Savolitinib Muaj Ntau Qhov Txaus Ntshai Thiab Muaj Peev Xwm Zoo Rau Kev Kho Mob Ntau Hom Kab Mob Khees Xawj

Kev ua haujlwm tsis txaus ntseeg ntawm MET txoj hauv kev tuaj yeem pom nyob rau hauv ntau hom mob qog nqaij hlav, tshwj xeeb tshaj yog mob ntsws ntsws, uas yog qhov tseem ceeb tshaj plaws hauv kev tsav tsheb. MET proto-oncogene tshwm sim ntawm caj npab ntev ntawm tib neeg cov chromosome 7, thiab cov khoom sib txuam protein yog c-MET protein, uas muaj tyrosine kinase kev ua si. Cov nqaij hlav muaj peev xwm ua tau ntau ntxiv txawv txav thiab dhau los ua dhau los ntawm HGF / MET txoj hauv kev.

Savolitinib (AZD6094) tau tshawb pom los ntawm Hutchison Whampoa Pharmaceuticals thiab tam sim no tau sib koom tsim los ntawm Hutchison Whampoa Pharmaceuticals thiab AstraZeneca. Nws yog qhov kev xaiv zoo tshaj c-Met receptor tyrosine kinase inhibitor. Xyoo no' s lub rooj sib tham txog kev kho mob, Savolitinib zoo siab heev thiab pom tias muaj peev xwm ntau rau kev kho mob.

1. MET cuam tshuam rau kev soj ntsuam ntawm papillary raum cell carcinoma, MET inhibitors zoo dua li kev kho mob qauv

Papillary lub raum cell carcinoma (PRCC) yog hom muaj ntau tshaj plaws ntawm qhov tsis pom tseeb cell carcinoma, kwv yees li 10% mus rau 15% ntawm lub raum malignancies. Txij li MET oncogene hloov tau yuav yog qhov tshwm sim ntawm qee tus neeg mob PRCC, kev txwv tsis pub MET hloov pauv kev ua pa yuav yog qhov kev kho kom haum. Xyoo 2020 American Clinical Oncology Conference (ASCO) tau tshaj tawm cov txiaj ntsig ntawm Theem III SAVOIR txoj kev tshawb fawb los soj ntsuam ntxiv qhov ua tau zoo ntawm Savolitinib piv nrog kev kho mob sunitinib hauv MET-driven PRCC.

Qhov no yog qhov qhib-ntawv randomized soj ntsuam tshawb. Cov neeg mob nrog metastatic PRCC nrog paub tseeb MET hloov pauv (MET thiab / lossis HGF ua kom nrov dua, nce ntxiv ntawm cov chromosome 7 thiab / lossis MET kinase domain hloov pauv) tau faib ua ob pawg, feem tau txais kev kho mob Savolitinib (600m, ib hnub ib zaug) thiab kev kho mob sunitinib (50mg, ib hnub ib zaug), kev kho mob rau 4 lub lis piam / nres rau 2 lub lis piam. Lub ntsiab ntawm qhov kev kawm tseem ceeb yog kev tshuaj ntsuam xyuas kev ywj pheej (BICR) kev soj ntsuam txog kev vam meej tsis muaj kev vam meej (PFS) raws li RECIST 1.1. Cov chaw xaus thib ob suav nrog tag nrho cov kev muaj sia nyob (OS), lub hom phiaj teb (ORR), thiab kev nyab xeeb thiab tiv taus.

Raws li ntawm cov ntaub ntawv txiav tawm hauv lub Yim Hli 2019, tsuas yog 60 ntawm 180 qhov mob tau npaj kho rau cov neeg mob (sivotinib n=33, sunitinib n=27). Feem ntau cov neeg mob tau nce tus lej ntawm cov chromosome 7 (Savolitinib 91%; sunitinib 96%) thiab tsis tau txais kev kho mob yav dhau los (Savolitinib 85%; sunitinib 93%).

Piv nrog pab pawg Savolitinib, pawg PFS, OS thiab ORR ntawm Savolitinib pawg tau txhim kho txhua tus: tus PFS ntawm Savolitinib pab pawg thiab pawg pawg hnub nruab hnub yog 7.0 hli vs. 5.6 lub hlis (HR=0.71, P=0.313); OS twb tsis xav txog vs 13.2 lub hlis (HR=0.51, P=0.110); ORR yog 27% (9/33) vs 7% (2/27), 6-lub hlis tiv thaiv kab mob (DCR) feem Nws yog 48% vs 37%, thiab 12-lub hlis DCR yog 30% vs 22%.

Txawm hais tias tus naj npawb ntawm cov neeg mob thiab lub sijhawm taug qab yog tsawg, Syvotinib tau qhia tias muaj kev txhawb zog siab, thiab piv nrog sunitinib, nws qhov kev nyab xeeb tau zoo dua.

2. MET inhibitors tuaj yeem cuam tshuam loj heev kev loj hlob ntawm cov qog nqaij hlav hauv lub plab ua kom muaj zog los ntawm MET

Kev hais lus tsis txaus ntawm mucin tuaj yeem txhawb kev hloov pauv epithelial-mesenchymal (EMT), ua rau cov qog ntshav. Tumor ntsig txog cov hauv kev xws li c-MET thiab muc-catenin-ntsig txog mucin. 2020ASCO tshaj tawm txoj kev tshawb nrhiav qhov tseem ceeb uas tshawb nrhiav cov yam ntxwv ntawm MET, MUC5AC, MUC5B thiab MUC6 EMT cov paib qhia txog tib neeg mob plab (GC) ntawm tes, thiab qhia ntxiv meej txog qhov sib txawv ntawm qhov rhiab ntawm cov xovtooj ntawm tes rau Tepotinib.

Txoj kev tshawb no tau soj ntsuam los tiv thaiv cov qog ntshav ntawm Tepotinib hauv GC kab xovtooj ntawm tes. Qhov cuam tshuam ntawm Tepotinib ntawm lub xovtooj ntawm kev muaj peev xwm (IC50), apoptotic cell tuag, EMT, c-MET, thiab β-catenin signaling pathways tau txheeb xyuas los ntawm MTS, ntws cytometry, sab hnub poob blotting thiab lub sijhawm PCR (qRT-PCR) cov hau kev.

Tepotinib muaj koob tshuaj tiv thaiv kev loj hlob inhibitory ntxim rau SNU620, MKN45 thiab KATO Ⅲ cov hlwb ua haujlwm ntau los ntawm c-MET, thiab tuaj yeem ua rau mob apoptosis, tab sis Tepotinib tsis muaj kev kho mob rau MKN28 thiab AGS hlwb nrog txo c-MET. Tepotinib tseem tuaj yeem txo qis phosphorylated c-MET, tag nrho c-MET, phosphorylated ERK, tag nrho ERK, cat-catenin thiab c-Myc protein hauv SNU620 thiab MKN45 hlwb. Ntawm qhov tsis sib xws, cov tshuaj tsawg dua ntawm KATO. Cov hlwb. Tepotinib txo qis cov lus qhia ntawm MMP7, COX-2, WNT1, MUC5B thiab c-Myc thiab lwm cov EMT-txhawb nqa cov noob hauv MET qhia GC cov hlwb, thiab nce kev tshaj tawm ntawm GSK3β thiab ECAD thiab lwm yam MUC5AC thiab MUC6 EMT inhibitory noob. Hauv cov qauv kev coj ua ntawm nas, cov qog loj ntawm cov nas hauv Tepotinib 10mg / kg / d txhua hnub qhov ncauj kho pab pawg tau txo qis, thiab keeb kwm, Tepotinib ntxias cov kev tawm tsam ntau dua li pawg pab pawg.

Cov ntaub ntawv tau hais tias Tepotinib yuav muaj qhov ua kom zoo rau c-MET amplified GC, thiab cov kev tshawb fawb soj ntsuam yog xav tau kom paub meej tias qhov kev kho no ua kom zoo.

3. Tsis Muaj Cov Nqaij Hlawv Mob Qeb Hauv Cev - Sevotinib Txheej Txheem Txheej Txheem II Sau Npe Soj Ntsuam Kev Kawm (NCT02897479)

Thaum ASCO lub rooj sib tham txhua xyoo hauv 2020, pab pawg ntawm xibfwb Lu Shun los ntawm Thoracic Tsev Kho Mob ntawm Shanghai Jiaotong University tau tshaj tawm txog kev kho mob ntawm MET 14 exon hla kev hloov pauv PSC (pulmonary sarcomatoid carcinoma) lossis lwm yam NSCLC subtypes nrog Syvotinib. Qhov tseeb tshwm sim los ntawm kev tshawb fawb soj ntsuam. Hauv no Suav ntau qhov chaw, ib leeg-caj npab theem II kawm, 70 cov neeg mob nrog MET 14 exon dhia hloov tau suav nrog. Tus PSC piv tau ntau npaum li 35.7%, thiab 45 kis (64.3%) ntawm lwm yam ntawm NSCLC subtypes. Tus neeg mob tau txais Syvotinib 600 mg (hnyav ≥ 50 kg) lossis 400 mg (lub cev hnyav< 50="" kg)="" ib="" hnub="" ib="" zaug="" rau="" 21="" hnub="" kom="" txog="" thaum="" tus="" kab="" mob="" loj="" zuj="" zus="" lossis="" tsis="" tuaj="" yeem="" tsis="" tuaj="" yeem="" siv="" tshuaj="" lom.="" lub="" ntsiab="" kev="" tshawb="" fawb="" tseem="" ceeb="" yog="" lub="" hom="" phiaj="" cov="" lus="" teb="" (orr)="" raug="" soj="" ntsuam="" los="" ntawm="" independent="" review="" committee="" (irc)="" raws="" li="" recist="" v1.1="" tus="" qauv.="" cov="" theem="" ob="" kawg="" suav="" nrog="" kev="" tswj="" cov="" kab="" mob="" (dcr),="" lub="" sijhawm="" tiv="" thaiv="" (dor),="" sijhawm="" ua="" haujlwm="" (ttr),="" pfs,="" 6-lub="" hlis="" pfs="" tus="" nqi,="" tag="" nrho="" cov="" kev="" muaj="" sia="" nyob="" (os),="" kev="" nyab="" xeeb="" thiab="" tiv="">

Raws li kev tshawb xyuas pawg raws kev mob kab mob tseem ceeb, ORR ntawm PSC cov neeg mob tau 50%, DCR yog 90%, thiab DoR tseem tsis tau txog; ORR ntawm cov neeg mob nrog lwm cov NSCLC pawg yog 48.8%, DCR yog 95,1%, thiab DoR mus txog 9.6 lub hlis, nrog PFS nruab nrab nce mus txog 9.7 lub hlis. Raws li kev tshawb xyuas pawg me raws li tus xov tooj ntawm cov kab kev kho mob, ORR ntawm cov neeg kho tshiab yog 54.2%, thiab DCR yog 95.8%; ORR ntawm cov neeg mob kho yog 46.0%, thiab DCR yog 91.9%, thiab DoR tseem tsis tau txog.

Syvotinib kev kho mob ntsig txog qhov xwm txheej tsis zoo (AE) feem ntau yog qib 1 txog 2. Cov kev mob tshwm sim tsis sib xws (≥15%) muaj xws li mob peripheral edema, xeev siab, nce AST / ALT, thiab ntuav. Qhov tshwm sim ntawm kev kho mob cuam tshuam vim kev cuam tshuam los ntawm kev kho mob ntawm AEs muaj tsawg, li ntawm 14%, thiab tsis muaj kev cuam tshuam los ntawm kev mob ntsws.

Tam sim no, txawm hais tias tsis muaj MET-TKI tau pom zoo nyob hauv Suav teb, txoj haujlwm hauv tsev II sau npe rau kev tshawb fawb soj ntsuam (NCT02897479) ntawm Suav thawj MET-TKI Savolitinib rau cov neeg Suav tau ua tiav zoo. Raws li cov kev tshawb fawb no, NMPA twb tau kho Savolitinib los kho MET. Daim ntawv thov cov tshuaj tshiab rau NSCLC nrog 14 exon hla kev hloov pauv tau suav nrog hauv kev tshuaj xyuas ua ntej. Txog tam sim no, hauv kev tshawb fawb soj ntsuam uas muaj ntau tshaj li 1,000 tus neeg mob thoob ntiaj teb, Savolitinib tau pom tias muaj txiaj ntsig zoo hauv kev kho mob hauv ntau cov qog uas muaj cov caj ces MET tsis zoo thiab muaj cov yam ntxwv muaj kev nyab xeeb zoo. Peb cia siab tias Savolitinib coj peb ntau qhov xav tsis thoob hauv kev tshawb nrhiav rov qab.