Ukuhlaziywa kweDacomitinib Dacomitinib: Uyiphatha njani iNSCLC? -AASraw
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Dacominib

 

  1. I-FDA ivuma i-dacomitinib yomhlaza wesifo somhlaza ongasencinci
  2. Umhlaza wemiphunga
  3. Isicelo seKlinikhi ye-Dacomitinib kumhlaza wamaphaphu ongekho mncinci
  4. Uphengululo lweDacomitinib
  5. Inkqubo yeDacomitinib yesenzo
  6. Ukusetyenziswa kweDacomitinib
  7. Iziphumo ezibi zeDacomitinib
  8. Unyango lweCell Lung Cancer olungelulo oluncinci: iDacomitinib VS Gefitinib
  9. Uyithenga njani i-Dacomitinib Powder kwi-Intanethi?

 

FI-DA iyayivuma i-dacomitinib yomhlaza wesifo semiphunga esingeyonto encinci

Nge-27 kaSeptemba, ngo-2018, uLawulo lwezoKutya kunye neDrug livume iipilisi ze-dacomitinib (i-VIZIMPRO, i-Pfizer Pharmaceutical Company) kunyango lokuqala lonyango lwezigulana ezine-metastatic umhlaza wemiphunga ongekho mncinci (NSCLC) kunye ne-epidermal factor factor receptor (EGFR) exon 19 ukususwa okanye i-exon 21 L858R yokutshintsha endaweni njengoko kufunyenwe kuvavanyo oluvunyiweyo lwe-FDA.

Ukuvunywa kwakusekwe kwilingo elingenamkhethe, elinemisebenzi emininzi, ilebhile evulekileyo, uvavanyo olulawulwayo olusebenzayo (i-ARCHER 1050; i-NCT01774721) ngokuthelekisa ukhuseleko kunye nokusebenza kwe-dacomitinib ukuya kwi-gefitinib kwizigulana ezingama-452 ezingafumanekiyo, ze-metastatic NSCLC. Izigulana bekufuneka zingabinalo unyango lwangaphambi kwesifo se-metastatic okanye isifo esiphindaphindayo ubuncinci iinyanga ezili-12 ezingenasifo emva kokugqitywa kwenkqubo ye-non-EGFR ye-TKI; Intsebenzo yeQela leNtsebenzo yeOncology yeQela le0 okanye 1; nokususwa kwe-EGFR 19 okanye ukucinywa kwe-exon 21 L858R. Izigulana zazingenangqondo (1: 1) ukufumana nokuba yi-dacomitinib 45 mg ngomlomo kube kanye yonke imihla okanye i-gefitinib 250 mg ngomlomo kube kanye yonke imihla de ukuqhubela phambili kwesifo okanye ityhefu engamkelekanga.

Ityala libonakalise ukuphucuka okubonakalayo ekusindeni ngaphandle kokuqhubela phambili; akukho phuculo kumgangatho wokuphendula ngokubanzi okanye ukusinda ngokubanzi kubonisiwe. Ukuqhubeka kokuhamba ngokukhululekileyo okuphakathi, njengoko kumiselwe yikomiti yokuphonononga ezimeleyo. yayiyi-14.7 kunye ne-9.2 yeenyanga kwi-dacomitinib kunye neengalo ze-gefitinib, ngokwahlukeneyo (umngcipheko we-0.59; 95% CI: 0.47, 0.74; p <0.0001).

Ulwazi lokumisela luqulethe izilumkiso kunye nokuthintela izifo zesifo semiphunga (i-ILD), isifo sohudo kunye nokusabela okungalunganga kwesikhumba. Kwizigulana ezingama-394 ezifumene i-dacomitinib, iimpembelelo ezimbi zenzeke kwi-27%. Ezona mpembelelo zixhaphakileyo zixhomekeke ekuyekisweni kwe-dacomitinib yayisisifo sorhudo kunye ne-ILD. Ezona zixhaphakileyo (> 20%) iimpendulo ezingalunganga ze-dacomitinib yayisisifo sorhudo, irhashalala, i-paronychia, i-stomatitis, ukunciphisa ukutya, isikhumba esomileyo, ukwehla kobunzima, i-alopecia, ukukhwehlela kunye nepruritus).

 

Umhlaza wemiphunga

Umhlaza wemiphunga ngowona mhlaza uxhaphakileyo kwihlabathi liphela, ngaphezulu kwezigidi ezibini zamatyala amatsha afunyaniswa kwihlabathi liphela ngo-2018. Phantse iipesenti ezingama-85 zayo yonke imihlaza yomhlaza yemiphunga ichongiwe njengeseli engeyiyo encinci, kwaye malunga neepesenti ezingama-75 zezi zemastastatic, okanye eziphambili, xa kufunyaniswa isifo. .

I-EGFR yiprotein enceda iiseli zikhule kwaye zahlule. Xa uhlobo lwe-EGFR luguqukile kunokubangela ukuba iprotein isebenze kakhulu kukhokelela ekubeni iiseli zomhlaza zenze. Utshintsho lwe-EGFR lunokwenzeka kwiipesenti ezili-10 ukuya kwezingama-35 zamathumba e-NSCLC kwihlabathi liphela, kwaye olona tshintsho luqhelekileyo lusebenzayo kususwe kwi-exon 19 kunye ne-exon 21 L858R endaweni yoko, ezihlangeneyo zingaphezulu kweepesenti ezingama-80 ezaziwayo zokwenza utshintsho kwi-EGFR. Esi sifo sinxulunyaniswa namazinga okusinda aphantsi kunye nokuqhubela phambili kwezifo kuhlala kungumngeni.

 

Isicelo seKlinikhi ye-Dacomitinib kumhlaza wamaphaphu ongekho mncinci

I-Dacomitinib sisizukulwana sesibini se-EGFR tyrosine kinase inhibitor (TKI) ebophelela ngokungaguqukiyo ebopha kwaye inqanda i-EGFR / Her1, Her2 kunye ne-Her4 subtypes ngokusebenza ngokuthelekiswa nezinye i-TKIs. Kwilingo le-ARCHER 1050, ukuqhubeka kokungabikho kwenkqubela phambili kwaphuculwa ngu-dacomitinib xa kuthelekiswa ne-gefitinib, exhasa i-dacomitinib njengokhetho lodidi lokuqala kunyango lomhlaza wemiphunga ongekho mncinci kunye nokutshintsha kwe-EGFR. Ngokumalunga nezinga eliphezulu leziganeko ezichaseneyo, ukunciphisa idosi akunciphisanga ukusebenza kwe-dacomitinib kwaye kunokunciphisa ngokufanelekileyo imeko kunye nobukrakra bezehlo ezimbi. Ukujonga imeko eguqukayo yomhlaza we-EGFR-mutant non-small-cell lung cancer, intloko yexesha elizayo ukuya entloko ngokuthelekisa phakathi kwe-dacomitinib kunye ne-osimertinib inokubonelela ngolwazi oluphambili lokufumanisa ishedyuli efanelekileyo yonyango ye-TKI.

 

Dacominib

 

Iziganeko eziphezulu zeCarcer Lung Cancer engekho emincinci inyanzelise ukuba sicinge ngeendlela zonyango, indlela yokufumana iindlela ezifanelekileyo? Dacominib unyango luya kunconywa kuwo wonke umntu. Okulandelayo, makhe sijonge Dacominib:

 

Uphengululo lweDacomitinib

I-Dacomitinib, eyilelwe njenge (2E) -N-16-4- (piperidin-1-yl) kodwa-2-enamide, yinxalenye yomlomo ekhetheke kakhulu ye-quinazalone yesigaba sesibini se-tyrosine kinase inhibitors ezibonakaliswa kukungazibopheleli okubophayo Idomeyini ye-ATP yommandla wokukhula kwe-receptor yommandla we-kinase domains. I-Dacomitinib lunyango lonyango lwe-non-small-cell lung carcinoma (NSCLC). Sisithintelo esikhethiweyo nesingenakuguqulwa se-EGFR.

I-Dacomitinib yaphuhliswa yi-Pfizer Inc kwaye yamkelwa yi-FDA ngo-Septemba 27, 2018. Obunye ubungqina kuncwadi bucebisa amandla onyango e-dacomitinib kwi-epithelial ovarian modeli, nangona kufuneka uphando oluthe kratya.

Okwangoku, iDacomitinib powder (CAS:1110813-31-4) inokubonelelwa nge-AASraw evela e-China.

 

Inkqubo yeDacomitinib yesenzo

I-Dacomitinib yinto engenakuphinda ibuyiselwe kwimolekyuli encinci yento eyenziweyo yento eyenzekayo ekukhuleni kosapho lomntu (EGFR) yosapho (i-EGFR / HER1, HER2, kunye ne-HER4) tyrosine kinases. Ifezekisa isithintelo esingenakuphinda senziwe ngokudibana ngokudibeneyo kwi-cysteine ​​residues kwimimandla ye-catalytic ye-HER receptors. Ukudibana kwe-dacomitinib kubonisiwe ukuba kune-IC50 ye-6 nmol / L.

I-ErbB okanye i-epidermal factor factor (EGF) yosapho idlala indima ekukhuleni kwesisu, imastastasis, kunye nonyango lokunganyangeki ngokuhambisa iindlela zokudlulisa umqondiso osezantsi ezinje ngeRas-Raf-MAPK, PLCgamma-PKC-NFkB kunye nePI3K / AKT nge-tyrosine I-kinase eqhutywa yi-phosphorylation kwi-carboxy-terminus.1 Malunga ne-40% yamatyala abonisa ukukhula kwe-EGFR gene kunye ne-50% yamatyala abonisa utshintsho lwe-EGFRvIII olubonisa ukucinywa okuvelisa ukusebenza okuqhubekayo kwesizinda se-tyrosine kinase se-receptor.

 

Ukusetyenziswa kweDacomitinib

I-Dacomitinib ivunyiwe ukuba inyange: Umhlaza wamaphaphu ongaqhelekanga (NSCLC) oye wasasazeka (wasasazeka kwamanye amalungu omzimba). Isetyenziswa njengonyango lodidi lokuqala kwizigulana ezinamathumba ane-EGFR.

UDacomitinib ukwafundwa kunyango lwezinye iintlobo zomhlaza.

 

Iziphumo ezibi zeDacomitinib

Izinto ezibalulekileyo ekufuneka uzikhumbule malunga neziphumo ebezingalindelekanga zedacomitinib:

Abantu abaninzi abayi kufumana zonke iziphumo ebezingalindelekanga ze-dacomitinib ezidweliswe apha.

▪ Iziphumo ebezingalindelekanga zeDacomitinib zihlala ziqikelelwa ngokuqala kwazo, ubude bexesha kunye nobukhali bazo.

▪ Iziphumo ebezingalindelekanga zeDacomitinib ziya kuphucula emva kokuba unyango lugqityiwe.

▪ Iziphumo ebezingalindelekanga zeDacomitinib zinokulawulwa. Kukho iindlela ezininzi zokunciphisa okanye ukukhusela imiphumo emibi ye-dacomitinib.

 

Iziphumo zilandelayo zixhaphakile (zenzeka ngaphezulu kwe-30%) kwizigulana ezithatha i-dacomitinib:

▪ Ukudumba kolusu

▪ Usulelo lwezikhonkwane lwe-bacterial okanye fungal (paronychia)

▪ Isikhumba esomileyo

▪ Ialbumin ephantsi

▪ Ikhalsiyam ephantsi

▪ Iswekile yegazi ephezulu

▪ Urhudo

Izilonda zomlomo

▪ Ukunciphisa ukutya

▪ Igazi (ihemoglobin esezantsi)

Inani eliphantsi leeseli ezimhlophe zegazi

▪ Ukwanda kwee-enzymes zesibindi

 

Ezi ziziphumo ebezingalindelekanga eziqhelekileyo (ezenzeka nge-10-29%) kwizigulana ezifumana i-dacomitinib:

▪ Intlungu yesifuba

▪ Ukuphuthelwa

▪ Ukulahleka kweenwele

▪ Ukurhawuzelela

▪ Ububomvu, ukudumba, kunye nentlungu ezintendeni zezandla kunye / okanye ezinyaweni

▪ I-potassium ephantsi, amanqanaba e-magnesium kunye ne-sodium

▪ Ukwehla kobunzima

▪ I sizathu

▪ Ukuqunjelwa

▪ Iintlungu zomlenze

▪ Intlungu yezihlunu

▪ Ukuba buthathaka / ukunqongophala kwamandla

▪ Ukudumba okanye ukosuleleka kwamehlo

▪ Ukwanda kwe-serum creatinine

▪ Isikhohlela, imiqondiso neempumlo, ukuphefumla nzima kunye nosuleleko lwephepha lokuphefumla

Ayizizo zonke iziphumo ebezingalindelekanga ezidweliswe apha ngasentla. Iziphumo ebezinqabile kakhulu-ezenzeka ngaphantsi kweepesenti ezili-10 zezigulana- azidweliswanga apha. Kodwa kuya kufuneka usoloko umazisa umboneleli wakho wezempilo ukuba ufumana naziphi na iimpawu ezingaqhelekanga.

 

Unyango lweCell Lung Cancer olungelulo oluncinci: iDacomitinib VS Gefitinib

Phakathi kwezigulana ezine-EGFR-positive, non-brain metastatic non- small cell cancer cancer (NSCLC), umgca wokuqala dacomitinib uphucula ukuqhubeka kokuhamba (PFS) ngaphezulu kwe-gefitinib, ngokwesigaba sesi-3 sophando olupapashwe kwi-Lancet Oncology.Dacominib

Isizukulwana sokuqala se-EGFR-tyrosine kinase inhibitors (TKIs), kubandakanya i-gefitinib, zisetyenziswa kumgca wokuqala kwizigulana ezine-EGFR-position position, ezenza phakathi kwe-10% kunye ne-44% yazo zonke i-lung adenocarcinomas. Uphononongo lwangaphambili aluchazanga ukuba isizukulwana sesibini se-EGFR-TKIs siphezulu kunodidi lwesizukulwana sokuqala.

Kule ilebhile ivulekileyo, isifundo esingenamkhethe (ARCHER 1050; ClinicalTrials.gov Isazisi: NCT01774721), ethe yabhalwa ngababhali sisigaba sokuqala sophando ukuthelekisa isizukulwana sesibini se-EGFR-TKI kunye nesizukulwana sokuqala se-EGFR-TKI kolu seto. , Abaphandi babhalisa abaguli abangama-3 ukufumana i-dacomitinib (izigulana ezingama-452) okanye i-gefitinib (izigulana ezingama-227). Izigulana ezine-metastases yengqondo zazingafanelekanga.

Ekulandeleni okuphakathi kweenyanga ezingama-22.1, i-median PFS yayiziinyanga ezili-14.7 ze-dacomitinib vs iinyanga eziyi-9.2 ze-gefitinib; Uhlalutyo lwamagqabantshintshi luye lwathandwa yi-dacomitinib. Iimpendulo ezilishumi elinambini ezipheleleyo zarekhodwa kwiqela le-dacomitinib vs 4 kwiqela le-gefitinib. Iqondo leempendulo zenjongo, nangona kunjalo, zazifana (iipesenti ezingama-75 ze-dacomitinib kunye ne-72% ye-gefitinib; P = .4234).

Izigulana ezingamashumi amabini ananye ezifumana i-dacomitinib zinesigulo esibi esimalunga nonyango (AE); Oku kuyinyani kwizigulana ezili-10 ezifumana i-gefitinib. Ukufa okunxulumene nonyango kwaxelwa kwizigulana ezi-2 ezifumana i-dacomitinib vs 1 ye-gefitinib.

Ababhali baqukumbele ngelithi “unyango lwe-dacomitinib lwalungaphezulu kuno sifile ngokumalunga ne- [PFS] kunye nexesha lokuphendula kunyango lokuqala lwezigulana ezine-EGFR-mutation-positive NSCLC kwaye kufuneka zithathelwe ingqalelo njengonyango olutsha kuluntu. ”

 

Uyithenga njani i-Dacomitinib Powder kwi-Intanethi?

Baninzi abathengisi / abavelisi be-dacomitinib powder kwimarike, ukufumana eyinyani kubaluleke kakhulu kubo bonke abantu abafuna le mveliso ngokungxamisekileyo. Xa sithatha isigqibo sokuthenga i-dacomitinib powder kwimarike, kufuneka sifunde ulwazi malunga nayo, siyazi indlela yokuyisebenzisa kunye nendlela yokusebenza, nayiphi na ingozi xa sithatha i-dacomitinib powder…. Ukongeza, ixabiso kunye nomgangatho kufuneka ibe yinkxalabo yethu ngaphambi kokuba uyithenge.

Emva kokuba sihlolisise ii-datas ezivela kwiimarike, xa kuthelekiswa nabanikezeli abaninzi, i-AASraw ibukeka kakuhle kubantu abafuna ukuthenga ezininzi i-dacominib powder, imveliso yabo yayilawulwa ngokungqongqo phantsi kwe-cGMP imeko, umgangatho unokulandelwa nangaliphi na ixesha kwaye banokubonelela ngazo zonke iingxelo zovavanyo xa uzi-odola. Ngokubhekisele kwiindleko ze-dacomitinib powder / ixabiso, kufanelekile, emehlweni am. Ngenxa yokuba ndinamaxabiso amaninzi kubanikezeli abohlukeneyo, xa kuthelekiswa nomgangatho, ndicinga ukuba i-aasraw ayizukukhetha kakubi.

 

isingqiniso

[1] UKobayashi Y, uFujino T, uNishino M, et al. I-EGFR T790M kunye ne-C797S zotshintsho njengeendlela zokuchasana ne-dacomitinib. UJ Thorac Oncol. 2018; 13 (5): 727-731. ikhonkco: 10.1016 / j.jtho.2018.01.009.

[2] UKris MG, uCamidge DR, uGiaccone G, et al. Ukujolisa ekugxothweni kwe-HER2 njengabaqhubi abasebenza kumhlaza wemiphunga: inqanaba lesibini lokuvavanywa kwepan-HER tyrosine kinase inhibitor dacomitinib kwizigulana ezine-HER2-mutant okanye amplified tumors. UAnn Oncol. 2015; 26 (7): 1421-1427. ikhonkco: 10.1093 / annonc / mdv383.

[3] Ipaki K, Tan EH, O'Byrne K, et al. I-Afatinib xa ithelekiswa ne-gefitinib njengonyango lokuqala lwezigulana ezine-EGFR mutation-positive non-small-cell cell cancer (LUX-Lung 7): isigaba 2B, open-label, randomized trial. ILancet Oncol. Ngo-2016; 17 (5): 577-589. ikhonkco: 10.1016 / S1470-2045 (16) 30033-X.

[4] Ukwahlula ME, Keefe DM, Sonis S, et al. Isifundo sesigaba II (i-ARCHER 1042) yokuvavanya unyango lweprophylactic ye-dacomitinib-indased dermatologic kunye neziganeko ezichaseneyo zesisu kwizigulo zomhlaza wamaphaphu ongekho mncinci. UAnn Oncol. Ngo-2016; 27 (9): 1712-1718. ikhonkco: 10.1093 / annonc / mdw227.

[5] I-Reckamp KL, iGiaccone G, iCamidge DR, okqhubekayo. Isilingo sesi-2 sokuvavanywa kwe-dacomitinib (PF ‐ 00299804), ipani yomlomo, engenakuguqulwa- HER (i-human epidermal growth factor receptor) inhibitor, kwizigulana ezinomhlaza wesifo somhlaza wamaphaphu ongekho mncinci emva kokungaphumeleli kwekhemotherapy kunye ne-erlotinib. Umhlaza. Ngo-2014; 120 (8): 1145–1154. ikhonkco: 10.1002 / cncr.28561.

[6] U-Engelman JA, uZejnullahu K, uMitsudomi T, et al. Ukunyusa i-MET kukhokelela kuxinzelelo lwe-gefitinib kumhlaza wemiphunga ngokwenza uphawu lwe-ERBB3. Inzululwazi. 2007; 316 (5827): 1039-1043. ikhonkco: 10.1126 / science.1141478.

[7] U-Liu X, uWang P, uZhang C, et al. I-receptor ye-Epidermal factor factor (EGFR): Inkwenkwezi ekhulayo ngexesha lokuchaneka kwamayeza omhlaza wemiphunga. Ukhenketho. Ngo-2017; 8 (30): 50209-50220.

[8] U-Girard N. Ukonyusa iziphumo kwi-NSCLC ye-EGFR yokuguqula imeko: yeyiphi i-tyrosine kinase inhibitor kwaye nini? Ixesha elizayo Oncol 2018.

[9] Inoue A, Kobayashi K, Maemondo M, okqhubekayo. Iziphumo zokugqibela zokusinda ze-NEJ002, ulingo lwesigaba sesithathu ngokuthelekisa i-gefitinib kunye ne-carboplatin (CBDCA) kunye ne-paclitaxel (TXL) njengonyango lokuqala lomhlaza wesifo somhlaza wamaphaphu ongekho mncinci (NSCLC) kunye notshintsho lwe-EGFR. J Klinikhi yase-Oncol 2011; 29: 7519.

[10] Uluhlu lweLV, Yang JC, Yamamoto N, et al. Isigaba sesi-III sifundo se-afatinib okanye i-cisplatin kunye ne-pemetrexed kwizigulana ezinemetastatic lung adenocarcinoma ene-EGFR. J Klinikhi yase-Oncol 2013; 31: 3327-34.

[11] ILin JJ, uCardarella S, uLydon CA, et al. Ukusinda kweminyaka emihlanu kwi-EGFR-Mutant Metastatic Lung Adenocarcinoma inyangwa nge-EGFR-TKIs. UJ Thorac Oncol 2016; 11: 556-65.

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