntsig ntawm qhov dhau los qhia EXPLORER txoj kev sim, Ayvakit kev kho mob txo qis lub nra ntawm mast hlwb, pom tau qhov feem ntau ntawm cov lus teb rov qab (ORR: 75%) thiab ua tiav cov lus teb tiav (CR), thiab cov kev pabcuam siv tau zoo, suav nrog kev ncua ntev tag nrho (OS)). 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. Raws li cov ntaub ntawv no, Blueprint Tshuaj npaj yuav xa cov ntawv thov tshuaj ntxiv tshiab (sNDA) rau Ayvakit rau kev kho mob siab kawg SM mus rau Asmeskas Chaw Tswj Khoom Noj thiab Tshuaj (FDA) hauv plaub lub hlis xyoo 2020.

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 thiab kev ua kom muaj mast hlwb zoo tuaj yeem ua rau muaj kev phom sij txog lub neej. Ntawm cov qib siab kawg SM subtypes, qhov nruab nrab zuag qhia tag nrho cov 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 ntawm 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 hauv 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 cov cai, ORR yog 28%. ORR txhais tau tias yog kev zam txim tag nrho, kho qee yam lossis txhim kho kho mob.

Andy Boral, MD, Tus Thawj Saib Xyuas Kev Kho Mob ntawm Blueprint Tshuaj tau hais tias: "Yuav muaj kev kho mob sai sai los daws cov teeb meem mast cell infiltration cuam tshuam nrog SM siab heev. Txawm hais tias muaj kev pab kho mob, qhov no feem ntau ua rau muaj kev puas tsuaj rau cov khoom nruab nrog cev thiab cov qis kev muaj sia nyob tsawg. Cov ntaub ntawv tseem ceeb tshaj plaws no hais txog kev hloov pauv hloov los ntawm Ayvakit: tus neeg mob lub mast cell load tau txo qis, cov lus teb tau ntev dhau los ua haujlwm ntev zuj zus, thiab tag nrho cov kev muaj sia nyob ntev dua piv rau keeb kwm kev tshwm sim. Raws li cov kev zoo no Qhov txiaj ntsig, Peb lub hom phiaj yog kom nrawm rau txoj kev kho kom zoo rau cov neeg mob, nrog lub hom phiaj txhim kho thiab txuas lawv lub neej ntev dua li cov kev kho mob tam sim no."

EXPLORER thiab PIONEER cov ntaub ntawv xeem:

Hauv ob txoj kev sim no, 85 tus neeg mob tau raug tshuaj saib xyuas qhov ua tau zoo raws li IWG-MRT-ECNM cov qauv (IWG cov 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 siab yog Lub Rau Hli 23, 2020, thiab kev soj ntsuam kev txo qis los ntawm lub chaw yuav ua tiav rau lub Cuaj Hli 2020. Cov ntawv sau npe kawg yog txiav txim siab los ntawm lub hauv paus 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 qhov kev sim EXPLORER, 53 tus neeg mob tuaj yeem raug ntsuas rau kev zam txim, qhov nruab nrab lub sijhawm taug qab 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 kev sim tshuaj nruab nrab ntawm 10.4 lub hlis, ib qho ORR ntawm 75% (95% CI: 57%, 89%), thiab 19 % tus 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 nyob rau sijhawm, 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 li kev npaj ua ntej kom ntsuas tau qhov zoo tshaj ntawm Ayvakit thiab yav dhau los tshaj tawm hais txog ORR (28%) ntawm cov tshuaj tiv thaiv ntau kinase inhibitor midostaurin raws li IWG cov qauv. Qhov txheeb xyuas ntu ib ntus tau mus txog qhov kawg qhov kawg (p=0.0000000016).

Hauv kev txheeb xyuas ntawm kev sib xyaw ua ke los ntawm 200mg QD koob tshuaj pawg, 44 tus neeg mob tuaj yeem raug soj ntsuam rau qhov ua tau, thiab kev soj ntsuam nruab nrab 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 zam tau zoo, 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 thaum pib ntawm 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 tus kab mob siab 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 tsis tu ncua, 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 ntau yam kev cuam tshuam los tiv thaiv kev cuam tshuam 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 ntsig txog kev tawm tsam kev pom zoo tam sim no kev kho mob.

Piv nrog kev pom zoo ntau lub kinase inhibitors, avapritinib yog qhov muaj kev xaiv ntau rau KIT thiab PDGFRA dua li lwm cov kinases. Ntxiv rau, 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 ntawm cov neeg mob laus uas tsis muaj kev tiv thaiv lossis metastatic GIST uas muaj 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 kev txhim kho thiab kev lag luam txoj cai ntawm peb tus neeg sib tw ua yeeb tshuaj suav nrog Ayvakit hauv Greater Suav. Thaum Lub Peb Hlis Ntuj 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 rau cov tshuaj tshiab avapritinib, yuav tsum vov 2 qhov ntsuas, uas yog: (1) Rau kev kho mob ntawm cov neeg mob nqa platelet-derived kev loj hlob tau txais 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 txais los ntawm NMPA, khij ib kauj ruam tseem ceeb hauv tuam txhab' s kev hloov pauv lag luam.