鹽酸?？颂婺嶂委烢GFR敏感突變非小細(xì)胞肺癌腦轉(zhuǎn)移患者的療效觀察

屈 濤 張 昕 李峻嶺 郝學(xué)志

【Abstract】ObjectiveTo investigate the efficacy of single-agenticotinib hydrochloride in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) with brain metastases.MethodsTwenty-two NSCLC patients with brain metastases from NSCLC admitted in our department from July 2013 to June 2017 were enrolled in this study.Retrospective analysis was conducted to evaluate the efficacy of oral icotinib in these patients.ResultsThe overall median progression-free survival (PFS)was 13.0 months (95% CI11.87～14.13),and the objective response rate (ORR) and disease control rate (DCR) were 40.9% and 100%,respectively.Subgroup analysis of PFS and ORR was conducted according to sex,smoking status,EGFR subtypes,and presence of previous treatment,showing no significant difference of PFS and ORR in these groups.ConclusionSingle-agent icotinib showed favorable efficacy as treatment for EGFR-mutated NSCLC with brain metastases.

【Keywords】 single-agenticotinib, EGFR, non-small cell lung cancer

中樞神經(jīng)系統(tǒng)是晚期非小細(xì)胞肺癌(non-small cell lung cancer，NSCLC)患者最常見(jiàn)的轉(zhuǎn)移部位之一，約20%～25%的晚期NSCLC患者就診時(shí)即出現(xiàn)腦轉(zhuǎn)移，約30%的NSCLC患者會(huì)在其病程中發(fā)生腦轉(zhuǎn)移[1～5]。與無(wú)腦轉(zhuǎn)移的患者相比，腦轉(zhuǎn)移患者預(yù)后更差。全腦放療、外科手術(shù)和立體定向放療是目前腦轉(zhuǎn)移患者的主要治療手段，但是這些治療手段均有其局限性，如認(rèn)知功能損傷、適應(yīng)癥人群等，且即使接受這些治療，患者依然會(huì)在6個(gè)月內(nèi)發(fā)生顱內(nèi)進(jìn)展，如何控制腦轉(zhuǎn)移依然是臨床實(shí)踐中的一個(gè)重大挑戰(zhàn)。

表皮生長(zhǎng)因子受體酪氨酸激酶抑制劑(epidermal growth factor receptor tyrosine kinase inhibitor，EGFR TKI)，如吉非替尼、厄洛替尼、鹽酸?？颂婺?、阿法替尼等，已廣泛應(yīng)用于NSCLC的治療，其在EGFR突變陽(yáng)性患者的療效已在多個(gè)大規(guī)模多中心三期研究中得到驗(yàn)證。EGFR TKI治療EGFR突變的晚期NSCLC腦轉(zhuǎn)移患者的總反應(yīng)率可達(dá)48.9%～87.8%，無(wú)進(jìn)展生存期可達(dá)6.6～14.9個(gè)月[6]。本研究通過(guò)回顧性分析EGFR TKI治療EGFR敏感突變非小細(xì)胞肺癌腦轉(zhuǎn)移患者的臨床療效，為這部分患者的治療提供更多的證據(jù)支持，現(xiàn)報(bào)告如下。

1.資料與方法

1.1 一般資料 選取我院門(mén)診2013年7月至2017年6月期間收治的非小細(xì)胞肺癌腦轉(zhuǎn)移患者22例，納入標(biāo)準(zhǔn)：經(jīng)過(guò)組織學(xué)或病理學(xué)檢查證實(shí)晚期非小細(xì)胞肺癌；結(jié)合患者的癥狀、體征及影像學(xué)檢查(頭顱MRI和/或CT)；EGFR突變陽(yáng)性(19 Del或21 L858R)；存在基于RECIST標(biāo)準(zhǔn)1.1的可測(cè)量病灶。22例患者中，中位年齡57歲(51～64歲)；男性8例，女性14例；所有患者均為IV期，7例患者存在吸煙史；一般狀況(PS)評(píng)分：0～1分21例，2分1例；均為腺癌；分別存在19Del和21L858R突變各11例；初治和復(fù)治患者分別為14例和8例。受試者基本臨床特征見(jiàn)表1。

1.2 治療 所有患者接受口服EGFR TKI鹽酸?？颂婺?凱美納，貝達(dá)藥業(yè)股份有限公司，杭州)治療，劑量為125mg，每日3次?；颊叱掷m(xù)服用該藥直到疾病進(jìn)展、死亡或者出現(xiàn)不可耐受的不良反應(yīng)。

表1 患者特征分析

1.3 療效評(píng)估 本研究主要療效觀察指標(biāo)包括：①無(wú)進(jìn)展生存期(progression-free survival，PFS)，定義為患者從服藥起直到疾病進(jìn)展、死亡或者出現(xiàn)不可耐受的不良反應(yīng)的時(shí)間。②腫瘤客觀緩解率(objective response rate，ORR)和疾病控制率(disease control rate，DCR)：根據(jù)RECIST標(biāo)準(zhǔn)1.1將腫瘤緩解分為完全緩解(CR)、部分緩解(PR)、穩(wěn)定(SD)和進(jìn)展(PD)，PR和CR在可評(píng)價(jià)療效患者中所占比例即ORR；PR，CR和SD在可評(píng)價(jià)療效患者中所占比例即DCR。

1.4 統(tǒng)計(jì)學(xué)方法 采用SPSS 22.0軟件進(jìn)行數(shù)據(jù)統(tǒng)計(jì)，以卡方檢驗(yàn)對(duì)比患者臨床特點(diǎn)與其中位無(wú)進(jìn)展生存期的相關(guān)性，當(dāng)P<0.05時(shí)差異具有統(tǒng)計(jì)學(xué)差異。使用Kaplan-Meier生存函數(shù)計(jì)算評(píng)估并進(jìn)行中位PFS分析，并采用Log-rank檢驗(yàn)比較不同組別的PFS差異。

2.結(jié)果

22例接受鹽酸?？颂婺岚邢蛑委煹哪X轉(zhuǎn)移患者的中位無(wú)進(jìn)展生存期為13.0個(gè)月(95%CI 11.87～14.13，圖1)。所有患者均可進(jìn)行療效評(píng)估，9例患者出現(xiàn)PR，13例患者出現(xiàn)SD，鹽酸?？颂婺嶂委烢GFR突變腦轉(zhuǎn)移患者的ORR和DCR分別為40.9%和100%。

圖1 總體PFS

將22例接受靶向治療的患者，根據(jù)性別、吸煙史、EGFR突變亞型、既往治療情況對(duì)其進(jìn)行PFS和ORR的影響的分析，具體結(jié)果見(jiàn)表2、表3和圖2。

表2 臨床特征與PFS

表3 臨床特征與ORR

3.討論

腦轉(zhuǎn)移是晚期非小細(xì)胞肺癌治療中備受關(guān)注的問(wèn)題之一，以放療為主的多學(xué)科綜合治療是腦轉(zhuǎn)移患者的主要治療方法，然而放療和化療均具有其局限性。全腦放療患者的生存期僅有6個(gè)月，且易發(fā)生認(rèn)知功能損傷；由于血腦屏障的存在，化學(xué)藥物等大分子、親水性物質(zhì)很難進(jìn)入顱內(nèi)發(fā)揮抗腫瘤作用。小分子靶向抗癌藥物的出現(xiàn)為腦轉(zhuǎn)移患者的治療帶來(lái)了新的選擇。

EGFR TKIs目前已廣泛應(yīng)用于臨床，目前國(guó)內(nèi)已有吉非替尼、厄洛替尼、阿法替尼、達(dá)可替尼和奧西替尼多個(gè)產(chǎn)品上市，涵蓋一代、二代和三代EGFR TKIs類(lèi)藥物。一代EGFR TKI方面，一例病例報(bào)告采用PET/CT檢測(cè)同位素標(biāo)記的厄洛替尼在EGFR突變患者體內(nèi)的分布，結(jié)果顯示，厄洛替尼可通過(guò)血腦屏障，在腦轉(zhuǎn)移病灶中濃聚；臨床療效方面，腦轉(zhuǎn)移病灶明顯縮小[7]。根據(jù)一些小樣本研究結(jié)果，吉非替尼和厄洛替尼治療存在EGFR突變的晚期NSCLC腦轉(zhuǎn)移患者無(wú)進(jìn)展生存期可達(dá)6.6～14.5個(gè)月[8～11]。阿法替尼是一種口服二代EGFR TKI，主要特點(diǎn)為不可逆的抑制EGFR-ErbB酪氨酸激酶受體。兩項(xiàng)隨機(jī)、對(duì)照、Ⅲ期研究LUX-Lung 3和LUX-Lung 6證實(shí)了阿法替尼作為一線治療在EGFR突變陽(yáng)性NSCLC的療效[12,13]，一項(xiàng)基于這兩項(xiàng)Ⅲ期研究的亞組分析進(jìn)一步證實(shí)了阿法替尼治療腦轉(zhuǎn)移患者同樣有效，與標(biāo)準(zhǔn)化療相比，阿法替尼可顯著延長(zhǎng)EGFR突變陽(yáng)性NSCLC腦轉(zhuǎn)移患者的PFS(8.2 vs 5.4個(gè)月；HR,0.50；P=0.0297)[14]。為了克服一代及二代EGFR TKIs的耐藥問(wèn)題，可同時(shí)抑制EGFR敏感突變和T790M耐藥突變的三代EGFR TKI應(yīng)運(yùn)而生，主要代表藥物為奧昔替尼。AURA研究中，奧希替尼在攜帶EGFR T790M突變的患者(n=127)療效顯著，ORR和DCR分別為61%和95%，中位PFS為9.6個(gè)月[15]?；贏URA研究的結(jié)果，一項(xiàng)Ⅱ期、開(kāi)放、單臂AURA2進(jìn)一步驗(yàn)證了奧希替尼在EGFR-TKI治療失敗攜帶EGFR T790M突變的局部晚期或轉(zhuǎn)移性NSCLC患者中作用，結(jié)果顯示，經(jīng)獨(dú)立盲審中心評(píng)定的ORR為70%，中位緩解持續(xù)時(shí)間DoR和PFS分別為11.4和9.9個(gè)月[16]。Goss等進(jìn)一步對(duì)腦轉(zhuǎn)移患者進(jìn)行分析，結(jié)果顯示，基線經(jīng)影像學(xué)確認(rèn)存在可評(píng)估病灶的50例腦轉(zhuǎn)移患者中，顱內(nèi)ORR和DCR分別為54%和92%，無(wú)論此前是否接受過(guò)腦部放療，均可觀察到顱內(nèi)病灶緩解[17]。

鹽酸?？颂婺崾俏覈?guó)自主研發(fā)的一代EGFR TKI，其Ⅲ期注冊(cè)臨床研究(ICOGEN)采用隨機(jī)、雙盲、對(duì)照臨床試驗(yàn)設(shè)計(jì)，以吉非替尼250mg，1次/日為陽(yáng)性對(duì)照，共入組399例化療后進(jìn)展的晚期復(fù)發(fā)或轉(zhuǎn)移的ⅡB/Ⅳ期NSCLC患者，主要終點(diǎn)指標(biāo)為PFS。結(jié)果顯示，鹽酸?？颂婺岬闹形籔FS為4.6個(gè)月，長(zhǎng)于吉非替尼組3.4個(gè)月[18]。CONVINCE研究進(jìn)一步證實(shí)了鹽酸?？颂婺嵩诔踔蜤GFR突變患者中的療效，該研究對(duì)照組患者接受培美曲塞/順鉑方案化療后，未進(jìn)展的患者繼續(xù)接受培美曲塞單藥維持治療，鹽酸?？颂婺峤M與對(duì)照組的中位PFS分別為11.2和7.9個(gè)月，鹽酸?？颂婺犸@著優(yōu)于對(duì)照組[19]。腦轉(zhuǎn)移方面，鹽酸?？颂婺崧?lián)合WBRT治療EGFR突變陽(yáng)性患者的ORR可達(dá)51.2%～80%，顱內(nèi)PFS為 11～18.9個(gè)月[20～22]。近期，廣東省腫瘤醫(yī)院吳一龍教授牽頭的一項(xiàng)大型的3期、隨機(jī)對(duì)照BRAIN研究發(fā)布了結(jié)果，該研究開(kāi)創(chuàng)性地對(duì)比鹽酸?？颂婺釂嗡幣c全腦放療在EGFR突變NSCLC患者中的療效和安全性，與其他研究不同，受試者需要有3個(gè)及以上的腦轉(zhuǎn)移病灶，主要研究終點(diǎn)為顱內(nèi)PFS。結(jié)果顯示，鹽酸?？颂婺峤M和化療組的顱內(nèi)中位PFS分別為10.0和4.8個(gè)月，鹽酸?？颂婺峤M顯著優(yōu)于全腦放療組(HR 0.56，95% CI 0.36～0.90；P=0.014)[23]。

本研究結(jié)果顯示，鹽酸?？颂婺釂嗡幹委熗砥贓GFR突變NSCLC腦轉(zhuǎn)移患者具有較好的療效，PFS和ORR均與既往研究一致。性別、吸煙史、EGFR突變亞型、既往治療情況等對(duì)PFS和ORR均無(wú)明顯影響。盡管沒(méi)有統(tǒng)計(jì)學(xué)差異，但19Del突變患者的ORR高于21L858R突變患者的ORR(63.6% vs 18.2%)，由于本研究樣本量較小，EGFR突變亞型對(duì)療效的影響值得進(jìn)一步探討。本研究由具有若干局限性，如回顧性設(shè)計(jì)和較小的樣本量，且未明確是否有顱內(nèi)靶病灶、顱內(nèi)病灶數(shù)量、顱外腫瘤負(fù)荷與整體腫瘤緩解情況的關(guān)系，未來(lái)仍需大樣本前瞻性研究進(jìn)一步對(duì)這些問(wèn)題進(jìn)行探索。

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