POSEIDON研究：度伐利尤單抗±Tremelimumab＋化療一線治療轉(zhuǎn)移性NSCLC的患者報(bào)告結(jié)局

POSEIDON研究：度伐利尤單抗±Tremelimumab＋化療一線治療轉(zhuǎn)移性NSCLC的患者報(bào)告結(jié)局Patient-reportedoutcomeswith1Ldurvalumab,withorwithouttremelimumab,pluschemotherapyinmetastaticNSCLC:ResultsfromPOSEIDON5MOEdwardB.Garon,1

Byoung

ChulCho,2AlexanderLuft,3JorgeAlatorre-Alexander,4

SarayutLucienGeater,5Sang-WeKim,6

GrygoriiUrsol,7

MaenHussein,8

FarahLouiseLim,9Cheng-TaYang,10LuizHenriqueAraujo,11

HaruhiroSaito,12NielsReinmuth,13

NenadMedic,14HelenMann,14

XiaojinShi,15SolangePeters,16

TonyMok,17MelissaJohnson181DavidGeffenSchoolofMedicineatUCLA,LosAngeles,CA,USA;2YonseiCancerCenter,Seoul,RepublicofKorea;3LeningradRegionalClinicalHospital,StPetersburg,Russia;4HealthPharmaProfessionalResearch,MexicoCity,Mexico;5PrinceofSongklaUniversity,Songkhla,Thailand;6AsanMedicalCenter,UniversityofUlsanCollegeofMedicine,Seoul,RepublicofKorea;7Acinus,Kropyvnytskyi,Ukraine;8FloridaCancerSpecialists–SarahCannonResearchInstitute,Leesburg,FL,USA;9QueenMaryUniversityofLondon,London,UK;10ChangGungMemorialHospital,TaoyuanCity,Taiwan;11InstitutoNacionaldeCancer-INCA,RiodeJaneiro,Brazil;12KanagawaCancerCenter,Yokohama,Japan;13AsklepiosLungClinic,Munich-Gauting,Germany;14AstraZeneca,Cambridge,UK;15AstraZeneca,Gaithersburg,MD,USA;16CentreHospitalier

UniversitaireVaudois,LausanneUniversity,Lausanne,Switzerland;17ChineseUniversityofHongKong,HongKong,China;18SarahCannonResearchInstitute,TennesseeOncology,PLLC,Nashville,TN,USA背景III期POSEIDON研究證實(shí)，與化療相比，一線使用tremelimumab+度伐利尤單抗+CT在統(tǒng)計(jì)學(xué)和臨床價(jià)值上均顯著改善了mNSCLC患者的PFS和OS1*與化療相比，度伐利尤單抗+CT顯著提高了mNSCLC一線治療的PFS，OS未顯著獲益但具有積極的改善趨勢(shì)D+CTCT事件,n/N(%)264/338(78.1)285/337(84.6)

mOS,

月(95%CI)13.3(11.4–14.7)11.7(10.5–13.1)HR(95%CI)0.86

(0.72–1.02)P值0.07581處于風(fēng)險(xiǎn)患者數(shù)D+CT338296247212176142126112978581513315500CT33728423620416013211191726252382113600處于風(fēng)險(xiǎn)患者數(shù)T+D+CT3382982562171831591371201099588644120900CT337284236204160132111917262523821136001.003691215183621自隨機(jī)化開(kāi)始的時(shí)間(月)0.00.20.40.60.82427303339424548OS率29.6%22.1%1.003691215183621自隨機(jī)化開(kāi)始的時(shí)間(月)0.00.20.40.60.82427303339424548OS率32.9%22.1%T+D+CTCT事件,n/N(%)251/338(74.3)285/337(84.6)

mOS,

月份

(95%CI)14.0(11.7–16.1)11.7(10.5–13.1)HR(95%CI)0.77

(0.65–0.92)P值0.00304*PFSDCO,2019年7月24日:刪失患者中位隨訪,10.3個(gè)月(范圍0.0?23.1);OSDCO,2021年3月12日:刪失患者中位隨訪,34.9個(gè)月(范圍0.0–44.5)1L,一線;CI,置信區(qū)間;CT,化療;D,度伐利尤單抗;DCO,數(shù)據(jù)截止日期;HR,風(fēng)險(xiǎn)比;mNSCLC,轉(zhuǎn)移性非小細(xì)胞肺癌;mOS,中位OS;OS,總生存期;PFS,無(wú)進(jìn)展生存期;T,tremelimumab1.JohnsonM,etal.OralpresentedatWCLC2021(PL02.01)POSEIDON研究設(shè)計(jì)一項(xiàng)III期、全球、隨機(jī)、開(kāi)放標(biāo)簽、多中心研究其他次要終點(diǎn)PROs,采用EORTCQLQ-C30和QLQ-LC13評(píng)估此處對(duì)患者報(bào)告的癥狀、功能和HRQoL進(jìn)行分析患者人群IV期NSCLC*無(wú)EGFR或ALK突變ECOGPS0or1初治轉(zhuǎn)移性疾病N=1013(隨機(jī)分組)Tremelimumab+度伐利尤單抗

+CT?q3w

(4周期)度伐利尤單抗+CT?q3w

(4周期)Tremelimumab(僅限第16周)§+度伐利尤單抗q4w+培美曲塞?直至PD度伐利尤單抗q4w+培美曲塞?直至PD含鉑化療?q3w(最多6周期)培美曲塞?

直至PD分層:PD-L1表達(dá)?(TC≥50%vs<50%)疾病分期?(IVAvsIVB)組織學(xué)

(鱗癌vs非鱗癌)R1:1:1主要終點(diǎn)經(jīng)BICR評(píng)估的PFS(D+CTvsCT)OS(D+CTvsCT)關(guān)鍵次要終點(diǎn)經(jīng)BICR評(píng)估的PFS(T+D+CTvsCT)OS(T+D+CTvsCT)*IASLC胸部腫瘤分期手冊(cè)(第8版);?VENTANAPD-L1(SP263)分析;?CT方案:

吉西他濱+卡鉑/順鉑(鱗癌),培美曲塞+卡鉑/順鉑(非鱗癌),或白蛋白結(jié)合型紫杉醇+卡鉑(任一組織學(xué)類型);§患者CT后接受一次額外劑量tremelimumab(第5劑);?適用于僅在1L治療期間初始接受培美曲塞治療的非鱗癌患者(如符合標(biāo)準(zhǔn))ALK,間變性淋巴瘤激酶;BICR,盲法獨(dú)立中心審查;C30,core30;ECOG,東部腫瘤協(xié)作組;EGFR,表皮生長(zhǎng)因子受體;EORTC,歐洲癌癥研究和治療組織;HRQoL,健康相關(guān)生活質(zhì)量;IASLC,國(guó)際肺癌研究協(xié)會(huì);LC13,肺癌13;PD,疾病進(jìn)展;PD-L1,程序性細(xì)胞死亡配體-1;PROs,患者報(bào)告結(jié)果;PS,體能狀態(tài);q3w,每3周一次;q4w,每4周一次;QLQ,生活質(zhì)量調(diào)查問(wèn)卷;TC,腫瘤細(xì)胞患者報(bào)告結(jié)局分析采用Cox比例風(fēng)險(xiǎn)模型進(jìn)行分層log-rank檢驗(yàn)分析至惡化時(shí)間(TTD)*，采用Kaplan-Meier法評(píng)估中位數(shù)基于邏輯回歸分析改善率?依從性和基線評(píng)分依從率≥60%(接受性良好)，tremelimumab+度伐利尤單抗+CT治療最多88周，度伐利尤單抗+CT治療最多64周，單用CT治療最多24周治療組間PROs的基線評(píng)分基本相似q3w化療誘導(dǎo)期q4w

直至PDq8w直至二次進(jìn)展評(píng)估R*TTD定義為自隨機(jī)化至隨后評(píng)估中經(jīng)確認(rèn)的首次有臨床意義的惡化1(癥狀增加≥10分;功能項(xiàng)目和整體健康狀態(tài)/QoL下降≥10分)或死亡的時(shí)間;?改善率定義為在2次連續(xù)評(píng)估中具有臨床意義改善1(癥狀減少≥10分;功能項(xiàng)目和整體健康狀態(tài)/QoL增加≥10分)的患者百分比QoL,生活質(zhì)量;TTD,至惡化時(shí)間1.OsobaD,etal.JClinOncol1998;16:139–44

至惡化時(shí)間粗體字表示預(yù)先設(shè)定的值得關(guān)注的終點(diǎn)。對(duì)基線功能和整體健康狀態(tài)/QoL評(píng)分≥10和癥狀評(píng)分≤90(0–100分量表)的患者進(jìn)行惡化時(shí)間分析事件/

患者,n/NHR(95%CI)事件/

患者,n/N

HR(95%CI)QLQ-C30整體健康狀態(tài)/QoL361/6370.78(0.63–0.96)384/6390.79(0.64–0.96)身體功能382/6430.75(0.61–0.92)388/6450.70(0.57–0.87)角色功能388/6180.81(0.66–1.00)390/6170.75(0.61–0.92)認(rèn)知功能377/6410.79(0.64–0.97)396/6410.87(0.71–1.06)情緒功能335/6370.87(0.70–1.08)339/6370.83(0.66–1.03)社交功能362/6340.85(0.69–1.04)372/6330.88(0.72–1.09)疲勞452/6310.90(0.75–1.08)447/6320.83(0.69–1.00)疼痛356/6140.70(0.56–0.86)379/6090.84(0.68–1.03)惡心/嘔吐373/6410.81(0.65–0.99)394/6410.91(0.74–1.12)呼吸困難344/6110.84(0.68–1.05)346/6110.86(0.69–1.06)失眠346/6120.74(0.60–0.92)356/6050.84(0.68–1.04)食欲減退337/6130.94(0.75–1.17)364/6211.05(0.85–1.31)便秘338/6210.78(0.63–0.97)353/6200.84(0.68–1.04)腹瀉302/6441.00(0.79–1.26)306/6440.97(0.77–1.22)QLQ-LC13咳嗽304/5970.91(0.72–1.15)310/6090.87(0.69–1.09)咳血261/6430.77(0.60–0.98)276/6440.81(0.63–1.03)呼吸困難431/6410.77(0.63–0.94)431/6410.81(0.67–0.98)胸痛323/6280.85(0.68–1.07)327/6310.86(0.69–1.08)手臂疼痛/肩膀疼痛329/6220.93(0.74–1.16)330/6210.94(0.75–1.17)其他部位疼痛346/6180.74(0.60–0.92)355/6200.77(0.62–0.96)T+D+CTvsCTCT更優(yōu)T+D+CT更優(yōu)10.52D+CTvsCTD+CT更優(yōu)CT更優(yōu)10.52至惡化時(shí)間預(yù)先設(shè)定的值得關(guān)注的終點(diǎn)(EORTCQLQ-C30)T+D+CTD+CTCT中位，月

(95%CI)8.3(6.4–10.2)7.8(6.5–9.5)5.6(4.4–7.5)T+D+CTD+CTCT中位,

月

(95%CI)7.7(5.9–9.4)8.3(6.6–10.0)5.3(4.2–6.5)T+D+CTD+CTCT中位,

月

(95%CI)7.2(5.7–9.4)7.2(4.7–8.8)7.0(5.6–9.6)T+D+CTD+CTCT中位,

月

(95%CI)3.7(2.8–5.0)3.8(2.9–4.9)2.8(2.1–3.7)疲勞0無(wú)惡化率自隨機(jī)化開(kāi)始的時(shí)間(月)03691215182124273033360.20.40.60.81.0394245食欲減退0無(wú)惡化率自隨機(jī)化開(kāi)始的時(shí)間(月)03691215182124273033360.20.40.60.81.0394245整體健康狀態(tài)/QoL0無(wú)惡化率03691215182124273033360.20.40.60.81.0394245自隨機(jī)化開(kāi)始的時(shí)間(月)身體功能0無(wú)惡化率自隨機(jī)化開(kāi)始的時(shí)間(月)0.20.40.60.81.00369121518212427303336394245至惡化時(shí)間預(yù)先設(shè)定的值得關(guān)注的終點(diǎn)(EORTCQLQ-LC13)T+D+CTD+CTCT中位,

月

(95%CI)9.7(7.3–13.3)11.0(8.7–13.5)8.8(6.8–12.3)咳嗽T+D+CTD+CTCT中位,

月

(95%CI)5.4(4.2–6.4)5.0(3.8–6.4)3.6(2.6–4.5)呼吸困難T+D+CTD+CTCT中位,

月

(95%CI)10.0(7.7–13.3)9.5(7.8–11.8)8.6(6.8–11.4)胸痛隨機(jī)化開(kāi)始的時(shí)間(月)0無(wú)惡化率隨機(jī)化開(kāi)始的時(shí)間(月)03691215182124273033360.20.40.60.81.0394245036912151821242730333639424500.20.40.60.81.0無(wú)惡化率03691215182124273033363942隨機(jī)化開(kāi)始的時(shí)間(月)無(wú)惡化率00.20.40.60.81.045改善率事件/

患者,n/N優(yōu)勢(shì)比(95%CI)事件/

患者,n/N優(yōu)勢(shì)比

(95%CI)QLQ-C30整體健康狀態(tài)/QoL211/6011.38(0.98–1.93)203/6031.22(0.87–1.71)身體功能167/4541.56(1.06–2.32)161/4591.34(0.91–1.99)角色功能195/3921.31(0.87–1.95)190/3831.33(0.88–2.00)認(rèn)知功能159/3131.23(0.79–1.93)156/3121.21(0.77–1.91)情緒功能183/3851.72(1.14–2.60)174/3891.35(0.90–2.03)社交功能177/3411.44(0.94–2.23)173/3491.20(0.78–1.85)疲勞245/5491.26(0.90–1.77)254/5461.48(1.05–2.08)疼痛275/4541.60(1.09–2.36)247/4421.10(0.75–1.61)惡心/嘔吐106/1672.46(1.25–4.91)87/1591.23(0.65–2.33)呼吸困難178/4321.16(0.79–1.71)181/4241.35(0.92–2.00)失眠171/3451.25(0.81–1.92)174/3391.41(0.91–2.17)食欲減退171/3081.43(0.91–2.25)169/3151.21(0.77–1.89)便秘114/2041.97(1.12–3.49)122/2122.17(1.25–3.82)咳血69/962.40(0.92–6.71)71/1071.22(0.53–2.80)QLQ-LC13咳嗽236/5031.08(0.76–1