2025年美国临床肿瘤学年会（2025 ASCO）于5月30日-6月3日在美国芝加哥举行。作为全球规模最大、学术水平最高且最具权威性的临床肿瘤学盛会，ASCO年会汇聚了全球肿瘤学领域的医生、专业人士、患者倡导者、工业界代表以及主流媒体，共同聚焦国际前沿的研究发现与临床试验成果。

 

本届ASCO大会，来自纪念斯隆凯特琳癌症中心（MSKCC）的Jamie E.Chaf教授公布了NeoADAURA研究结果，该研究旨在探索新辅助奥希替尼作为单一疗法或联合化疗与单独化疗在可切除的II-IIIB期EGFRm NSCLC患者中的疗效和安全性。《肿瘤瞭望》特邀Jamie E.Chaf教授现场解读该项研究成果、分享新辅助靶向治疗在肺癌领域探索进展及未来展望。特此整理，以飨读者。

 

 

Neoadjuvant(neoadj)osimertinib(osi)±chemotherapy(CT)vs CT alone in resectable(R)epidermal growth factor receptor-mutated(EGFRm)NSCLC:NeoADAURA.

新辅助奥希替尼（osi）±化疗（CT）对比单纯CT治疗可切除（R）EGFRm NSCLC：NeoADAURA研究

 

Jamie E.Chaft

纪念斯隆凯特琳癌症中心（MSKCC）胸部肿瘤内科医生，专注肺癌治疗，擅长多学科协作制定个性化方案，涵盖手术、放化疗、免疫治疗及靶向治疗。

主持开展多项早期非小细胞肺癌（NSCLC）临床策略探索研究，包括新辅助免疫治疗和生物标志物驱动的精准医疗研究。

 

 

基于III期ADAURA研究结果，奥希替尼——一款三代EGFR-TKI类药物，获批用于EGFR突变的Ib-IIIa期非小细胞肺癌（NSCLC）患者术后辅助治疗。既往研究表明，新辅助治疗可提高手术切除率并可能改善患者长期预后。NeoADAURA研究是一项全球、III期、随机对照、三臂临床研究，旨在评估新辅助奥希替尼±化疗相较于单纯化疗在EGFR突变阳性NSCLC患者的疗效及安全性。

 

 

在这项研究中，患者年龄≥18周岁，PS评分0-1分，患者携带19del或21L858R突变，分期为II-IIIb期（第8版分期）。研究基于分期（II vs.III期）、种族（非亚裔、中国人、其他亚裔）和突变类型（19del vs.21L858R）进行分层。符合入组标准的患者按1:1:1的比例，随机分为奥希替尼80 mg，口服，每日一次，治疗时间超过9周；联合3周期化疗（顺铂或卡铂联合培美曲塞）或超过9周的标准剂量的奥希替尼治疗，或单纯化疗。所有患者均可以接受术后辅助奥希替尼治疗。主要研究终点为独立评审委员会评估的MPR，次要研究终点包括pCR、EFS及安全性。数据随访截止时间2024年10月15日。

 

 

共计358例患者随机分配，奥希替尼联合化疗组、单药奥希替尼组、单纯化疗组分别入组121例，117例和120例患者，基线特点均衡可比。II期患者占比分别为49%、50%和51%；非亚裔患者占比分别为27%、26%和25%；19del患者占比分别为50%、51%和51%。接受新辅助治疗后，分别有92%、97%和89%的患者接受手术治疗。

 

有效性评估中，奥希替尼联合化疗组、单纯奥希替尼组和单纯化疗组的MPR分别为26%、25%和2%；pCR率分别为4%、9%和0%；12个月EFS率分别为93%、95%和83%。EFS中期分析结果（15%成熟度）展示了奥希替尼联合化疗以及单药奥希替尼的获益趋势。三组均有超过80%的患者接受了术后辅助奥希替尼的治疗。

 

 

安全性评估，在新辅助治疗阶段，奥希替尼联合化疗组、单药奥希替尼组、单纯化疗组，≥3级全因不良反应发生率分别为36%、13%和33%，因不良反应而导致治疗终止的比例分别为9%、3%和5%。30天内无患者出现死亡事件。

 

 

新辅助奥希替尼联合或不联合化疗，相较于单纯化疗显著改善了EGFR突变可切除NSCLC患者的MPR。EFS数据并不成熟，但展示了支持含有奥希替尼治疗策略的趋势，没有新的安全性信号出现。对于可手术切除的携带EGFR突变的NSCLC患者，奥希替尼为基础的新辅助治疗策略应当被考虑。

Prof.Jamie E.Chaft：我很荣幸在今年ASCO上分享了Ⅲ期NeoADAURA研究结果，该研究旨在评估在可切除的EGFR突变非小细胞肺癌（NSCLC）患者中，术前新辅助使用奥希替尼联合或不联合化疗对比单纯化疗的疗效。该研究纳入了基线时诊断为可切除的Ⅱ–IIIB期EGFR突变阳性NSCLC患者，随机平均分配至奥希替尼联合化疗组、单药奥希替尼组、单纯化疗组。主要终点是手术时由盲态独立中心评估的主要病理缓解（MPR）。次要终点包括无事件生存期（EFS）、病理完全缓解（pCR）、安全性和耐受性。通过盲态独立评审，含奥希替尼的两组较单纯化疗组在MPR率上均显示出具有统计学意义的显著改善。

 

Q1：Please interpret the key findings and clinical implications of the NeoADAURA study presented at the conference?

 

Prof.Jamie E.Chaft：I was so honored to present the phaseⅢNeoADAURA study at ASCO this year，which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery，in patients with EGFR-mutated resectable non-small-cell lung cancer.The study enrolled patients with stage stage II–IIIB EGFR mutation-positive NSCLC determined to be receptible at baseline，and the randomization was equal between arms.The primary end point was centrally assessed major pathological response(MPR)at the time of surgery.Secondary end points include event-free survival，pathological complete response，nodal downstaging at the time of surgery，disease-free survival，overall survival and health-related quality of life.Safety and tolerability will also be assessed.By blinded independent review，both osimertinib containing arms showed statistically significant improvement in the MPR rate over chemotherapy alone.

 

Prof.Jamie E.Chaft：在既往研究及临床实践中，我们普遍认为，两种药物联合使用的毒性会比单一药物更大，在本项研究中亦然，但整体来看，NeoADAURA研究中的毒性特征与我们从FLAURA2研究及其他研究中对该联合方案的认知完全一致，仅有1例患者因不良事件导致无法接受手术切除，这个数字实际上相当可喜。该研究并未探讨不同患者选择最优方案的问题，我认为这正是医学的艺术性所在。我们当然知道化疗可以提高可切除NSCLC患者的治愈率，但究竟是术前给予奥希替尼并在术后给予辅助化疗，还是在术前一线治疗中同时给予两者，我们目前尚无答案。我认为在现阶段，我们只能根据患者的病情及体能状态来做出判断。

 

Q2：Data showed that the MPR were comparable between the osimertinib monotherapy group and the combination chemotherapy group，while the incidence of≥Grade 3 AE in the combination chemotherapy group was significantly higher than that in the monotherapy group.Based on this data，what factors do you believe should be primarily considered in clinical practice when selecting between"neoadjuvant osimertinib±chemotherapy"strategies?

 

Prof.Jamie E.Chaft：So I can say the toxicity was greater in the combination arm that anticipated，right?We would expect toxicity to be more with two drugs versus one.And the profiles were entirely consistent with what we know of the combination from FLAURA2 and other studies.There was only one adverse event that precluded surgical resection.So that’s actually a pretty amazing number.So who to choose for which approach is not something that this study addressed.I think that’s where the art of medicine comes in.We certainly understand that chemotherapy can improve the cure rate in patients with respectable NSCLC，whether to give osimertinib pre-operatively and chemotherapy adjuvantly or to give both together in the front line setting before surgery is a question we don’t have the answer to.I think at this point we just have to use our judgment about the fitness of the patient.

 

Prof.Jamie E.Chaft：我认为需要开展一项比我们所进行的研究规模更大的研究，才能证明这种治疗方法具有总生存获益。我们确实观察到了早期的无事件生存优势。然而，这一优势可能会因所有患者在各治疗组中均接受辅助治疗而被稀释，因此，本研究中未将总生存作为预设终点。不过，未来若开展大规模真实世界研究，我确实认为可将生存曲线的早期分离最终将转化为临床获益。

 

Q3：Combining the long-term benefit data from the adjuvant therapy arm in the ADAURA study，how do you view the potential impact of neoadjuvant osimertinib on the overall survival benefit for early-stage NSCLC patients?

 

Prof.Jamie E.Chaft：I think it would take a much larger study than we performed to show an overall survival benefit of this approach.What we do see is an early event，Free survival advantage.However，that will likely be watered down by the adjuvant prescription across arms to all patients.So this study，I would be surprised if it showed an overall survival outcome.It’s actually not the planned endpoint of the study.However，if we had a much larger real world study，I do imagine that early separation of the curves is going to ultimately translate into clinical benefit.

 

Prof.Jamie E.Chaft：不可否认，开展这类研究难度很大，而且该领域仍存在很多争议——哪些患者需要新辅助治疗，以及需要多少新辅助治疗。我承认，尽管无论是否联合化疗，奥希替尼治疗都比单纯化疗效果好得多，但我希望我们能做得更好，希望我们的病理完全缓解率能达到或超过野生型人群中新辅助化疗联合免疫治疗的效果。因此，我希望未来我们能找到真正杀死肿瘤细胞的药物，但目前我们仍在等待这些新型药物及联合治疗方案的出现。

 

Q4:Based on the current results，what do you consider the future research directions for neoadjuvant targeted therapy in resectable(R)EGFR-mutated NSCLC?

 

Prof.Jamie E.Chaft：These studies are admittedly difficult to run，and there remains a lot of debate in the field about who needs neoadjuvant therapy and how much I will admit that while giving osimertinib with or without chemotherapy was much better than chemotherapy alone，I wish we were doing even better and that our pathologic complete response rates were as good or better than those we see with neoadjuvant chemo-IO in wild type populations.

 

So I hope we can find drugs that truly kill the cancer in the future.And but we’re still waiting for those novel combinations to exist.

 

Prof.Jamie E.Chaft：本届ASCO年会我所关注的热点话题包括扩大我们针对其他罕见基因驱动肺癌的口服靶向治疗手段的耐受性。在本届大会中，我们看到了针对EGFR、Her-2以及KRAS靶向治疗的出色数据。此外，我们也看到使用循环肿瘤DNA（ct-DNA）指导治疗的实际应用，期待未来在这方面有更多进展。

 

Q5:As the premier global conference in oncology，the ASCO Annual Meeting shows the most cutting-edge clinical oncology research achievements and treatment technologies.As an expert in the field of lung cancer，could you share your conference experience and key focuses of interest?

 

Prof.Jamie E.Chaft：I think the hot topics we have moving forward are expanding our arsenal of tolerated，oral targeted therapies for other oncogene driven lung cancers.We saw great data are presented for EGFR and Her-2 targeted therapies as well as KRAS.I also think we’re beginning to see the practical implications of using ct-DNA to guide therapy，and I look forward to more of that in the future.