CStone's Pralsetinib Hauv Kev Kho Mob Ntawm Cov Neeg Mob Suav Nrog RET Fusion-positive Advanced Kuaj Mob Cancer: Tag Nrho Cov Kev Pov Tseg Ntawm 57%!

CStone Pharmaceuticals tsis ntev los no tau tshaj tawm cov kev tshawb fawb tseem ceeb ntawm RET inhibitor pralsetinib hauv ntiaj teb theem I / II ARROW ntawm 21st World Lung Cancer Conference (WCLC) online sib tham hauv xyoo 2020 los ntawm International Association rau Kev Tshawb Nrhiav Kab Mob Cancer. Cov txiaj ntsig ntawm kev kawm ntawm cov neeg mob nyob hauv Suav teb. Cov txiaj ntsig pom tau hais tias pralsetinib muaj kev ua haujlwm zoo tshaj thiab ntev ntev los kho kev tiv thaiv qog thiab yog qhov ua tau zoo thiab muaj kev nyab xeeb rau cov neeg mob Suav nrog RET fusion-zoo tsis-me me ntawm cov ntsws mob ntsws (NSCLC) uas yav tas los tau txais kev kho mob platinum-based.

pralsetinib yog qhov muaj zog thiab xaiv RET inhibitor tsim los ntawm Blueprint Tshuaj, ib tus khub ntawm CStone Cov Tshuaj Kho Mob. Nyob rau lub Rau Hli 2018, CStone Cov Tshuaj thiab Cov Thauj Cov Tshuaj mus txog kev sib koom tes tshwj xeeb thiab kev tso cai kom tau txais tshwj xeeb kev txhim kho thiab kev lag luam txoj cai ntawm pralsetinib hauv Greater Tuam Tshoj, suav nrog Tuam Tshoj Mainland, Hong Kong, Macau thiab Taiwan.

Nws tsim nyog teev tias thaum Lub Xya Hli 2020, Roche thiab Blueprint Cov Tshuaj Kho Mob tau kos npe rau daim ntawv tso cai thiab kev sib koom tes, tau txais txoj cai tshwj xeeb los tsim kho thiab ua lag luam rau qhov ncauj RET inhibitor pralsetinib sab nraud Tebchaws Asmeskas (tsis suav Suav Tuam Tshoj). Hauv Tebchaws Meskas, Genentech, Roche pabcuam, tau txais kev sib koom ua lag luam txoj cai ntawm pralsetinib thiab sib koom cov txiaj ntsig sib npaug.

pralsetinib yog qhov ncauj, ib zaug ib hnub, muaj zog thiab xaiv tau RET inhibitor, nrog lub npe lag luam Gavreto. Tam sim no, cov tshuaj tau pom zoo los ntawm Asmeskas FDA rau kev kho mob ntawm: (1) Cov neeg mob loj uas muaj metastatic RET fusion-positive tsis muaj cov kab mob ntsws mob ntsws uas tau lees paub los ntawm FDA-pom zoo txoj kev kuaj pom; (2) 12 xyoos thiab siab dua uas xav tau kev kho mob rau cov neeg laus thiab cov menyuam yaus uas muaj siab lossis metresatic RET-mutated medullary thyroid cancer; (3) Cov neeg laus thiab cov menyuam yaus uas muaj lub siab los yog metastatic RET fusion-positive thyroid cancer uas yuav tsum muaj kev kho mob ua haujlwm thiab yog refractory rau radioiodine (yog tias siv tau). pralsetinib tsis tau pom zoo rau lwm cov kev qhia hauv Tebchaws Meskas, thiab Tuam Tshoj thiab cov koomhaum tsis muaj cai kho mob hauv lwm thaj chaw tau txiav txim siab pom zoo rau cov kev qhia rau pralsetinib.

Kev kawm txog ARROW (NCT03037385) yog qhov kev kawm thoob ntiaj teb I / II soj ntsuam los soj ntsuam kev nyab xeeb ntawm pralsetinib hauv cov neeg mob RET fusion-positive NSCLC, RET mutant medullary thyroid carcinoma (MTC) thiab lwm yam kev mob qog nrog RET fusion, thev taus ntev thiab ua tau zoo. Cov. Cov ntaub ntawv qhia tau hais tias pralsetinib muaj kev ua haujlwm ntau thiab ntev-ntev los tiv thaiv qog cov qog ua haujlwm nyob rau hauv ntau qhov ua tiav RET cov kabmob sib txawv (suav nrog RET fusion-positive NSCLC).

Cov txiaj ntsig tau tshaj tawm ntawm lub rooj sib tham pom tau hais tias rau cov neeg mob Suav nrog RET fusion-positive NSCLC uas yav dhau los tau txais platinum-based chemotherapy nyob rau hauv txoj kev tshawb fawb ARROW, qhov kev ua tau zoo thiab kev nyab xeeb ntawm pralsetinib (400 mg ib hnub ib zaug) tau zoo ib yam li cov ntaub ntawv qhia dhau los ntawm ntiaj teb cov neeg mob. Qhov no yog thawj zaug uas pralsetinib raug siv los kho cov neeg mob Suav nrog RET fusion-positive NSCLC uas yav dhau los tau txais platinum-muaj tshuaj kho.

Raws li cov ntaub ntawv txiav-hnub (Tsib Hlis 22, 2020), tag nrho ntawm 37 cov neeg mob uas muaj RET fusion-zoo NSCLC los ntawm 10 lub chaw tshawb fawb hauv Suav tau suav nrog hauv kev tshawb nrhiav thoob ntiaj teb ARROW thiab tau txais pib ntawm 400 mg (ib zaug ib zaug hnub) pralsetinib kev kho mob. Txhua tus neeg mob tau txais tsawg kawg ib platinum-based chemotherapy kev kho mob kiag li ib nrab, txog li ib nrab (49%) ntawm cov neeg mob tau txais>=3 qhov kev kho qhov system, thiab 32% ntawm cov neeg mob tau txais>=3 tshuaj kho mob ntxiv. Lub pob qog tshem tawm tau raug soj ntsuam los ntawm qhov muag tsis pom kev ntawm qhov chaw nruab nrab saib xyuas (BICR) siv" Qhov Kev Ntsuas Cov Qog Cov Lus Teb Ntsuas Kev Ntsuas" (TXAIS TOS) version 1.1.

Kev Ua Tau Zoo: pralsetinib qhia cov chaw muaj zog ua haujlwm ntawm RET fusion-positive NSCLC tom qab platinum-muaj cov tshuaj tua mob: (1) Ntawm 32 tus neeg mob uas muaj qhov txhab mob uas tsis tseem ceeb ntawm lub hauv paus txiav txim tau los ntawm BICR, qhov tseeb lub hom phiaj ntawm cov lus teb (ORR) yog 56% (95% CI) : 38-74%), suav nrog 1 txoj kev zam tag nrho thiab 17 feem ib qho kev zam txim (PR). Ntxiv rau, muaj 2 PRs kom paub tseeb. Tus nqi tiv thaiv kab mob (DCR) yog 97%, ntawm 1 qhov xwm txheej no nws tsis txaus ntshai. (2) Ntawm 18 cov neeg mob uas tau txais kev pom zoo kom kho dua tshiab, lub sijhawm nruab nrab mus rau kev kho mob thawj zaug yog 1.9 lub hlis. (3) Raws li cov ntaub ntawv txiav tawm hnub, 89% (16/18) ntawm kev pom zoo kev kho mob cov neeg mob tseem tau txais kev kho mob. (4) Qhov nruab nrab ntawm kev teb rov qab (DOR) tsis tau txog, thiab 6-lub hlis DOR tus nqi yog 83%. (5) Tsis hais txog ntawm RET fusion genotype, muaj kev zam txim.

Kev Nyab Xeeb: pralsetinib tau pom zoo zoo thiab nws txoj kev nyab xeeb yog tswj tau. Hauv txoj kev tshawb nrhiav, pralsetinib tau pom zoo zoo, thiab tsis muaj kev kho mob kev txiav tawm lossis kev tuag tshwm sim los ntawm cov xwm txheej tsis zoo cuam tshuam txog pralsetinib.

Cov qauv tsim ntawm pralsetinib (duab los ntawm: aobious.com)

RET-qhib lub fusions thiab hloov pauv yog qhov tseem ceeb tsav tsheb rau ntau hom mob cancer, suav nrog NSCLC thiab MTC. RET fusion koom nrog li 1-2% ntawm NSCLC cov neeg mob thiab li 10-20% ntawm cov neeg mob papillary thyroid carcinoma (PTC), thaum RET cuam tshuam cuam tshuam txog li 90% ntawm cov neeg mob MTC siab. Ntxiv rau, qhov kev hloov pauv tsawg tsawg RET kuj tseem tau pom nyob rau hauv txoj hnyuv mob cancer, mob cancer mis, mob qog nqaij hlav thiab lwm yam mob qog nqaij hlav, thiab RET fusion kuj tau pom nyob hauv cov neeg mob uas siv tshuaj, EGFR-mutated NSCLC.

pralsetinib tau tsim los ntawm pab neeg tshawb fawb ntawm Blueprint Tshuaj raws li nws lub tsev qiv ntawv khoom ntiag tug. Hauv cov kev tshawb fawb preclinical, pralsetinib yeej ib txwm qhia sub-nanomolar titers tiv thaiv cov feem ntau RET noob fusions, ua kom muaj kev cuam tshuam kev hloov thiab kev hloov tshuaj yeeb tshuaj. Ntxiv rau, qhov xaiv ntau ntawm pralsetinib rau RET ua tau zoo dua piv nrog kev pom zoo multi-kinase inhibitors. Ntawm lawv, cov kev ua haujlwm ntawm pralsetinib yog ntau dua 90 lub sij hawm siab dua li ntawm VEGFR2. Los ntawm inhibiting cov kev hloov pauv thawj thiab theem nrab, pralsetinib cia siab tias yuav kov yeej thiab tiv thaiv qhov tshwm sim ntawm kev tshawb nrhiav tshuaj. Cov txheej txheem kev kho mob no cia siab kom ua tiav kev kho mob ntev ntev hauv cov neeg mob uas muaj RET sib txawv, thiab muaj kev nyab xeeb zoo.

Nws tsim nyog teev tias Eli Lilly Retevmo (selpercatinib) yog thawj zaug pom zoo RET inhibitor. Cov tshuaj no tau tsim los ntawm Loxo Oncology, lub tuam txhab oncology nyob hauv Eli Lilly thiab tau pom zoo los ntawm Asmeskas FDA thaum lub Tsib Hlis 2020. Nws yog siv los kho cov neeg mob nrog 3 hom qog nrog kev hloov caj ces (hloov mus los yog fusions) hauv RET gene: non -small cell cell mob cancer (NSCLC), Medullary thyroid Cancer (MTC), lwm yam mob qog ua cancer.

Hais txog kev noj tshuaj, Retevmo noj ntawm qhov ncauj ob zaug ib hnub, nrog lossis tsis noj mov. Retevmo yog thawj cov tshuaj kho tau pom zoo tshwj xeeb rau cov neeg mob cancer nqa RET caj hloov. Cov tshuaj yog qhov tsim nyog rau kev kho mob ntawm: (1) Cov neeg laus cov neeg mob siab heev lossis metastatic NSCLC; (2) Cov neeg mob uas muaj MTC tshaj los yog metastatic uas muaj hnub nyoog ≥12 xyoos thiab xav tau kev kho mob tas li; (3) Muaj hnub nyoog ≥12 xyoos thiab xav tau kev kho mob zoo thiab muaj cov neeg mob hluav taws xob nrog cov mob RET fusion-zoo cov qog nqaij hlav cancer uas tau tso tseg tsis kho cov tshuaj iodine lossis tsis tsim nyog rau kev kho hluav taws xob iodine. Nws yog qhov tshwj xeeb tshaj tawm tias txog li 50% ntawm RET fusion-positive NSCLC cov neeg mob yuav muaj cov kab mob qog hlwb metastases. Ntawm cov neeg mob uas muaj lub hauv paus ntawm lub hlwb metastases, Retevmo tau qhia tias muaj zog, nrog kev kho mob sab nrauv (CNS-ORR) kom txog 91% (n=10/11).