xov xwm

Non-small cell ntsws cancer (NSCLC) suav txog li 80% -85% ntawm tag nrho cov qog nqaij hlav ntsws, thiab kev phais phais yog qhov zoo tshaj plaws rau kev kho mob radical thaum ntxov NSCLC. Txawm li cas los xij, tsuas yog 15% txo qis hauv kev rov tshwm sim thiab 5% kev txhim kho hauv 5-xyoo txoj sia nyob tom qab siv tshuaj kho mob perioperative, muaj qhov xav tau kev kho mob loj heev.

Perioperative immunotherapy rau NSCLC yog qhov kev tshawb fawb tshiab hotspot nyob rau hauv xyoo tas los no, thiab cov txiaj ntsig ntawm ntau theem 3 randomized tswj kev sim tau tsim txoj haujlwm tseem ceeb ntawm perioperative immunotherapy.

Kev siv tshuaj tiv thaiv kab mob rau cov neeg mob uas ua haujlwm tau ntxov ntxov uas tsis yog mob qog noj ntshav hauv lub ntsws (NSCLC) tau ua tiav qhov kev vam meej nyob rau xyoo tas los no, thiab cov tswv yim kho mob no tsis yog tsuas yog txuas ntxiv kev ciaj sia ntawm cov neeg mob, tab sis kuj tseem txhim kho lub neej zoo, muab kev pabcuam zoo rau kev phais ib txwm.

Nyob ntawm seb thaum twg immunotherapy raug tswj hwm, muaj peb yam tseem ceeb ntawm kev tiv thaiv kab mob hauv kev kho mob ntawm NSCLC thaum ntxov:

1. Neoadjuvant immunotherapy ib leeg: Immunotherapy yog ua ua ntej kev phais kom txo qhov loj ntawm cov qog thiab txo qhov kev pheej hmoo ntawm rov tshwm sim. Txoj kev tshawb nrhiav CheckMate 816 [1] tau pom tias kev tiv thaiv kab mob ua ke nrog cov tshuaj khomob tau txhim kho kev muaj sia nyob tsis muaj sia nyob (EFS) hauv theem neoadjuvant piv rau kev kho mob ib leeg. Tsis tas li ntawd, neoadjuvant immunotherapy kuj tseem tuaj yeem txo tus nqi rov qab thaum txhim kho cov kab mob ua tiav cov lus teb (pCR) ntawm cov neeg mob, yog li txo qis qhov tshwm sim ntawm kev rov ua haujlwm tom qab.
2. Perioperative immunotherapy (neoadjuvant + adjuvant): Hauv hom no, immunotherapy yog siv ua ntej thiab tom qab kev phais kom ua kom nws cov nyhuv antitumor thiab ntxiv tshem tawm qhov tsawg kawg nkaus qhov txhab tom qab phais. Lub hom phiaj tseem ceeb ntawm cov qauv kev kho mob no yog txhawm rau txhim kho txoj sia nyob mus ntev thiab kho tus nqi rau cov neeg mob qog los ntawm kev sib txuas cov tshuaj tiv thaiv kab mob hauv cov theem neoadjuvant (pre-operative) thiab adjuvant (post-operative) theem. Keynote 671 yog tus sawv cev ntawm tus qauv no [2]. Raws li tsuas yog randomized tswj kev sim (RCT) nrog EFS zoo thiab OS kawg cov ntsiab lus, nws tau soj ntsuam qhov ua tau zoo ntawm palizumab ua ke nrog cov kws khomob nyob rau hauv perioperatively resectable theem Ⅱ, ⅢA, thiab ⅢB (N2) NSCLC cov neeg mob. Piv nrog rau kev siv tshuaj khomob ib leeg, pembrolizumab ua ke nrog cov kws khomob tau txuas ntxiv qhov nruab nrab EFS los ntawm 2.5 xyoo thiab txo qhov kev pheej hmoo ntawm kev kis kab mob, rov tshwm sim, lossis tuag los ntawm 41%; KEYNOTE-671 kuj yog thawj txoj kev tshawb fawb txog kev tiv thaiv kab mob los ua kom pom kev muaj sia nyob tag nrho (OS) tau txais txiaj ntsig hauv kev kho NSCLC, nrog rau 28% txo qhov kev pheej hmoo ntawm kev tuag (HR, 0.72), qhov tseem ceeb hauv neoadjuvant thiab adjuvant immunotherapy rau kev ua haujlwm thaum ntxov NSCLC

3. Adjuvant immunotherapy ib leeg: Hauv hom no, cov neeg mob tsis tau txais kev kho tshuaj ua ntej kev phais, thiab cov tshuaj immunodrugs tau siv tom qab kev phais los tiv thaiv cov qog nqaij hlav rov qab, uas tsim nyog rau cov neeg mob uas muaj kev pheej hmoo rov qab los. Txoj kev tshawb fawb IMpower010 tau soj ntsuam qhov ua tau zoo ntawm kev ua haujlwm tom qab adjuvant attilizumab tiv thaiv kev kho kom zoo rau cov neeg mob uas tau raug tshem tawm tag nrho theem IB rau IIIA (AJCC 7th edition) NSCLC [3]. Cov txiaj ntsig tau pom tias kev kho mob txuas ntxiv nrog attilizumab cuam tshuam nrog kev muaj sia nyob tsis muaj kab mob ntev (DFS) hauv PD-L1 cov neeg mob zoo nyob rau theem ⅱ txog ⅢA. Tsis tas li ntawd, KEYNOTE-091 / PEARLS txoj kev tshawb fawb tau soj ntsuam cov nyhuv ntawm pembrolizumab raws li kev kho mob ntxiv rau cov neeg mob uas tau raug kho nrog theem IB mus rau IIIA NSCLC [4]. Pabolizumab tau ntev heev nyob rau hauv tag nrho cov pejxeem (HR, 0.76), nrog ib tug nruab nrab DFS ntawm 53.6 lub hlis nyob rau hauv pab pawg neeg Pabolizumab thiab 42 lub hlis nyob rau hauv cov placebo pab pawg neeg. Hauv pawg neeg mob ntawm cov neeg mob uas muaj PD-L1 qog cov qhab nia (TPS) ≥50%, txawm hais tias DFS tau ncua ntev hauv pab pawg Pabolizumab, qhov sib txawv ntawm ob pawg tsis yog qhov tseem ceeb vim yog cov qauv me me, thiab kev soj ntsuam ntev dua yog xav tau kom paub meej.

Raws li seb puas muaj kev tiv thaiv kab mob ua ke nrog lwm cov tshuaj lossis kev ntsuas kev kho mob thiab kev sib xyaw ua ke, qhov kev pab cuam ntawm neoadjuvant immunotherapy thiab adjuvant immunotherapy tuaj yeem muab faib ua peb hom hauv qab no:

1. Ib leeg tshuaj tiv thaiv kab mob: Hom kev kho no suav nrog cov kev tshawb fawb xws li LCMC3 [5], IMpower010 [3], KEYNOTE-091/PEARLS [4], BR.31 [6], thiab ANVIL [7], tus cwj pwm los ntawm kev siv tshuaj tiv thaiv kab mob ib leeg raws li (tshiab) adjuvant therapy.
2. Kev sib xyaw ntawm cov tshuaj tiv thaiv kab mob thiab tshuaj tua kab mob: Cov kev tshawb fawb no suav nrog KEYNOTE-671 [2], CheckMate 77T [8], AEGEAN [9], RATIONALE-315 [10], Neotorch [11], thiab IMpower030 [12]. Cov kev tshawb fawb no tau saib ntawm qhov cuam tshuam ntawm kev sib txuas ntawm cov tshuaj tiv thaiv kab mob thiab tshuaj tua kab mob hauv lub sijhawm perioperative.
3. Kev sib xyaw ntawm cov tshuaj tiv thaiv kab mob nrog rau lwm hom kev kho mob: (1) Kev sib xyaw nrog lwm cov tshuaj tiv thaiv kab mob: Piv txwv li, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) tau ua ke hauv NEOSTAR test [13], lymphocyte activation gene 3 (LAG-3) antibody tau ua ke hauv NEO-Log-1 thiab Predict-cell4 ITIM cov qauv tau muab tso ua ke hauv SKYSCRAPER 15 Kev Tshawb Fawb Kev Tshawb Fawb xws li TIGIT antibody ua ke [15] tau txhim kho cov nyhuv tiv thaiv qog los ntawm kev sib xyaw ntawm cov tshuaj tiv thaiv kab mob. (2) Ua ke nrog kev kho hluav taws xob: piv txwv li, duvaliumab ua ke nrog stereotactic radiotherapy (SBRT) yog tsim los txhim kho cov nyhuv ntawm NSCLC thaum ntxov [16]; (3) Kev sib xyaw ua ke nrog cov tshuaj tiv thaiv angiogenic: Piv txwv li, EAST ENERGY txoj kev tshawb fawb [17] tshawb pom cov txiaj ntsig zoo ntawm ramumab ua ke nrog kev tiv thaiv kab mob. Kev tshawb nrhiav ntau hom tshuaj tiv thaiv kab mob qhia tau tias daim ntawv thov txheej txheem ntawm kev tiv thaiv kab mob hauv lub sijhawm ua haujlwm tseem tsis tau nkag siab tag nrho. Txawm hais tias immunotherapy ib leeg tau pom cov txiaj ntsig zoo hauv kev kho mob perioperative, los ntawm kev sib txuas cov kws khomob, kev kho hluav taws xob, kev kho mob antiangiogenic, thiab lwm yam tshuaj tiv thaiv kab mob xws li CTLA-4, LAG-3, thiab TIGIT, cov kws tshawb fawb vam tias yuav ntxiv dag zog rau kev siv tshuaj tiv thaiv kab mob.

Tseem tsis muaj qhov xaus ntawm qhov kev pom zoo ntawm kev tiv thaiv kab mob rau kev ua haujlwm thaum ntxov NSCLC, tshwj xeeb tshaj yog seb puas yog perioperative immunotherapy piv nrog neoadjuvant immunotherapy ib leeg, thiab seb puas ntxiv cov tshuaj tiv thaiv kab mob ntxiv tuaj yeem ua rau muaj txiaj ntsig ntxiv, tseem tsis muaj qhov kev sib piv ncaj qha.
Forde et al. siv qhov kev tshawb nrhiav kev xav tau qhov ntsuas qhov ntsuas qhov hnyav los simulate cov txiaj ntsig ntawm kev sim tshuaj ntsuam xyuas, thiab kho cov kab ke hauv paus thiab cov kab mob ntawm cov neeg kawm sib txawv kom txo tau qhov cuam tshuam tsis zoo ntawm cov xwm txheej no, ua rau cov txiaj ntsig ntawm CheckMate 816 [1] thiab CheckMate 77T [8] zoo sib xws. Lub sijhawm ua raws nruab nrab yog 29.5 lub hlis (CheckMate 816) thiab 33.3 lub hlis (CheckMate 77T), feem, muab sijhawm txaus los saib xyuas EFS thiab lwm yam kev ntsuas tseem ceeb.
Hauv kev tsom xam qhov hnyav, HR ntawm EFS yog 0.61 (95% CI, 0.39 txog 0.97), qhia txog 39% qis dua kev pheej hmoo ntawm kev rov qab los lossis kev tuag nyob rau hauv perioperative nabuliumab ua ke cov kws khomob (CheckMate 77T hom) piv nrog neoadjuvant nabuliumab 8 pawg (kev sib xyaw ua ke chemo). Cov pab pawg kws kho mob perioperative nebuliuzumab ntxiv rau cov kws khomob tau pom tias muaj txiaj ntsig zoo rau txhua tus neeg mob ntawm theem pib, thiab cov txiaj ntsig tau tshwm sim ntau dua rau cov neeg mob uas muaj tsawg dua 1% qog PD-L1 qhia (49% txo qhov kev pheej hmoo rov qab los lossis tuag). Tsis tas li ntawd, rau cov neeg mob uas tsis ua tiav pCR, perioperative nabuliumab ua ke pab pawg kws khomob tau pom tias muaj txiaj ntsig zoo dua ntawm EFS (35% txo qis ntawm kev pheej hmoo rov qab los yog tuag) dua li neoadjuvant nabuliumab ua ke pab pawg kws khomob. Cov txiaj ntsig no qhia tau tias tus qauv perioperative immunotherapy muaj txiaj ntsig zoo dua li tus qauv neoadjuvant immunotherapy ib leeg, tshwj xeeb tshaj yog rau cov neeg mob uas tsis tshua muaj PD-L1 qhia thiab qog cov qog tom qab pib kho.
Txawm li cas los xij, qee qhov kev sib piv tsis ncaj (xws li meta-analyses) tau pom tias tsis muaj qhov sib txawv tseem ceeb hauv kev ciaj sia ntawm neoadjuvant immunotherapy thiab perioperative immunotherapy [18]. Ib qho kev tshuaj ntsuam xyuas raws li tus neeg mob cov ntaub ntawv pom tau hais tias perioperative immunotherapy thiab neoadjuvant immunotherapy muaj cov txiaj ntsig zoo sib xws ntawm EFS hauv ob pawg pCR thiab tsis yog PCR hauv cov neeg mob uas ua haujlwm tau thaum ntxov NSCLC [19]. Tsis tas li ntawd, qhov kev pab cuam ntawm lub adjuvant immunotherapy theem, tshwj xeeb tshaj yog tom qab cov neeg mob ua tiav pCR, tseem yog qhov tsis sib haum xeeb hauv tsev kho mob.
Tsis ntev los no, US Food and Drug Administration (FDA) Oncology Drug Advisory Committee tau tham txog qhov teeb meem no, hais txog tias lub luag haujlwm tshwj xeeb ntawm kev kho tshuaj tiv thaiv kab mob tseem tsis tau paub meej [20]. Nws tau tham txog tias: (1) Nws yog ib qho nyuaj rau kev paub qhov txawv ntawm txhua theem ntawm kev kho mob: vim hais tias cov kev pab cuam perioperative muaj ob theem, neoadjuvant thiab adjuvant, nws yog ib qho nyuaj rau txiav txim siab tus neeg pab cuam ntawm txhua theem rau tag nrho cov nyhuv, ua rau nws nyuaj rau txiav txim seb lub theem twg yog qhov tseem ceeb tshaj, los yog seb ob theem yuav tsum tau nqa tawm ib txhij; (2) Qhov muaj peev xwm ntawm kev kho mob ntau dhau: yog tias kev siv tshuaj tiv thaiv kab mob koom nrog hauv ob theem kev kho mob, nws yuav ua rau cov neeg mob tau txais kev kho mob ntau dhau thiab ua rau muaj kev pheej hmoo ntawm kev phiv; (3) Kev kho mob hnyav ntxiv: Kev kho mob ntxiv hauv cov txheej txheem kho mob ntxiv tuaj yeem ua rau muaj kev kho mob ntau dua rau cov neeg mob, tshwj xeeb tshaj yog tias muaj kev tsis paub meej txog nws qhov kev pab cuam rau tag nrho cov txiaj ntsig. Nyob rau hauv cov lus teb rau qhov kev sib cav saum toj no, txhawm rau txhawm rau txiav txim siab meej, tsim kom muaj kev sib tw tswj hwm nruj dua yog xav tau rau kev txheeb xyuas ntxiv yav tom ntej.