TKI加化疗:能改善EGFR突变阳性NSCLC患者的一线治疗吗?

AME AME科研时间 2018-11-13

Francesco Passiglia, Antonio Russo


Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy


Correspondence to:Antonio Russo, MD, PhD.Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Via del Vespro 129 – 90127, Palermo, Italy.Email:antonio.russo@usa.net.


Provenanc:This is an invited Editorial commissioned by Section Editor Shaohua Cui (Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China).


Comment on:Cheng Y, Murakami H, Yang PC, et al.Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations.J Clin Oncol 2016;34:3258-66


Submitted Dec 01, 2016.Accepted for publication Dec 15, 2016. doi:10.21037/tcr.2016.12.32


View this article at:

http://dx.doi.org/10.21037/tcr.2016.12.32


近期,程颖等在《临床肿瘤学杂志》(Journal of Clinical Oncology)上报道了一项II期随机试验的结果[1]。该研究比较了培美曲塞联合吉非替尼与吉非替尼单药治疗表皮生长因子受体(EGFR)敏感突变东亚晚期非鳞非小细胞肺癌(NSCLC)初治患者的疗效。该研究在意向治疗人群中达到其主要终点。无进展生存期(PFS)在联合治疗组(15.8个月)显著长于单药组(10.9个月)[危险比(HR):0.68;95%CI:0.48~0.96;单侧P=0.01;双侧P=0.029]。PFS的显著改善与特定的突变类型无关(EGFR外显子19缺失 vs EGFR外显子21L858R点突变)。此外,吉非替尼加培美曲塞也显著延长了疾病进展时间(16.2个月 vs 10.9个月;HR:0.66;95%CI:0.47~0.93)和缓解期(15.4个月 vs 11.3个月;HR:0.74;95%CI:0.50~1.08),但两组间的缓解率无差异(RR:80% vs.74%)。联合治疗组中报告3~4级药物不良事件(AEs)的患者所占比例显著高于单药组(42% vs 19%),因AEs而停止治疗的患者占比在联合治疗组接近单药组的一倍。


之前有一些随机III期试验[2-10]指出,对于EGFR突变阳性NSCLC患者,EGFR-酪氨酸激酶抑制剂(TKI)可显著改善RR、PFS和生活质量(QoL)(与含铂双药化疗作为一线治疗相比)。此后,对LuxLung3和LuxLung6试验的汇总分析也表明,即使EGFR-TKI阿法替尼(afatinib)仅限于治疗EGFR外显子19缺失的患者亚组,也能达到更高的总体存活率(OS)[9]。总体来看,所有这些研究的结果令人信服地证明,对于有EGFR激活突变的NSCLC患者亚组,最佳的策略是首先以EGFR-TKI进行治疗,其中可包括吉非替尼、厄洛替尼或阿法替尼[11,12]。程颖等[1]开展的试验表明,EGFR-TKI加化疗可进一步改善EGFR突变非鳞NSCLC患者的转归。


临床前研究显示,EGFR-TKI、厄洛替尼和多靶点叶酸拮抗剂培美曲塞对于NSCLC细胞系具有潜在的协同作用[13,14]。这种协同作用的分子机制可包括对EGFR和Akt磷酸化的调节,也可包括胸苷酸合成酶(TS)在所有NSCLC细胞中的表达和活性均显著降低。随后,一些I~II期研究显示,EGFR-TKI+培美曲塞联合治疗经治NSCLC患者具有良好的活性和耐受的安全性[15];与临床选定的不吸烟非鳞癌患者中单用两种药物相比,该联合疗法可显著延长PFS[16]


数项III期研究探讨了EGFR-TKI联用化疗作为一线治疗的疗效[17-20],并未发现这些联合疗法在存活期方面有何效益,这可能是因为在研究过程中纳入了野生型患者。其中,CALGB30406研究[21]评价了厄洛替尼联用或未联用含铂化疗的疗效。受试者系临床选择的晚期肺腺癌患者,无吸烟史或既往系轻度吸烟者;在总体研究人群中两个治疗组间疗效相似。随后的EGFR突变分析表明,EGFR突变阳性肿瘤患者最有可能受益,厄洛替尼单药组中位PFS达14.1个月,OS为31.3个月;厄洛替尼+含铂化疗则更高(PFS 17.2个月,OS为38.1个月)。这些数据表明,EGFR TKIs同步联合化疗可改善特定分子学亚组患者的生存期。类似地,FASTACT2随机III期研究[22]也显示,化疗+厄洛替尼序贯联用可延长EGFR突变阳性NSCLC患者的生存期。


最近,NEJ005随机II期研究[23]前瞻性地比较了EGFR突变阳性的东亚NSCLC患者吉非替尼+卡铂/培美曲塞同期用药方案与序贯交替用药方案。研究结果显示,同期用药组PFS呈现较佳趋势(18.3个月 vs 15.3个月;HR:0.71;95%CI,0.42-1.20;P=0.20),OS则有显著改善(41.9个月 vs 30.7个月;HR:0.51;95%CI,0.26 - 0.99;P=0.042)。该研究首次证实了吉非替尼+卡铂/培美曲塞起始联合的优势,目前正在III期NEJ009研究中作一步探讨。程颖等[1]的试验表明,在一线治疗中,EGFR-TKI加单药化疗可能足以改善EGFR突变患者的转归。这一发现引人瞩目,但需要结合近期的NEJO5研究进行解读。两项研究均发现PFS有所改善;与先前在EGFR突变阳性NSCLC患者中单用吉非替尼一线治疗的研究中所观察到的9~10个月的PFS[2]相比,也更具优势。这可能与及早同期使用细胞毒药物对抗原发性耐药有关;不过,由于未采集组织标本用于生物标记物分析,我们很难评估分子学数据。不过,我们也应探讨培美曲塞加用吉非替尼后是否有助于延长OS。的确,OS的改善有助于我们评估此类患者的最佳治疗顺序,并最终接受潜在的起始联合治疗可能带来的不良事件和成本。虽然作者宣称“含铂疗法在疾病进展后仍可使用”,但实验组中的患者将永远不会接受标准的治疗方案(即铂类-培美曲塞联合疗法,继以培美曲塞维持疗法)[24],这可对患者最终的OS构成不利影响。


此外,鉴于本领域其他有前景的治疗方案还在不断出现,我们需要讨论化疗+吉非替尼联合疗法的临床获益。


在东亚EGFR突变阳性NSCLC患者中,在EGFR-TKI(厄洛替尼)中加入贝伐单抗后,患者中位PFS可达16个月,显著高于厄洛替尼单药组(9.7个月);同时,疾病进展风险显著降低了50% [HR:0.54(0.36–0.79)][25]。虽然针对亚洲人群和高加索人群的随机III期研究仍在进行中,这一联合用药策略最近已被美国食品和药物管理局(FDA)和欧洲医疗机构(EMA)批准用于一线治疗。来自AURA Ⅰ期试验[26]一线队列的数据尤其令人兴奋,因其显示第三代EGFR TKI奥希替尼具有令人印象深刻的活性:其中位PFS达19个月,ORR为77%;在此基础了开展了III期随机FLUROA试验,对奥希替尼vs吉非替尼/厄洛替尼一线用药进行比较。尽管用抗PD1/PDL1单药进行免疫治疗似乎对携带EGFR突变的非小细胞肺癌无效[27],但是目前一些试验正在探讨免疫检查点抑制剂与EGFR-TKI的潜在组合,以进一步改善患者预后。


总之,程颖等的研究是改善EGFR突变阳性NSCLC患者一线治疗的一次极有意义的尝试。该方案可延长PFS,而药物毒性仅有适度增加,表明在EGFR-TKI中加入化疗可能是对此类患者的有效治疗方法。然而,如前所述,为确定培美曲塞和吉非替尼起始联合治疗的有效性,应明确其在改善OS方面的效益。最后,考虑到有前景的新药/新联合方案层出不群,我们所面临床的一项主要挑战是:如何联用所有这些药物并最终确定EGFR突变阳性NSCLC患者的最佳治疗顺序。


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