Asmeskas FDA tso cai RET inhibitor Gavreto rau kev kho mob RET fusion-zoo mob ntsws ntsws

CStone Pharmaceuticals khub tus tswv cuab Blueprint tshuaj tsis ntev los no tshaj tawm tias Tsoomfwv Meskas Cov Khoom Noj thiab Tshuaj (FDA) tau pom zoo rau kev siv tshuaj loog rau lub cev, RET kinase inhibitor Gavreto (pralsetinib), rau kev kho mob RET fusion-positive tau lees paub los ntawm FDA-pom zoo kuaj cov qauv ntawm cov neeg laus cov neeg mob uas mob metastatic tsis yog-tes mos ua cancer (NSCLC).

Nyob rau tib hnub, FDA kuj tau lees txais Gavreto' s Daim Ntawv Thov Tshuaj Tshiab Tshiab (NDA) rau kev kho mob RET-mutant medullary thyroid carcinoma (MTC) thiab RET fusion-positive thyroid cancer, uas yuav raug tshuaj xyuas los ntawm qhov tseeb sij hawm oncology tshuaj xyuas (RTOR) qhov project sim. FDA tau tso cai rau NDA Qhov Tshuaj Xyuas Qhov Tseem Ceeb, thiab Daim Ntawv Qhia Txog Tshuaj Rau Cov Neeg Siv Tshuaj (PDUFA) hnub tim yog Lub Ob Hlis 28, 2021.

Nws tsim nyog teev tias Gavreto tsuas yog RET qhov kev kho mob tshwj xeeb uas tau noj ntawm qhov ncauj ib zaug ib hnub, thiab nws tau qhia txog kev ua kom tau ntev ntev thiab tau txais txiaj ntsig zoo ntawm cov neeg mob hauv RET fusion-positive NSCLC. Qhov kev pom zoo yog txiav txim siab raws li cov lus teb ntawm cov qog ntshav los ntawm Ntu I / II ARROW kawm. Cov txiaj ntsig pom tau hais tias tsis hais los ntawm RET fusion tus khub lossis lub hauv nruab nrab cov hlab hlwb koom nrog, Gavreto ua tau zoo rau cov neeg mob RET fusion-positive NSCLC, thiab qee cov neeg mob tau ua tiav kev kho kom tiav.

Raws li kev koom tes ntawm kev pom zoo nrog Roche, Blueprint thiab Roche' s Genentech yuav sib koom ua lag luam Gavreto hauv Asmeskas lag luam. Thaum Lub Xya Hli lub xyoo no, ob tog tau kos npe rau daim ntawv tso cai thiab ua dej num sib koom ua lag luam txog $ 1.7 txhiab. Roche tau txais cov cai tshwj xeeb ntawm Gavreto nyob sab nraud Tebchaws Asmeskas (tsis suav Suav Tebchaws Suav) thiab kev sib koom ua lag luam nyob hauv Tebchaws Meskas cov khoom lag luam. Cov Khoom Siv Tshuaj Cstone muaj qhov tsuas yog kev tso cai ntawm Gavreto hauv Tebchaws Suav.

Gavreto yog qhov ib zaug ib zaug RET qhov ncauj tsom kev kho mob tsim thiab tsim los ntawm Blueprint Cov Tshuaj. Nws tuaj yeem xaiv thiab muaj peev xwm txwv tsis pub hloov RET (fusions thiab hloov pauv, suav nrog kev kwv yees kev hloov pauv tshuaj) uas ua rau muaj ntau hom qog nqaij hlav, suav nrog kwv yees li 1 -2% ntawm NSCLC cov neeg mob. Tam sim no, RET yog ib qho ntawm xya NSCLC biomarkers uas tuaj yeem raug tsom los ntawm FDA-pom zoo precision oncology tshuaj.

Gavreto yog ib ntsiav tshuaj 100mg, thiab qhov kev pom zoo pib siv yog 400mg ib hnub ib zaug. RET kev kuaj mob biomarker yog tib txoj kev los txheeb xyuas seb tus neeg mob nrog metastatic NSCLC puas tsim nyog rau kev kho mob Gavreto. RET fusions tuaj yeem txheeb xyuas los ntawm cov kev tshawb nrhiav biomarker, suav nrog cov cim tom ntej ntawm cov qog nqaij hlav los yog ua kua nqaij. Hauv qhov txuj ci ARROW, cov cim tom ntej tom ntej, FISH, lossis lwm txoj hauv kev yog siv los kuaj RET fusion.

Raws li cov ntaub ntawv kho cov qog ntawm Phase I / II ARROW kev kawm, Gavreto tau txais kev pom zoo nrawm los ntawm FDA. Txuas ntxiv kev pom zoo rau cov tshuaj' s qhia yuav ua raws li cov ntawv pov thawj thiab piav qhia txog cov txiaj ntsig tau hauv cov chaw kuaj mob. Hauv txoj kev tshawb no, cov neeg mob RET fusion-positive NSCLC tau txais Gavreto 400 mg ib hnub ib zaug. Cov ntaub ntawv qhia tau hais tias: (1) Ntawm 87 tus neeg mob uas tau txais platinum-muaj tshuaj khomob, lub hom phiaj teb (ORR) yog 57% (95% CI: 46-68%), cov lus teb tiav (CR) yog 5.7%, thiab Lub sijhawm me ntsis ntawm kev teb (DOR) tseem tsis tau tiav (95% CI: 15,2 hli, tsis kwv yees). (2) Ntawm 27 tus neeg mob nyuam qhuav kho tshiab uas tsis tau txais tshuaj pleev xim platinum, ORR yog 70% (95% CI: 50-86%), CR yog 11%, thiab nruab nrab DOR yog 9.0 lub hlis (95% CI: 6.3 lub hlis, tsis tuaj yeem kwv yees). Gavreto cov ntawv qhia tshuaj muaj cov lus ceeb toom thiab kev ceev faj txog kev tiv thaiv kab mob ntsws / mob ntsws, mob ntshav siab, mob siab rau lub siab, ntshav los ntawm cov xwm txheej, muaj kev pheej hmoo ntawm lub qhov txhab tsis zoo, thiab kev pheej hmoo ntawm embryo-fetal toxicity.

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, li ntawm 10-20% ntawm cov neeg mob papillary thyroid carcinoma (PTC), thiab RET cuam tshuam cuam tshuam txog li 90% ntawm cov neeg mob uas muaj MTC siab heev. Ntxiv rau, qhov kev hloov pauv tsawg tsawg RET kuj tseem tau pom hauv kev mob qog nqaij hlav cancer, mob cancer mis, mob qog ntshav thiab mob qog nqaij hlav, thiab RET fusion kuj tau pom nyob hauv cov neeg mob uas muaj tshuaj tiv thaiv, EGFR-mutant NSCLC.

pralsetinib yog 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 sib hloov, thiab kev hloov tawm tsam. 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-npaug ntau 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 tau tsim los ntawm Loxo Oncology, lub tuam txhab oncology nyob hauv Eli Lilly thiab tau pom zoo los ntawm Asmeskas FDA hauv lub Tsib Hlis xyoo no. Nws yog siv los kho cov neeg mob nrog peb hom qog nrog kev hloov caj ces (hloov pauv los yog fusions) hauv RET gene: tsis mob qog nqaij hlav hauv hlwb tsawg (NSCLC), Medullary thyroid carcinoma (MTC), lwm yam mob qog nqaij hlav 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 qib siab lossis ua paug MTC uas laus dua 12 xyoos thiab xav tau kev kho mob tas li; (3) Cov hnub nyoog laus dua 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 rau 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 hauv (CNS-ORR) kom txog 91% (n=10/11).