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通讯作者:

张鹏(1979-),男,河北沧州人,博士生导师,主要从事肺癌的复发转移和免疫机制研究。E-mail:zhangpeng1121@tongji.edu.cn;

章靖,张乐乐为共同第一作者

中图分类号:R734.2,R730.51

文献标识码:A

文章编号:2096-8965(2021)04-0019-08

DOI:10.12287/j.issn.2096-8965.20210403

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目录contents

    摘要

    肺癌的发病率和死亡率普遍较高,严重威胁大众身体健康。近年来,免疫检查点抑制剂的出现给晚期非小细胞肺癌的治疗带来了新的希望。结合理论基础,科学家推测非小细胞肺癌患者可能受益于新辅助免疫治疗。随着研究的深入, 发现新辅助免疫治疗非小细胞肺癌具有较高的安全性和可行性,并可获得振奋人心的病理缓解率。但目前仍存在缺乏远期预后,以及尚未明确潜在受益人群、合理的治疗方案和疗程等问题。本文对新辅助免疫治疗非小细胞肺癌的发展过程、作用机制、研究现状以及与治疗相关的挑战进行综述。

    Abstract

    The morbidity and mortality of lung cancer rank higher, which seriously threatens public health. Recently, the emergence of immune checkpoint inhibitors has brought bright light for the treatment of advanced non-small cell lung cancer (NSCLC). Based on the theoretical basis, it is speculated that NSCLC may benefit from neoadjuvant immunotherapy. With the development of various studies, it is demonstrated that neoadjuvant immu‐ notherapy for NSCLC is safe and feasible, and can contribute greatly to the exciting outcome of pathological re‐ sponse. However, current results do not contain long-term prognosis, distinguish potential beneficiaries, develop a rational therapeutic regimen and course, and so on. In this review, we will conclude the development processes, molecular mechanisms, current research status and treatment-related challenges of neoadjuvant immunotherapy for NSCLC.

  • 在全球范围内,肺癌每年的发病率和死亡率均位居恶性肿瘤前列。GLOBOCAN 2020数据显示,肺癌每年新发约220万患者 (11.4%),仅次于乳腺癌发病人数;因肺癌死亡人数约180万 (18%),位居恶性肿瘤死亡人数第一 (发病率第二) [1]。而在我国,肺癌的发病率和因肺癌而死亡的人数均位居癌症第一,每年约新发73.3万人,死亡61万人[2]。其中非小细胞肺癌 (Non-Small Cell Lung Cancer,NSCLC) 是肺癌的主要亚型,约占全部肺癌的85%。针对Ⅰ、Ⅱ期和局部晚期的NSCLC患者,手术切除或联合放化疗是目前首选的治疗方式,但仍存在整体有效率较低的问题。近年来,免疫药物治疗在晚期NSCLC患者中取得了振奋人心的成效,并逐步革新了肺癌的治疗模式。此外,越来越多的证据提示,新辅助免疫治疗联合手术治疗可能提高患者的预后。本文拟对NSCLC的新辅助免疫治疗的发展过程、作用机制、治疗方案、以及面临的挑战和前景等方面进行总结,期望为相关临床试验提供借鉴。

  • 1 新辅助免疫治疗NSCLC的发展过程

  • 在探索肿瘤治疗方案的过程中,Frei[3] 提出了 “新辅助治疗”这一概念,期望通过术前化疗、靶向治疗、放疗等方案,缩小肿瘤体积,进而提高根治性手术切除的机会;期望消除潜在的微小转移病灶,进而减少复发转移风险,改善患者的预后。后续的研究揭示,与单纯手术治疗相比,新辅助化疗联合手术治疗可提高NSCLC患者的预后,但5年生存率仅提高了5%,仍低于50%[4]。随着治疗理念的更新和技术的发展,人们意识到免疫治疗可通过 “唤醒”自身免疫,达到清除肿瘤细胞的目的。为此,科学家和临床医师进行了肿瘤疫苗、免疫细胞疗法、免疫检查点抑制剂 (Immune Checkpoint In⁃ hibitors,ICI) 等免疫治疗的探索。

  • 肿瘤疫苗主要包括树突状细胞疫苗或与肿瘤相关的抗原疫苗等,通过主动免疫激活放大患者体内的抗肿瘤免疫反应,进而期望取得较好的治疗效果[5]。然而,研究发现辅助治疗使用肿瘤特异性抗原MAGE-A3 (MAGE Family Member A3) 疫苗后, NSCLC患者的无病生存期并未获益,此外,后续关于MAGE-A3疫苗在NSCLC中的应用研究也被叫停[6]。免疫细胞疗法通过收集患者外周血中的免疫细胞,体外编辑、激活并回输,从而对肿瘤细胞进行杀伤,但目前的免疫细胞疗法对实体肿瘤治疗欠佳[7]

  • 常见的免疫检查点包括程序性凋亡受体1 (Programmed Death 1,PD-1), 程序性凋亡配体1 (Programmed Death 1Ligand 1,PD-L1)、含Ig及ITIM结构域的T细胞免疫受体 (T Cell Immunore⁃ ceptor with Ig and ITIM Domains,TIGIT)、细胞毒性T淋巴细胞抗原4 (Cytotoxic T LymphocyteAssociated Antigen-4,CTLA-4) 等。近年来,围绕着免疫检查点,科学家研制出相关的ICI,并在黑色素瘤、肝癌、肺癌等多种实体肿瘤的治疗中取得了良好疗效[8]。在探索NSCLC治疗方案的过程中,ICI免疫治疗已经从晚期NSCLC的二线方案走向一线治疗方案[9-13]。此外,研究者发现,使用新辅助免疫治疗可切除NSCLC后,患者的主要病理缓解率 (Major Pathological Response,MPR)(即肿瘤或淋巴结中残余肿瘤细胞少于10%) 可达45%; 完全病理缓解率 (pathological Complete Response, pCR)(即肿瘤或淋巴结中未发现残余肿瘤细胞) 为15%,良好的治疗效果为NSCLC患者的治疗提供了新的思路[14]。本文将介绍ICI在NSCLC新辅助免疫治疗中的机制及其作用。

  • 2 新辅助免疫治疗NSCLC的作用机制

  • 2.1 新辅助免疫作用机制

  • 人体的免疫系统在肿瘤的免疫治疗过程中扮演着重要角色。当机体细胞基因突变累积形成肿瘤细胞后,可引发人体的巨噬细胞、自然杀伤细胞等固有免疫细胞介导的先天性免疫反应;也可依赖抗原提呈细胞 (如巨噬细胞、树突状细胞),提呈肿瘤抗原,进而激活T细胞和B细胞等,介导适应性免疫[15]。然而肿瘤细胞可通过负性共刺激分子PD-1、 PD-L1、TIGIT、CTLA-4等抑制免疫细胞,形成免疫抑制微环境,进而逃逸机体免疫细胞监控[16]

  • 逃逸的肿瘤细胞具有较强的免疫适应性。相比于辅助免疫治疗,新辅助免疫治疗的患者,肿瘤区域内血管和淋巴结结构更完整,新辅助免疫治疗可更好地激活免疫细胞,杀伤肿瘤细胞;此外,新辅助免疫治疗还可更好地激活免疫细胞识别特异性肿瘤抗原,后续原发肿瘤切除后,机体内仍存在特异性抗肿瘤的T细胞和B细胞,进而建立长久的免疫记忆,消除潜在转移灶,提高治愈率。为比较辅助免疫和新辅助免疫治疗的特点,Liu等[17] 学者利用两种自发性转移性乳腺癌小鼠模型进行体内验证,结果显示新辅助免疫治疗可更好地清除远处转移,提高小鼠生存期;此外,新辅助免疫治疗后,小鼠的外周血中以及转移的组织器官中 (肺、肝脏) 特异性CD8+ T细胞具有记忆细胞特性,且比例显著提高。上述结果提示,与辅助免疫治疗相比,新辅助免疫治疗可提高机体的免疫功能,进而获得更明显、更持久的疗效,达到长期生存获益,但具体结果仍有待于进一步临床试验验证。

  • 2.2 新辅助免疫联合化疗作用机制

  • 化疗是恶性肿瘤的传统治疗方式之一。通过化疗,可以杀死肿瘤细胞,进而降低肿瘤负荷,达到治疗或治愈肿瘤患者的目的。随着新辅助免疫治疗方案的出现,推测新辅助免疫疗法和化疗之间可能存在一定的协同作用。机体经过化疗后,可以导致肿瘤细胞出现更多基因突变,产生新表位,进而增强肿瘤的免疫原性,提高免疫治疗的疗效[18, 19]。此外,某些化疗药物通过引起肿瘤细胞凋亡,释放三磷酸腺苷 (Adenosine-5'-triphosphate,ATP) 招募巨噬细胞和树突状细胞到肿瘤周围,进一步提高机体免疫活性;或化疗药物增加肿瘤细胞的主要组织相容性复合体 (Major Histocompatibility Complex, MHC) Ⅰ的表达或抑制STAT通路活性降低肿瘤细胞PD-L2表达,减少免疫逃逸,促进树突状细胞成熟和T细胞增殖[19]。故新辅助免疫联合化疗方案可能会更好的激活机体免疫,建立长期免疫,取得更好的抗肿瘤疗效。

  • 2.3 新辅助免疫联合放疗作用机制

  • 放疗也是许多肿瘤的标准治疗方式之一。放疗不但可以杀伤抑制性间质细胞,间接提高机体抗肿瘤效应,也可以诱导免疫原性细胞死亡,暴露钙蛋白细胞表面,释放高迁移率蛋白 (High Mobility Group Box 1,HMGB1) 和ATP等免疫刺激成分,激活树突状细胞和效应T细胞,进而提高机体抗肿瘤能力[20]。此外,放疗也可诱导多种促炎细胞因子的表达,如白介素-1β (Interleukin-1β,IL-1β),肿瘤坏死因子α (Tumor Necrosis Factor α,TNFα),引发肿瘤炎性微环境,进而诱导免疫细胞富集[20, 21]。当放疗联合新辅助免疫治疗后,可能会比单药治疗方式取得更好的疗效,具体疗效有待进一步临床试验验证。

  • 3 新辅助免疫治疗NSCLC的现状

  • 判定新辅助免疫治疗NSCLC疗效的金标准是长期生存时间,但由于新辅助免疫治疗的开始时间较短,目前尚缺乏长期预后的研究,影响人们对新辅助免疫治疗效果的判断。Junker等[22] 学者首次定义MPR,并发现获得MPR的患者预后显著提高。随后的研究证明,MPR与患者的预后存在显著正相关性[23],并被认为是长期预后的替代指标[24]。因此,目前的新辅助免疫治疗临床试验一般选择病理缓解率作为主要研究终点,但病理缓解率仍不能完全替代长期生存,其准确性有待检验。本文从病理缓解率角度阐述NSCLC新辅助免疫治疗的疗效及现状。

  • 3.1 新辅助免疫治疗

  • 在自发性肿瘤动物模型中,新辅助免疫治疗的疗效明显优于辅助免疫治疗[17],激发了学者们探索新辅助免疫治疗在NSCLC患者中应用的兴趣,也为后续临床试验 (见表1) 的开展提供了坚实的基础。2018年,Forde等[14] 学者首次报道了新辅助免疫治疗NSCLC的临床试验CheckMate159,揭示了PD-1药物Nivolumab新辅助治疗的安全性和可行性。该试验招募了22例未治疗、可切除的NSCLC (Ⅰ~ⅢA期) 患者,20例患者接受2个周期的Niv⁃ olumab治疗后,行根治性手术治疗,1例患者因3级肺炎,在接受1周期的Nivolumab治疗后,行手术治疗。研究结果也显示,新辅助免疫治疗耐受性良好,相关的副反应仅23%(5/22),其中只有1例有3级不良反应,未出现手术延迟。此外,患者的肿瘤MPR高达45%(9/20),其中3例患者原发肿瘤获得pCR,80%(16/20) 患者术后无复发 (术后中位随访时间为12个月)。在新辅助免疫药物 (Sintilimab) 治疗NSCLC的ⅠB期临床试验中,入组40例ⅠA~ⅢB的NSCLC患者,接受了2周期的Sintilimab药物治疗和治疗前后的PET-CT (Posi⁃ tron Emission Tomography-Computed Tomography) 检查。在这些患者中,10%(4/40) 患者发生3级或以上的不良反应,其中37例行根治性手术治疗,未出现手术延迟,术后病理显示40.5%(15/37) 的患者获得了MPR,其中16.2%(6/37) 的患者达到了pCR,深入分析发现鳞癌患者的病理缓解率优于腺癌 (MPR:48.4%vs 0%),PET-CT结果亦提示MPR与肿瘤代谢摄取值 (Standard Uptake Value, SUV) 降低存在明显正相关性 (Pearson系数为0.86,P<0.000 01) [25]

  • 表1 新辅助免疫治疗可切除NSCLC临床试验汇总

  • LCMC3研究为免疫药物Atezolizumab新辅助治疗NSCLC患者的Ⅱ期临床研究。该研究入组181例未经治疗的ⅠB~ⅢB期可切除NSCLC患者,经过2个周期的Atezolizumab治疗后行手术治疗[26]。研究结果显示,新辅助免疫药物治疗耐受性良好,仅6%的患者术前发生3级或以上的不良反应,未出现手术延迟。在入组的181例患者中, 159例NSCLC (88%) 接受了手术治疗,其中92%(145/159) 患者达到完全切除 (R0),4%(7/159) 和4%(7/159) 的患者接受了R1和R2切除。在159例NSCLC患者中,8%(15/159) 的患者有驱动基因突变,144例NSCLC患者无驱动基因突变。在无驱动基因突变的患者中,30 (21%) 例患者获得了MPR,其中包含10(7%)例患者获得了pCR。Ⅰ~Ⅱ 期患者的1年总生存 (Overall Survival,OS) 率为92%,无病生存 (Disease Free Survival,DFS) 率为85%;Ⅲ期患者的1年OS为95%,DFS为85%。后续分析结果还发现,在PD-L1表达量≥50%的患者中,MPR高达33%,而在PD-L1表达量<50%的患者中,MPR仅有11%(P=0.004) [31]

  • 除了探索新辅助免疫单药治疗NSCLC外[27, 29, 30], NEOSTAR临床试验同时探索了新辅助免疫单药与双免疫药物治疗NSCLC患者的疗效。该试验一共入组44例Ⅰ~ⅢA期NSCLC患者,其中23例患者接受Nivolumab治疗,21例患者同时接受Nivolumab和Ipilimumab治疗。经过新辅助治疗后,两组患者治疗相关的3~4级不良反应率分别为13%(单药组) 和5%(双药组)。此外,39例患者进一步接受了手术治疗 (22例患者接受单药治疗,17例患者接受双药治疗),术后整体MPR率为25%(单药组17%,双药组33%),其中pCR率为18%(单药组9%,双药组29%),提示联合用药可能更优于单药治疗[28]

  • 3.2 新辅助免疫联合化疗

  • 为了探索更好的治疗方案,学者们也研究了免疫药物联合化疗的新辅助治疗方案 (见表2)。 NADIM是第一个探究新辅助免疫联合化疗在可切除NSCLC中疗效的研究,是一项多中心、开放性、 Ⅱ期研究。该研究共入组46例潜在可切除的ⅢA期NSCLC患者,经过3周期的治疗后 (紫杉醇+卡铂+ Nivolumab),14例患者发生治疗相关的3~4级不良反应,但未发生死亡及手术延迟,提示该联合方案的安全性。最终,89%(41/46) 的患者接受了根治手术切除,术后MPR高达83%,其中pCR更是高达59%。此外,术后24个月,患者无进展生存期高达77.1%,进一步证实了新辅助免疫联合化疗在可切除NSCLC中的可行性[32]。另一项新辅助免疫联合化疗 (紫杉醇+卡铂+Atezolizumab) 治疗可切除ⅠB~ⅢA期NSCLC患者的研究,共入组30例患者,其中77%(23/30) 的患者为ⅢA期。经过联合治疗后,发生严重的治疗相关的3~4级不良反应仅为6%,97%(29/30) 的患者接受了肿瘤切除术,其中87%的NSCLC患者行R0切除。术后病理结果发现MPR可达57%,pCR为33%[33]。国内的一项Ⅱ 期新辅助免疫联合化疗治疗潜在可切除NSCLC的研究,共招募33例ⅢA或ⅢB (T3-4N2M0) 期NSCLC患者,经过3周期联合治疗后,常见的治疗相关的3~4级不良反应率为6.1%,而术后MPR和pCR分别为66.7%和50%[34]。本课题组也开展了新辅助抗PD-1药物Sintilimab联合化疗治疗ⅠB~ⅢA期NSCLC患者的临床研究 (ChiCTR1900023758, LungMate001),经过2~4个周期的免疫联合化疗后,最终30例患者接受了手术治疗,术后MPR达到43.3%,pCR分别为20%,治疗相关的3~4级不良反应率仅为8%,相关研究报告正在发表中。

  • 表2 新辅助免疫联合化疗治疗可切除NSCLC临床试验汇总

  • 除上述临床试验外,Ⅲ期临床试验正在探索新辅助免疫联合化疗治疗NSCLC的安全性和可行性 (见表3)。CheckMate816 (NCT02998528) 是一项随机、多中心Ⅲ期临床试验,该试验的主要研究终点是评估Nivolumab联合化疗和单纯化疗组的无事件生存和pCR情况,2021年美国癌症研究协会年会以口头报告的形式发布了最新研究结果。Niv⁃ olumab联合化疗与单纯化疗组相比,3~4级不良事件发生率类似 (41%vs 44%),但Nivolumab联合化疗组患者R0切除却优于单纯化疗组 (83%vs 78%)。术后病理结果发现,在Nivolumab联合化疗治疗组中,24%的患者获得了pCR,36.9%的患者获得了MPR,而在单纯化疗组中,仅有2.2%的患者获得了pCR,8.9%的患者获得了MPR,进一步揭示了新辅助免疫联合化疗的安全性和可行性[35]。此外还有Impower030 (NCT03456063),AEGEAN (NCT03800134),KEYNOTE 671 (NCT03425643), CA209-77T (NCT04025879) 和JS001-029 (NCT04158440) 研究亦为Ⅲ期、随机、双盲临床试验,将分别探索Atezolizumab、Durvalumab、Pembroli⁃ zumab、Nivolumab、Toripalimab联合化疗对比单纯化疗在可切除NSCLC患者新辅助治疗中的疗效。这些临床试验将进一步明确新辅助免疫联合化疗在NSCLC中的作用。

  • 表3 正在进行的新辅助免疫联合化疗的Ⅲ期临床试验

  • Event-Free Survival (EFS):无事件生存率; Overall survival (OS):总生存期

  • 3.3 新辅助免疫联合放疗

  • 此外,人们发现放疗也可能会协同免疫治疗,提高联合治疗的疗效。为此,越来越多的临床试验正在探索新辅助免疫联合放疗在可切除NSCLC中的作用 (见表4),期望为NSCLC患者提供更好的治疗方式。ACTS-30研究是一项单臂的ⅠB期临床试验。该临床试验招募了26例NSCLC患者,其中24例Ⅲ期潜在可切除NSCLC患者符合入组标准,并接受了Durvalumab+化疗+放疗的新辅助治疗方案,与治疗相关的3~4级不良反应为16.7%(4/24),且无治疗相关的死亡,明确了该联合方案的安全性。目前,18例患者已接受手术治疗,术后MPR和pCR分别为77.8%和38.9%,进一步提示了该联合方案具有良好的疗效[36]。类似的,一项随机、单中心、Ⅱ期临床试验 (NCT03217071) 正在进行,该试验将评估Pembrolizumab联合放疗在Ⅰ~ⅢA期NSCLC患者新辅助治疗中的疗效,进一步明确新辅助免疫联合放疗方案的安全性和可行性。

  • 新辅助免疫治疗或免疫联合放化疗治疗可切除NSCLC患者初步取得了不错的研究结果,主要为:(1) 新辅助免疫或者联合治疗的3~4级不良反应率明显低于新辅助或辅助化疗,明确了新辅助免疫治疗的安全性;(2) 新辅助免疫治疗或联合治疗后,肿瘤标本的MPR、pCR明显高于既往新辅助治疗[37],进一步揭示了新辅助免疫治疗的有效性。但目前,新辅助免疫疗法治疗可切除NSCLC仍缺乏长期的生存数据,其确切的疗效仍有待深入探究。

  • 表4 新辅助免疫联合放疗治疗可切除NSCLC临床试验汇总

  • 4 新辅助免疫疗法治疗NSCLC面临的挑战

  • 尽管新辅助免疫疗法在NSCLC的治疗中取得了令人振奋的研究数据,但关于其在临床中的应用仍存在许多问题,有待后续探索。

  • 4.1 新辅助免疫治疗不良反应

  • 新辅助免疫治疗在NSCLC的3~4级不良反应率较低,但仍存在免疫治疗的相关不良反应,一般包括心肌炎、甲状腺炎,肾炎等,其中和肺癌最密切的是免疫性肺炎。免疫性肺炎早期症状不典型,以呼吸困难,干咳为主,部分患者早期并无症状,但影像学可早期发现[38]。考虑免疫性肺炎起病急、进展快,未及时处理可危及患者生命。因此,针对新辅助免疫治疗患者,需要密切关注治疗相关不良反应,做到早发现,早处理。

  • 4.2 新辅助免疫治疗方案

  • 新辅助免疫治疗的方案、疗程等有待进一步验证:目前,新辅助免疫治疗的方案包括免疫药物单药治疗、双免疫药物治疗、免疫药物联合化疗治疗、免疫药物联合放疗、免疫药物联合放化疗以及免疫药物联合抗血管治疗等方案。和传统治疗方案相比,新辅助免疫治疗获得了较高的MPR和pCR,但哪种方案受益最大化,仍需要随机、双盲的Ⅲ期临床试验进行验证。另外,新辅助免疫治疗的疗程也尚未达成共识。目前的治疗方案一般采用2~4个周期的新辅助治疗,大部分患者都顺利接受手术,但极少数患者因免疫相关的不良反应延迟或取消手术,如LCMC3试验中,有1例患者因3级免疫性肺炎延迟了手术时间[31]

  • 4.3 新辅助免疫治疗受益群体

  • 新辅助免疫治疗的主要评价指标为MPR,已报道的研究显示,新辅助免疫治疗的MPR范围为14%~83%。这种情况的产生可能与受益群体的选择有关。既往CheckMate 057、 OAKE和Keynote 010研究的亚组分析提示伴有驱动基因突变的患者不能获益于免疫治疗[10, 11, 39]。为探索可能的潜在受益群体,目前开展的临床研究也在积极推进中。 CheckMate159研究显示,肿瘤突变负荷 (Tumor Mutation Burden, TMB) 与MPR之间存在正相关[14],但LCMC3研究未发现两者存在相关性[31]。此外,LCMC3、NEOSTAR研究发现治疗前高表达PD-L1的患者MPR会更高,但在CheckMate159、 Shu等[14, 15, 31, 33] 的研究中未观察到上述现象。国内研究发现,SUV的降低与MPR存在明显正相关性,鳞癌患者的病理缓解率优于腺癌[25]。为进一步明确新辅助免疫治疗受益群体,我们还需开展相关临床研究进行验证。

  • 4.4 新辅助免疫治疗假性进展与超进展

  • 鉴别新辅助免疫治疗后假性进展与超进展问题:Forde等[14] 学者在CheckMate159临床试验中发现,2例NSCLC患者接受新辅助免疫治疗后,影像学提示肿瘤较治疗前发生增大,术前评估为肿瘤进展。然而术后病理结果提示这2例患者受益于免疫治疗,获得了MPR和pCR。这一现象可能与大量免疫细胞浸润相关。然而,部分患者接受免疫治疗后临床表现为快速进展,即称为超进展[40],这部分患者不能受益于免疫治疗。所以,如何及时、准确的鉴别出假性进展和超进展,并做出合适的治疗措施是亟待解决的问题。

  • 4.5 新辅助免疫治疗手术困境

  • 新辅助免疫治疗对术者的要求:目前大部分新辅助免疫治疗的临床试验主要招募的NSCLC患者为局部晚期,手术具有一定的难度。当患者接受2~4个周期新辅助免疫治疗后,肿瘤周围组织结构会出现黏连水肿,不但提高了组织解剖性分离的难度,也提高了R0切除的难度。因此,针对新辅助免疫治疗的患者,外科医生不但要熟练的掌握手术技巧,也要有泰然自若的心理素质,做到临危不乱。

  • 5 总结与展望

  • 相比于既往的治疗方案,新辅助免疫治疗的出现展示出了良好的安全性、耐受性和更好的MPR和pCR,给NSCLC患者的治疗带来了新的曙光。虽然在探索新辅助免疫治疗的过程中尚未明确潜在的受益人群、合适的治疗方案和疗程等问题,但后续更多的Ⅲ期临床试验将更深层次的进行探讨,为新辅助免疫治疗的规范应用提供坚实的依据。毫无疑问,新辅助免疫治疗的出现,不但提供了新的治疗模式,也将为NSCLC患者带来治疗的希望和胜利的曙光。

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