I-Immunotherapy kanye nokwelashwa komdlavuza
Eminyakeni yamuva nje, ukuthandwa kwe-immunotherapy emkhakheni we-oncology kuyaqhubeka nokukhuphuka. ULancet Oncol ushicilele imiphumela yokuqala yocwaningo lwe-Keynote-012 oluhlola ukusebenza kwe-PD-L1 inhibitor pembrolizumab ezigulini ezinomdlavuza wesisu othuthukile ngoMeyi 3, noludonse ukunaka okukhulu. USolwazi u-Elizabeth C Smyth waseRoyal Marsden Hospital eNgilandi uchaze lolu cwaningo, olungasilethela imicabango nezikhuthazo.
Ukubikezelwa komdlavuza wesisu osuthuthukile kubi, futhi ngaphansi kwe-10-15% yeziguli ze-metastatic zingaphila iminyaka engaphezu kwengu-2. I-Trastuzumab kanye ne-ramoluzumab yokwelashwa komugqa wesibili kweziguli ezinomdlavuza wesisu we-HER2 positive zingathuthukisa kancane ukusinda sekukonke. Ngenxa yokuthi kunezibonelo eziningi zokuhluleka kwemithi yokwelapha emkhakheni womdlavuza wesisu, kubonakala sengathi le mithi izuze impumelelo encane. Kulesi simo samanje esiyinselelo sokwelashwa okuthuthukisiwe komdlavuza wesisu, ucwaningo lwe-Keynote-012 olwenziwa nguSolwazi Kei Muro kanye nozakwabo ekuqaleni lubonise imiphumela emihle, ebonisa ukuthi i-PD-L1 inhibitors inenani lokwelapha elingase libe khona kumdlavuza wesisu othuthukile.
Imiphumela yocwaningo lwe-Keynote-012 iyamangaza
Ocwaningweni lwe-Keynote-012, iziguli ezine-PD-L1 ezinomdlavuza wesisu othuthukile zithole i-anti-PD-1 antibody pembrolizumab kuze kube yilapho isifo siqhubeka noma izehlakalo ezimbi ezingabekezeleleki. Ucwaningo luhlole ingqikithi yeziguli ze-162 ezinomdlavuza wesisu othuthukile, lapho ama-65 (40%) ayenayo i-PD-L1 inkulumo, futhi ekugcineni iziguli ezingama-39 (24%) zabhaliswa kulolu cwaningo lwamazwe ngamazwe lweSigaba 1B se-multicenter. Ngokujabulisayo, iziguli ezingu-17 kwezingu-32 (53%) zabhekana nokuhlehla kwesimila; Iziguli eziyisi-8 kwezingama-36 (22%) ezisebenza ngempumelelo ziye zaqinisekisa ukukhululwa okuyingxenye. Lesi silinganiso sokuxolelwa siyahambisana nemiphumela yokuhlolwa kwe-immunotherapy kwezinye izinhlobo zomdlavuza, nesikhathi sokuphendula esimaphakathi samasonto angama-40, futhi iziguli ezi-4 kwezingu-36 (11%) ezinokukhululwa kwezifo azizange zibonise ukuqhubeka kwesifo kusukela ngesikhathi sokubika. Njengoba bekulindelekile, iziguli eziyi-9 (23%) zaba nezigameko ezimbi ezihlobene nokuzivikela komzimba. Azikho iziguli eziyekile ukwelashwa ngenxa yezehlakalo ezimbi ezihlobene nokuzivikela komzimba. Uma kuqhathaniswa no-11% kuya ku-30% weziguli ocwaningweni lwe-chemotherapy lomugqa wesibili, imiphumela ibimangaza kakhulu. Uma kubhekwa iqiniso lokuthi imiphumela yokusinda yokuhlolwa kwamuva nje kwemitholampilo yomdlavuza wesisu wamazwe ngamazwe ithintwa umehluko wesifunda, uKei Muro kanye nozakwabo baphinde bafakazela ukuthi ukusinda kweziguli zase-Asia nezingezona zase-Asia ocwaningweni lwe-Keynote-012 kuyafana.
Ingabe inkulumo ye-PD-L1 ingabikezela ukusebenza kwe-immunotherapy?
Ukuhlolwa kokuhlolwa kwe-Keynote-012 kusebenzisa i-immunohistochemistry ukuze kutholwe ukuvezwa kwe-PD-L1. Iziguli ezinamaseli esimila, amaseli omzimba noma lezi nqwaba zamangqamuzana amabili zidinga ukuveza okungenani u-1% we-PD-L1 ukuze zifanelekele ukuhlolwa. Umbhali wabe esehlola kabusha isimo se-PD-L1 esebenzisa izivivinyo ezihlukene. Imiphumela yokuhlolwa kwesibili ikhombisa ukuthi ukuvezwa kwe-PD-L1 kumaseli omzimba, hhayi amaseli wesimila, kuhlotshaniswa nempumelelo ye-pembrolizumab kumdlavuza wesisu. Okwesibili, izibonelo ze-biopsy ezingu-8 kwezingu-35 ezingase zihlolwe zibe nomphumela ongemuhle we-PD-L1. Le miphumela ikhombisa ubunkimbinkimbi bokuhlaziywa kwe-PD-L1 ngokujwayelekile, ikakhulukazi ukuhlolwa kwama-biomarker omdlavuza wesisu. Lokhu kuchezuka kungase kube ngenxa yezinguquko eziguquguqukayo ekukhulumeni kwe-PD-L1 ngemva kokwelashwa, umehluko ezindleleni zokuhlola, kanye ne-heterogeneity yomdlavuza wesisu. Ngakho-ke, akucaci ukuthi ezivivinyweni zemitholampilo ezedlule ngaphandle kokuhlolwa kwe-biomarker, ezinye iziguli ezineziguli ezibonakala zingenayo i-PD-L1 ezathola ukwelashwa kwezidakamizwa ezilwa ne-PD1 zokukhululwa kwesifo zazihlobene nokuhluka kwenkulumo ye-biomarker, Noma ingabe kukhona ukuhlobana kwangempela. phakathi kwama-biomarker nokusebenza kahle. Kudingeka olunye ucwaningo
Indlela engcono kakhulu yokuhlola isisho se-PD-L1 nokuthi ingabe iyiqiniso futhi iyisibikezelo esisebenzayo se-biomarker ku-immunotherapy yomdlavuza wesisu. Ababhali baphinde babike imiphumela yokuqala ye-interferon gamma gene expression njenge-biomarker yokubikezela okuzimele kwesilonda kwezicubu. Uma lo mphumela uqinisekisiwe, kungasiza ukugwema ezinye izinkinga ezihlobene ne-immunohistochemistry esikhathini esizayo.
Izinkinga ezidinga ukucatshangelwa okwengeziwe
Vele, isivivinyo esincane sesampula esifana ne-Keynote-012 nakanjani sinezinkinga ezithile. Okokuqala, akucaci ukuthi kukhona yini ukusebenzisana phakathi kokwelashwa ngamakhemikhali okwatholwa esikhathini esidlule kanye nempumelelo ye-pembrolizumab. Nakuba ezinye iziguli ezisabelayo zazithole ukwelashwa ngamakhemikhali komugqa wokuqala noma ngaphansi ngaphambi kwe-pembrolizumab, iziguli eziningi (63%) ezisabelayo zazithole ukwelashwa komugqa wesibili noma ngaphezulu kokulwa nesimila. Ngaphezu kwalokho, i-Keynote-012 iyisampula encane yokuhlolwa kokuqala kwemitholampilo futhi ayikwazi ukufakwa ezigulini eziningi ezinomdlavuza wesisu othuthukisiwe nokusinda isikhashana, okungenza amazinga okuphendula ahlobene ne-immunotherapy athathe kancane kanye namanga ezikhathi ezithile.
Imiphumela yenqubekela phambili ayigculisi neze. Izivivinyo eziningi zomtholampilo eziqhubekayo zizama ukuthola iwindi lesikhathi elilungile le-immunotherapy yeziguli ezinomdlavuza wesisu. Okwesibili, nakuba ngokombono, iziguli ezinomdlavuza wesisu ezinama-microsomes angazinzile kufanele zifaneleke kakhulu i-immunotherapy, futhi
Ocwaningweni lwe-Keynote-012, isigamu kuphela seziguli ezinokungaqini kwe-microsatellite ezilashwe nge-pembrolizumab saphendula. Lolu hlobo oluncane lomdlavuza wesisu lubalelwa ku-22% yenani eliphelele leziguli ezinomdlavuza wesisu futhi kufanele ukuthi kuqhutshekwe nocwaningo. Okokugcina, imingcele ehlola imiphumela emihle yalesi sivivinyo somtholampilo se-immunotherapy yomdlavuza wesisu nayo idinga ukucatshangelwa ngokucophelela. Ingxenye yeziguli ezithole ukukhululwa kwezifo ocwaningweni lwe-Keynote-012 yayincane kunaleyo ovivinyweni lwe-RAINBOW nge-paclitaxel kanye ne-ramolizumab ehlanganisiwe. Eqinisweni, ukuhlolwa kwe-Keynote-012 kubi kusukela encazelweni yezibalo kuphela. Iziguli eziphendule ekwelashweni azizange zibonise ukuthuthukiswa okuphawulekayo ekusindeni-mahhala kokuqhubekela phambili kanye nokusinda okuphelele. Ngokuzayo, izinhlolo zokwelashwa eziqhubekayo nazo zidinga ukunaka lezi zinkinga.
Izivivinyo zemitholampilo ezihlobene nokwelashwa kwe-CTLA-4 kanye ne-anti-PD-1 zibe yimpumelelo enkulu ku-melanoma. Uma kuqhathaniswa, imiphumela yohlolo lwe-Keynote-012 ibonakala inethemba kancane. Nokho, izinga lokufa kwaminyaka yonke komdlavuza wesisu emhlabeni wonke liphindwe kathathu kune-melanoma eyingozi, ngakho imiphumela yalolu cwaningo isabaluleke kakhulu. Ezigulini eziningi ezinomdlavuza wesisu ezingenazo izindlela zokwelapha ezisebenzayo, okutholwe manje kuyisinyathelo sokuqala esijabulisayo ekufinyeleleni ukukhululwa kwesikhathi eside kwalesi sifo. Eminyakeni yamuva nje, ukuthandwa kwe-immunotherapy emkhakheni we-oncology kuyaqhubeka nokukhula. imiphumela yokuqala yocwaningo lwe-Keynote-012 oluhlola ukusebenza kwe-PD-L1 inhibitor pembrolizumab ezigulini ezinomdlavuza wesisu osezingeni eliphezulu ngoMeyi 3, olwadonsa ukunaka okukhulu.Uprofesa u-Elizabeth C Smyth waseRoyal Marsden Hospital eNgilandi uchaze lolu cwaningo, okungasilethela imicabango nezikhuthazo.
Ukubikezelwa komdlavuza wesisu osuthuthukile kubi, futhi ngaphansi kwe-10-15% yeziguli ze-metastatic zingaphila iminyaka engaphezu kwengu-2. I-Trastuzumab kanye ne-ramoluzumab yokwelashwa komugqa wesibili kweziguli ezinomdlavuza wesisu we-HER2 positive zingathuthukisa kancane ukusinda sekukonke. Ngenxa yokuthi kunezibonelo eziningi zokuhluleka kwemithi yokwelapha emkhakheni womdlavuza wesisu, kubonakala sengathi le mithi izuze impumelelo encane. Kulesi simo samanje esiyinselelo sokwelashwa okuthuthukisiwe komdlavuza wesisu, ucwaningo lwe-Keynote-012 olwenziwa nguSolwazi Kei Muro kanye nozakwabo ekuqaleni lubonise imiphumela emihle, ebonisa ukuthi i-PD-L1 inhibitors inenani lokwelapha elingase libe khona kumdlavuza wesisu othuthukile.
Imiphumela yocwaningo lwe-Keynote-012 iyamangaza
Ocwaningweni lwe-Keynote-012, iziguli ezine-PD-L1 ezinomdlavuza wesisu othuthukile zithole i-anti-PD-1 antibody pembrolizumab kuze kube yilapho isifo siqhubeka noma izehlakalo ezimbi ezingabekezeleleki. Ucwaningo luhlole ingqikithi yeziguli ze-162 ezinomdlavuza wesisu othuthukile, lapho ama-65 (40%) ayenayo i-PD-L1 inkulumo, futhi ekugcineni iziguli ezingama-39 (24%) zabhaliswa kulolu cwaningo lwamazwe ngamazwe lweSigaba 1B se-multicenter. Ngokujabulisayo, iziguli ezingu-17 kwezingu-32 (53%) zabhekana nokuhlehla kwesimila; Iziguli eziyisi-8 kwezingama-36 (22%) ezisebenza ngempumelelo ziye zaqinisekisa ukukhululwa okuyingxenye. Lesi silinganiso sokuxolelwa siyahambisana nemiphumela yokuhlolwa kwe-immunotherapy kwezinye izinhlobo zomdlavuza, nesikhathi sokuphendula esimaphakathi samasonto angama-40, futhi iziguli ezi-4 kwezingu-36 (11%) ezinokukhululwa kwezifo azizange zibonise ukuqhubeka kwesifo kusukela ngesikhathi sokubika. Njengoba bekulindelekile, iziguli eziyi-9 (23%) zaba nezigameko ezimbi ezihlobene nokuzivikela komzimba. Azikho iziguli eziyekile ukwelashwa ngenxa yezehlakalo ezimbi ezihlobene nokuzivikela komzimba. Uma kuqhathaniswa no-11% kuya ku-30% weziguli ocwaningweni lwe-chemotherapy lomugqa wesibili, imiphumela ibimangaza kakhulu. Uma kubhekwa iqiniso lokuthi imiphumela yokusinda yokuhlolwa kwamuva nje kwemitholampilo yomdlavuza wesisu wamazwe ngamazwe ithintwa umehluko wesifunda, uKei Muro kanye nozakwabo baphinde bafakazela ukuthi ukusinda kweziguli zase-Asia nezingezona zase-Asia ocwaningweni lwe-Keynote-012 kuyafana.
Ingabe inkulumo ye-PD-L1 ingabikezela ukusebenza kwe-immunotherapy?
Ukuhlolwa kokuhlolwa kwe-Keynote-012 kusebenzisa i-immunohistochemistry ukuze kutholwe ukuvezwa kwe-PD-L1. Iziguli ezinamaseli esimila, amaseli omzimba noma lezi nqwaba zamangqamuzana amabili zidinga ukuveza okungenani u-1% we-PD-L1 ukuze zifanelekele ukuhlolwa. Umbhali wabe esehlola kabusha isimo se-PD-L1 esebenzisa izivivinyo ezihlukene. Imiphumela yokuhlolwa kwesibili ikhombisa ukuthi ukuvezwa kwe-PD-L1 kumaseli omzimba, hhayi amaseli wesimila, kuhlotshaniswa nempumelelo ye-pembrolizumab kumdlavuza wesisu. Okwesibili, izibonelo ze-biopsy ezingu-8 kwezingu-35 ezingase zihlolwe zibe nomphumela ongemuhle we-PD-L1. Le miphumela ikhombisa ubunkimbinkimbi bokuhlaziywa kwe-PD-L1 ngokujwayelekile, ikakhulukazi ukuhlolwa kwama-biomarker omdlavuza wesisu. Lokhu kuchezuka kungase kube ngenxa yezinguquko eziguquguqukayo ekukhulumeni kwe-PD-L1 ngemva kokwelashwa, umehluko ezindleleni zokuhlola, kanye ne-heterogeneity yomdlavuza wesisu. Ngakho-ke, akucaci ukuthi ezivivinyweni zemitholampilo ezedlule ngaphandle kokuhlolwa kwe-biomarker, ezinye iziguli ezineziguli ezibonakala zingenayo i-PD-L1 ezathola ukwelashwa kwezidakamizwa ezilwa ne-PD1 zokukhululwa kwesifo zazihlobene nokuhluka kwenkulumo ye-biomarker, Noma ingabe kukhona ukuhlobana kwangempela. phakathi kwama-biomarker nokusebenza kahle. Kudingeka olunye ucwaningo
Indlela engcono kakhulu yokuhlola isisho se-PD-L1 nokuthi ingabe iyiqiniso futhi iyisibikezelo esisebenzayo se-biomarker ku-immunotherapy yomdlavuza wesisu. Ababhali baphinde babike imiphumela yokuqala ye-interferon gamma gene expression njenge-biomarker yokubikezela okuzimele kwesilonda kwezicubu. Uma lo mphumela uqinisekisiwe, kungasiza ukugwema ezinye izinkinga ezihlobene ne-immunohistochemistry esikhathini esizayo.
Izinkinga ezidinga ukucatshangelwa okwengeziwe
Vele, isivivinyo esincane sesampula esifana ne-Keynote-012 nakanjani sinezinkinga ezithile. Okokuqala, akucaci ukuthi kukhona yini ukusebenzisana phakathi kokwelashwa ngamakhemikhali okwatholwa esikhathini esidlule kanye nempumelelo ye-pembrolizumab. Nakuba ezinye iziguli ezisabelayo zazithole ukwelashwa ngamakhemikhali komugqa wokuqala noma ngaphansi ngaphambi kwe-pembrolizumab, iziguli eziningi (63%) ezisabelayo zazithole ukwelashwa komugqa wesibili noma ngaphezulu kokulwa nesimila. Ngaphezu kwalokho, i-Keynote-012 iyisampula encane yokuhlolwa kokuqala kwemitholampilo futhi ayikwazi ukufakwa ezigulini eziningi ezinomdlavuza wesisu othuthukisiwe nokusinda isikhashana, okungenza amazinga okuphendula ahlobene ne-immunotherapy athathe kancane kanye namanga ezikhathi ezithile.
Imiphumela yenqubekela phambili ayigculisi neze. Izivivinyo eziningi zomtholampilo eziqhubekayo zizama ukuthola iwindi lesikhathi elilungile le-immunotherapy yeziguli ezinomdlavuza wesisu. Okwesibili, nakuba ngokombono, iziguli ezinomdlavuza wesisu ezinama-microsomes angazinzile kufanele zifaneleke kakhulu i-immunotherapy, futhi
Ocwaningweni lwe-Keynote-012, isigamu kuphela seziguli ezinokungaqini kwe-microsatellite ezilashwe nge-pembrolizumab saphendula. Lolu hlobo oluncane lomdlavuza wesisu lubalelwa ku-22% yenani eliphelele leziguli ezinomdlavuza wesisu futhi kufanele ukuthi kuqhutshekwe nocwaningo. Okokugcina, imingcele ehlola imiphumela emihle yalesi sivivinyo somtholampilo se-immunotherapy yomdlavuza wesisu nayo idinga ukucatshangelwa ngokucophelela. Ingxenye yeziguli ezithole ukukhululwa kwezifo ocwaningweni lwe-Keynote-012 yayincane kunaleyo ovivinyweni lwe-RAINBOW nge-paclitaxel kanye ne-ramolizumab ehlanganisiwe. Eqinisweni, ukuhlolwa kwe-Keynote-012 kubi kusukela encazelweni yezibalo kuphela. Iziguli eziphendule ekwelashweni azizange zibonise ukuthuthukiswa okuphawulekayo ekusindeni-mahhala kokuqhubekela phambili kanye nokusinda okuphelele. Ngokuzayo, izinhlolo zokwelashwa eziqhubekayo nazo zidinga ukunaka lezi zinkinga.
Izivivinyo zemitholampilo ezihlobene nokwelashwa kwe-CTLA-4 kanye ne-anti-PD-1 zibe yimpumelelo enkulu ku-melanoma. Uma kuqhathaniswa, imiphumela yohlolo lwe-Keynote-012 ibonakala inethemba kancane. Nokho, izinga lokufa kwaminyaka yonke komdlavuza wesisu emhlabeni wonke liphindwe kathathu kune-melanoma eyingozi, ngakho imiphumela yalolu cwaningo isabaluleke kakhulu. Ezigulini eziningi ezinomdlavuza wesisu ezintula ukwelashwa okusebenzayo, okutholwe manje kuyisinyathelo sokuqala esijabulisayo sokuthola ukuxolelwa kwesikhathi eside kwesifo.
