作者：楊文化

資料來源：腫瘤信息

2018年ASCO肺癌靶向治療進展，EGFR突變肺癌的一線聯(lián)合治療是絕對主角，第一和兩項宣布一線TKI為對手的III期隨機控制實驗。

EGFR-TKI單藥治療是目前EGFR突變?nèi)巳旱囊痪€標準治療，但目前仍有兩個爭議的焦點：1、誰是更好的一線藥物（1代，2代，3代？）；2、更好的一線組合是什么。隨著FLAURA研究證實3代藥物奧希替尼對比1代藥物作為一線治療有OS改善的趨勢（注：非主要終點），以及后續(xù)諸如APPLE這樣的研究尚未成熟，一線選藥的爭議暫時偃旗息鼓，而今年ASCO公布的幾項重要結(jié)果，則點燃了對更高維度的抗擊策略的關(guān)注，聯(lián)用抗血管、化療以及其他具有抗腫瘤活性的藥物進行治療，能否取得更優(yōu)的治療效果？數(shù)據(jù)非常值得深入探討。

一線聯(lián)合抗血管治療

JO25567是首個研究在TKI基礎(chǔ)上加上抗血管治療的II期臨床試驗，對比貝伐單抗聯(lián)合厄洛替尼對比厄洛替尼單藥一線治療EGFR突變的晚期非鱗非小細胞肺癌患者，2014年ASCO已經(jīng)公布了PFS結(jié)果具有優(yōu)勢，中位PFS 從9.7個月顯著延長到16個月，ORR為聯(lián)合治療組65%對比單藥組62%，但此次ASCO公布的最終OS結(jié)果，則顯示BE聯(lián)合組在OS上與單藥厄洛替尼相比未表現(xiàn)出與PFS類似的優(yōu)勢，BE組 47.0 個月對比單藥組 47.4 個月 (HR, 0.81，p = 0.3267），單藥組后續(xù)治療中安維汀暴露情況只有8%（交叉效應對OS的影響甚微）。今年ASCO公布的后續(xù)III期研究NEJ026，比較貝伐單抗聯(lián)合厄洛替尼與厄洛替尼單藥治EGFR突變的晚期NSCLC患者，結(jié)果顯示BE聯(lián)合方案（貝伐單抗聯(lián)合厄洛替尼）可以提高療效且毒性耐受，ORR為72.3 %對比66.1%，PFS 為16.9個月對比13.3個 月，P = 0.0157。兩個研究基本已經(jīng)坐實了TKI一線聯(lián)合抗血管的PFS獲益，提示TKI聯(lián)合抗血管是一個非常具有潛力的一線治療策略。值得一提的是，今年張力教授課題組趙洪云教授公布的雙靶組合研究方案，一線吉非替尼聯(lián)合多靶點VEGFR抑制劑阿帕替尼對比吉非替尼單藥的隨機對照試驗，也是基于TKI聯(lián)合抗血管治療的原理，阿帕替尼還有其他靶點的抑制作用，而且由于都是口服藥物，實際應用更方便，非常期待最終結(jié)果，以及與TKI聯(lián)合貝伐單抗之間的對比。

NEJ026設(shè)計及結(jié)果

JO25567最終OS分析

一線聯(lián)合化療

至于聯(lián)合化療，此前發(fā)表的評估吉非替尼+培美曲塞相對吉非替尼單藥一線治療EGFR突變患者的II期對照試驗JMIT顯示，聯(lián)合組的中位PFS相對吉非替尼單藥組顯著延長近5個月（15.8月 vs 10.9月，HR=0.68，95% CI 0.48-0.96, P=0.029），兩組ORR相近（80% vs. 74%），而聯(lián)合治療組的DOR較單藥組延長4.1個月，而OS尚未公布。今年ASCO公布的III期試驗NEJ009，則研究了聯(lián)合卡鉑+培美曲塞的治療模式，該研究的結(jié)果顯示ORR為84.0 %對比67.4%，聯(lián)合組一線中位PFS為20.9個月，相比單藥組一線11.2個月的PFS有提高，但略低于單藥組耐藥后換化療的21.1個月的總PFS（PFS2），聯(lián)合組OS有明顯改善（52.2 月vs 38.8 月, HR 0.695, P =0.013）。

NEJ009設(shè)計及結(jié)果

一線聯(lián)合其他抗腫瘤活性藥物治療

壁報展示環(huán)節(jié)報告了一些有趣的嘗試：一項隨機對照II期臨床試驗在EGFR-TKI基礎(chǔ)上加入二甲雙胍，聯(lián)合組PFS明顯提高，14.0月 vs 10.0月， p = 0.017，ORR分別為67.4% vs. 47.5%，p = 0.044，OS分別為27.2月 vs. 19.0月，P= 0.015；另外一個II期RCT研究(GOAL研究)，吉非替尼聯(lián)合奧拉帕利并沒有明顯提高PFS，吉非替尼單藥組和吉非替尼聯(lián)合奧拉帕利組的中位PFS分別為10.4個月和12.8個月，P=0.329；ORR分別為68%及78%。

聯(lián)合免疫檢查點治療？

由于EGFR敏感突變抗原性弱，屬于典型的冷腫瘤，因此免疫檢查點單藥效果不佳。今年ASCO沒有一線聯(lián)合免疫檢查點抑制劑的研究，但有一項壁報討論再次顯示，在EGFR+的患者中，即便是PD-L1高于50%的人群，一線Pembrolizumab（PD-1單抗）的療效也不理想，在入組11個病人后，僅有1人顯示出療效（ORR=9%），入組中止。然而，這里需要強調(diào)的是，免疫檢查點抑制劑單藥治療EGFR突變患者不可取，但并非沒有用，在Impower150的亞組分析中，發(fā)現(xiàn)Atezolizumab（PD-L1單抗）+貝伐單抗+TC化療的治療方案，在EGFR+/ALK+靶向治療失敗后的人群中，明顯優(yōu)于貝伐單抗+TC化療，顯示了免疫檢查點抑制劑對EGFR突變?nèi)巳旱膬r值，也就是說，在聯(lián)合其他治療將冷腫瘤的狀態(tài)轉(zhuǎn)換成熱腫瘤之后，免疫檢查點抑制劑仍然能發(fā)揮作用。但值得注意的是，免疫治療聯(lián)合對應的TKI需要非常慎重，因為此前公布的PD-L1單抗聯(lián)合AZD9291以及PD-1單抗聯(lián)合克唑替尼均發(fā)生很強的疊加毒性。目前來看，靶向治療仍然是EGFR突變?nèi)巳旱氖走x，當靶向治療失敗后，在化療的基礎(chǔ)上加上免疫檢查點抑制劑作為挽救治療可能是更合理的使用模式。

Impower150驅(qū)動基因陽性亞組分析

專家點評

梁文華副教授

廣州醫(yī)科大學附屬第一醫(yī)院腫瘤科主任助理，碩士生導師

呼吸疾病國家重點實驗室/國家臨床醫(yī)學中心肺癌學組骨干及組長助理

廣東省胸部疾病學會秘書長及免疫治療專委會主任委員

中國臨床腫瘤學會（CSCO）青年委員、肺癌專委會委員

CSCO “全國35位最具潛力青年腫瘤醫(yī)生”

Transl Lung Cancer Res雜志副主編

J Thoracic Dis及Ann Transl Med雜志編委

ASCO Merit Award、IASLC Mentorship Award獲得者

EGFR突變?nèi)巳旱囊痪€治療要不要聯(lián)合抗血管或者化療等常規(guī)治療手段？從目前緩解率、退縮深度以及PFS數(shù)據(jù)來看，聯(lián)合抗血管或者化療獲益的主要機理是更大限度降低腫瘤負荷和異質(zhì)性儲備（使有效的更有效），從而延長緩解時間，即延緩耐藥的發(fā)生來延長PFS，此外聯(lián)合化療也能夠增加緩解人群（使一部分無效的變成有效，比如對TKI原發(fā)耐藥的患者）。盡管一線PFS數(shù)據(jù)喜人，但仍需確認OS的獲益，因為化療和抗血管都屬于耐藥后的常規(guī)治療選擇，將后備手段往前提，會減少一個挽救措施，同時相當于延長了后備手段的使用時間，考慮治療成本和毒性的增加，疊加的治療理應要能改變腫瘤的生物學行為從而延長總生存，因此應該使用OS作為主要終點，越來越多的證據(jù)顯示，后續(xù)治療的交叉不是解釋OS“失敗”的主要原因，如果一種治療方式能夠明顯改變腫瘤的生物學進程，一線治療對OS是起到?jīng)Q定性作用的。因此，目前來看，只有化療在將OS作為主要終點的III期研究中取得了陽性結(jié)果（NEJ009），而抗血管則未證實能夠改善OS，這個可能和上述的化療的雙重作用有關(guān)，當然我們還希望看到更多的試驗來佐證，并探索真正有必要添加化療的人群，比如合并原發(fā)耐藥機制。而對于其他藥物，目前我們還沒有足夠證據(jù)改變臨床常規(guī)，加入其它理論上具有協(xié)同作用的藥物是一種不錯的加法選擇，二甲雙胍和奧拉帕利 均提示能提高緩解率及增加有效人群，但要注意的是，聯(lián)合二甲雙胍盡管能改善PFS甚至OS，目前只是II期研究，也并未雙盲，因此需要III期安慰劑對照研究的證實，而奧拉帕利和PD-1的“失敗”，可能在于獲益人群未能明確而且在總?cè)巳褐斜壤^低，PD-1更是需要選擇合理的應用場景（比如聯(lián)合化療而非TKI）。聯(lián)合治療有非常廣闊的空間，多樣化的藥物和使用策略，可以讓我們的治療變得豐滿，與此同時，深入探究每種治療的真正獲益人群和使用時機，對試驗設(shè)計和合理使用都非常關(guān)鍵。

摘要原文

9006 Oral Abstract Session, Mon, 3:00 PM-6:00 PM

Phase III study comparing bevaCIzumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026.

Background: Development of treatment for EGFR-mutated non-small-cell lung cancer (NSCLC) had been focused on monotherapy of gefitinib, erlotinib, or afatinib. Combinations of EGFR-TKIs and VEGF inhibitors are one of candidates for next strategy for EGFR-mutated tumor. We conducted a phase III study comparing BE to E. Methods: Chemotherapy-naive pts with advanced non-squamous NSCLC harboring EGFR-mutation were randomly assigned to receive either combination with erlotinib (150mg daily) plus bevacizumab (15mg/kg iv q3w) or erlotinib (150 mg daily). Status of EGFR mutations in plasma samples were monitored routinely during the study treatment and a second-line treatment. The primary endpoint was PFS. Secondary endpoints were OS, RR, safety, and QoL. We hypothesized that hazard ratio of PFS was 0.63. It was estimated that 147events would be needed for the study to have a power of 80% and a two-sided significance level of 5%. Accordingly, this study was planned to enroll 214 pts in total. Results: Between Jun 3, 2015, and Aug 31, 2016,228 pts with EGFR mutations were enrolled. There were one cessation prior to the study treatment and onewithdrawal of consent; the remaining 226 pts were assigned to BE (n = 112) and E (n = 114). The interimanalysispreplanned was performed at 117 PFS events using full analysis set of 224 pts except for both an ineligible caseand a case lost to follow-up in E. Pts were followed up for a median of 12.4 months. The interimanalysis showedthat the study met its primary endpoint. At data cutoff (Sept 21, 2017), median PFS was 16.9 months (95% CI14.2-21.0) in BE and 13.3 months ) in E (p = 0.0157) (HR 0.605, 95% CI 0.417-0.877). Thoughhemorrhage, proteinuria, and hypertension as toxicities significantly increased in BE compared to in E, there wasno significant difference among other toxicities between BE and E. Five cases had low-grade pneumonitis in Ebut no pneumonitis inBE. There was no treatment-related dea: In this study, BEas a combinationofEGFR-TKIs andVEGF inhibitors achieved durable response and good tolerability. This regimen is consideredas a new standard treatment in EGFR-mutated NSCLC. Clinical trial information: UMIN000017069.

9005 Oral Abstract Session, Mon, 3:00 PM-6:00 PM

Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009).

Background: Although EGFR-TKI alone has been a standard first-line treatment for pts with advancedNSCLC with EGFR mutations, our phase II study (NEJ005) showed promising efficacy of GCP. NEJ009, anopen-label, randomized phase III study, was conducted to evaluate the superiority of GCP vs G in progressionfreesurvival (PFS), PFS2, and overall survival (OS). Methods: Pts with newly diagnosed stage III/IV/recurrent NSCLC harboring an EGFR activating mutations (exon 19 deletion or exon 21 L858R) wererandomized 1:1 to G 250 mg PO QD or GCP (G 250mg PO QD combined with carboplatin AUC 5 +pemetrexed 500mg/m2, every 3 weeks). The primary endpoints consisting of PFS, PFS2, and OS weresequentially analyzed according to a preplanned gate-keeping method. Secondary endpoints includedobjective response rate, safety, and quality of life. Results: In September 2017, a preplanned required numberof events of PFS2 was observed. The ITT population included 344 pts with baseline characteristics fairly wellbalanced between the arms. Although GCP demonstrated significantly better PFS compared to G, there was nodifference in PFS2 between the arms as below. Additional OS analysis (G:101 events vs GCP:83 events)revealed that median survival time of GCP was much longer than that of G months vs 38.8 months, HR:0.695, p = 0.013). Conclusions: NEJ009 was the first phase III study which evaluated the efficacy of acombination of EGFR-TKI and platinum doublet chemotherapy in untreated advanced NSCLC pts with EGFRmutations. Although GCP regimen failed to demonstrate its superiority in PFS2, it may increase long Population GCP (N = 169) G (N = 172) Median (months) Median (months) HR PFS 20.9 11.2 0.493 [95%CI: 18.0, 24.2] [95%CI: 9.0, 13.4] [95%CI: 0.390, 0.623] P,0.001 PFS2 20.9 21.1 0.891 [95%CI: 18.0, 24.2][95%CI: 17.9, 24.9] [95%CI: 0.708, 1.122] P = 0.806.

9013 Poster Discussion Session; Displayed in Poster Session (Board #336), Sun, 8:00 AM-11:30 AM, Discussed in Poster Discussion Session, Sun, 11:30 AM-12:45 PM

Combination of metformin plus TKI vs. TKI alone in EGFR(+) LUNG adenocarcinoma: A randomized phase II study.

Background: Metformin has been shown to have antitumor activity by increasing AMPK through differentmechanisms involving tumor suppressor gene, LKB1. LKB1 inactivation is common in Non-small cell lungcancer (NSCLC) and is associated with a more aggressive clinical phenotype. Retrospective studies haveshown that metformin could effectively increase the sensitivity to TKIs in NSCLC, thus improving ProgressionFree Survival (PFS) and potentially impacting Overall Survival (OS) in these patients. We compared the effectof metformin in combination with EGFR-TKI versus TKIs alone on the clinical prognosis of adenocarcinomapatients with EGFR mutations. Methods: In this phase 2 clinical trial (NCT03071705) we randomly assigned116 patients with stage IV EGFR-mutated lung adenocarcinoma to receive therapy with metformin + EGFRTKI(M+TKI) (n = 49) or EGFR-TKI (TKI) alone (n = 67). TKI was chosen upon clinician’s di were excluded if they had a history of diabetes or had received therapy with metformin or TKIs ( . 2cycles) previous to enrollment. The primary endpoint was PFS, secondary endpoints included objectiveresponse rate (ORR), disease control rate (DCR) and OS. Results: Baseline characteristics were well balancedbetween treatment arms. Mean patient follow up was 12.9 ) months. Median PFS was significantlylonger for patients receiving M+TKI compared to those who received TKI months vs. 10.0 months; p =0.017) . ORR was higher in the experimental arm of the trial, compared to the control group (67.4% vs. 47.5%; p = 0.044), although, the DCR was similar in the two groups (97% vs. 88.5%; p = 0.085). Median OS wa months. Patients receiving M+TKI had a longer OS compared to those receiving TKI months vs.19.0 months, p = 0.015). Multivariate analysis showed that, among others, the therapeutic arm (M+TKI vs.TKI) is an independently associated factor for both PFS and OS. Conclusions: Our study strongly suggests thatthe addition of Metformin to standard EGFR-TKI therapy has a significant effect in PFS, ORR and OS ofpatients with EGFR-mutated NSCLC. Metformin use is a safe and efficacious addition to the therapeuticscheme of EGFR+ NSCLC. Clinical trial information: NCT03071705.

9012 Poster Discussion Session; Displayed in Poster Session (Board #335), Sun, 8:00 AM-11:30 AM, Discussed in Poster Discussion Session, Sun, 11:30 AM-12:45 PM

Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A randomized phase 2 study (GOAL, Spanish Lung Cancer Group).

Background: Low BRCA1 mRNA levels correlate with longer progression free survival (PFS) in erlotinibtreated EGFR mutant NSCLC patients (p), while risk of shortened PFS was associated with intermediate/highBRCA1 levels (HR, 8.46; P,0.0001). We explored the combination of the poly (ADP-ribose) polymerase(PARP) inhibitor, olaparib with gefitinib in EGFR mutant NSCLC p. In a previous phase 1 trial, the safety ofthe combination was confirmed. Recommended phase 2 dose (RP2D) is gefitinib, 250 mg daily, and olaparib,200 mg thrice daily. Methods: Stage IV treatment na¨?ve NSCLC p with centrally confirmed EGFR mutationsand measurable disease were recruited in the study (NCT01513174). We randomly allocated p (1:1) to receivegefitinib 250 mg daily or the combination at the RP2D. The primary endpoint was PFS. PFS related to BRCA1mRNA was a secondary endpoint, and 53BP1 and enhancer of zeste homolog 2 (EZH2) were analyzed asmodulators of BRCA1, overall survival (OS), response rate (RR), safety and tolerability. Target accrual was186 p. This sample provided 80% power to detect HR of 0.63 after 116 PFS events. The first PFS analysis, sideeffect profile and RR had a February 28th, 2018 cut-off, minimum follow-up of 18 months (mo). Results: Ofthe 182 p who underwent randomization, 91 received gefitinib and 91 received gefitinib+olaparib, with nodifferences in gender, age, never smoker, performance status, bone or brain metastases or EGFR mu PFS for exon 19 deletions and exon 21 L858R EGFR mutations was 10.4 mo for gefitinib group and12.8 mo for gefitinib + olaparib group (HR for disease progression or death, 0.83; P=0.329). RR was 68% ingefitinib group and 78% in gefitinib + olaparib group. Conclusions: The gefitinib+olaparib combination didnot provide significant benefit over gefitinib alone. Median PFS was 2.4mo longer for the combination and riskof disease progression or death was 17% lower with gefitinib+olaparib than gefitinib alone. The pre-specifiedassessment of BRCA1, 53BP1 and EZH2 could determine if a subgroup of p might obtain major benefit fromthe combination. Clinical trial information: NCT01513174.

9014 Poster Discussion Session; Displayed in Poster Session (Board #337), Sun, 8:00 AM-11:30 AM, Discussed in Poster Discussion Session,Sun，11:30 AM-12:45 PM

A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor (TKI) na¨?ve patients with advanced NSCLC.

Background: Despite the significant antitumor activity of pembrolizumab in non-small cell lung cancer(NSCLC), clinical benefit has been less frequently observed in patients whose tumors harbor epidermal growthfactor receptor (EGFR) mutations compared to EGFR wild-type patients. Our single center experience on theKEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinaseinhibitor (TKI) na¨?ve, had superior clinical outcomes to those previously treated with a TKI. As TKI na¨?veEGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisionsin this patient population is lacking, particularly in patients with PD-L1 expression $50%. Methods: Weconducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutationpositive, advanced NSCLC and PD-L1 positive ($1%, 22C3 antibody) tumors. Pembrolizumab wasadministered 200mg q3wks. The primary endpoint was objective response rate. Secondary endpoints includedsafety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFRTKI after pembrolizumab. Results: Enrollment was ceased due to lack of efficacy after 11 of 25 plannedpatients were treated. 82% of trial patients were treatment na¨?ve, 64% had sensitizing EGFR mutations, and73% had PD-L1 expression$50%. Only 1 patient had an objective response (ORR: 9%), but repeat analysis ofthis patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observedtreatment related adverse events were similar to prior experience with pembrolizumab, but two deaths within6 months of enrollment, including one attributed to pneumonitis, were of concern. Conclusions: Pembrolizumab’slack of efficacy in TKI na¨?ve, PD-L1+, EGFR-mutant patients with advanced NSCLC, includingthose with PD-L1 expression $50%, suggests that it is not an appropriate therapeutic choice in this trial information: NCT02879994.

版權(quán)聲明

版權(quán)屬腫瘤資訊所有。歡迎個人轉(zhuǎn)發(fā)分享，其他任何媒體、網(wǎng)站如需轉(zhuǎn)載或引用本網(wǎng)版權(quán)所有內(nèi)容，須獲得授權(quán)，且在醒目位置處注明“轉(zhuǎn)自：良醫(yī)匯-腫瘤醫(yī)生APP”。