编者按：近年来，EGFR突变晚期非小细胞肺癌（NSCLC）的诊疗策略持续演进，从EGFR-TKI单药治疗逐步拓展至联合治疗，从静脉输注发展为皮下给药，从经验性管理迈向生物标志物驱动的个体化决策，临床格局正经历深刻变革。2026年美国临床肿瘤学会（ASCO）年会公布了多项关键研究数据，涵盖EGFR经典突变、20号外显子插入（exon 20ins）突变及PACC突变等多个亚型的一线治疗、耐药后管理及脑转移控制等热点方向，为临床实践提供了新的循证依据与诊疗思路。
基于此，《肿瘤瞭望》特邀同济大学附属上海市肺科医院任胜祥教授与韩国国家癌症中心Beung-Chul Ahn教授，结合最新研究进展与真实世界经验，深入探讨EGFR突变NSCLC的一线治疗格局重塑、给药方式革新、不良反应管理、耐药后策略及未来方向，为临床实践提供参考。
一线治疗格局重塑
从单药到联合，埃万妥单抗联合方案OS突破5年新纪元
《肿瘤瞭望》：首先请您结合临床实践经验及相关研究进展谈谈，近年来EGFR突变晚期NSCLC的一线治疗格局发生了哪些实质性改变？
任胜祥教授：众所周知，晚期非小细胞肺癌（NSCLC）患者中表皮生长因子受体（EGFR）突变的发生率很高。自2004年发现EGFR突变以来，从一代到三代EGFR酪氨酸激酶抑制剂（TKI）的迭代发展不断推动着治疗进步。目前中国已有多款三代EGFR-TKI获批上市，在临床实践中广泛应用。
然而，三代EGFR-TKI单药治疗似乎已面临疗效瓶颈。既往研究显示，三代EGFR-TKI单药治疗的中位无进展生存期（PFS）约为18个月[1]。在此背景下，联合治疗成为突破这一瓶颈的重要方向，包括EGFR-TKI联合化疗以及双特异性抗体等。其中，埃万妥单抗联合兰泽替尼以在国内获批用于携带EGFR 19号外显子缺失（19del）或21号外显子L858R置换突变的局部晚期或转移性NSCLC成人患者的一线治疗，为中国EGFR突变晚期NSCLC患者的一线治疗提供了新的选择。
MARIPOSA研究和FLAURA2研究显示，联合治疗的中位OS可延长至4年以上[2-4]。MARIPOSA研究最终总生存期（OS）分析显示，埃万妥单抗联合兰泽替尼组OS显示出统计学意义和临床意义的显著改善，中位OS预计超过49个月，有望达到57.7个月[4]；尤其值得关注的是，MARIPOSA研究亚洲人群数据显示，埃万妥单抗联合兰泽替尼组中位OS有望超5年，达到64.5个月，这无疑是EGFR突变NSCLC领域的一大突破[5]。
ONCOLOGY FRONTIER: From your clinical practice experience and relevant research advances, what substantive changes have occurred in the first-line treatment landscape for advanced EGFR-mutant NSCLC in recent years?
Prof. Ren: So as we know, the patient population with advanced non-small cell lung cancer has a high incidence of EGFR mutations. Since 2004, the EGFR mutation was first found, and the first generation of TKIs, second generation, and third generation of TKIs have already been approved worldwide for the treatment of advanced stage non-small cell lung cancer with EGFR mutations. Nowadays, several third-generation EGFR TKIs have already been approved in China. Recently, a lot of combination therapy studies, such as TKIs plus chemotherapy, and also the bispecific antibody plus TKIs have been reported. Now the TKIs plus amivantamab have also gained indication in China for different treatment strategies.
As we know, when using TKI monotherapy alone, the median overall survival is more than 3 years. However, if we use combination therapy, as we know from the FLAURA2 study and the MARIPOSA study, the median overall survival(OS) is longer than 4 years. Especially in the Asian population of the MARIPOSA study, the median OS is expected to exceed 5 years, reaching 64.5 months, which means that there has been great progress for patients with EGFR-mutant non-small cell lung cancer. I think this is a big advance in this field.
《肿瘤瞭望》：对于L858R、非经典突变以及20ins这些既往预后相对较差的亚型，今年的ASCO数据是否提供了更加明确的治疗路径？
Beung-Chul Ahn教授：既往研究表明，与19del相比，L858R突变的预后更差。然而，MARIPOSA研究亚组分析显示，埃万妥单抗联合兰泽替尼在所有常规EGFR突变中显示出相似的风险比[6]。由此可见，以埃万妥单抗为基础的联合治疗对L858R突变患者至关重要。
对于非经典突变，2026年美国临床肿瘤学会（ASCO）年会上公布的CHRYSALIS-2试验亚组队列显示，中位随访31.3个月时，埃万妥单抗联合兰泽替尼一线治疗的12个月和24个月OS率分别为85%和72%，预测中位OS约为42个月（3.5年）[7]。这一数据非常令人振奋，因为既往研究表明，阿法替尼的中位OS为19.4个月（95% CI, 16.4-26.9），且95%的患者在治疗开始后2年内中止治疗，其结果对于改变非经典突变的一线治疗具有重要价值。
对于exon20ins突变，此前PAPILLON研究已证实，埃万妥单抗联合化疗可带来显著疗效，该结果发表于《新英格兰医学杂志》。全球人群中位PFS达11.4个月，化疗组为6.7个月（HR=0.40; 95% CI, 0.30-0.53; p<0.001），18个月PFS率分别为31%和3%[8]。此外，2026年ASCO大会上，中国自主研发的EGFR-TKI同样展现出良好的疗效。因此，该领域目前有多种可供选择的药物，但尚缺乏头对头的比较研究，期待未来随着临床数据的不断积累，能够逐步形成更加明确的治疗序列。
ONCOLOGY FRONTIER: For subtypes with historically poorer prognoses-L858R, uncommon mutations, and exon 20 insertions do the ASCO 2026 data provide clearer treatment pathways?
Prof. Ahn: For the L858R mutation, as has been published in the previous literature, such L858R mutations seem to have a worse prognosis compared to exon 19 deletions. However, the bispecific regimen seems to have a similar hazard ratio among all those conventional EGFR mutations. Therefore, the combination strategy is very crucial to treat these L858R mutations. For the uncommon mutations, this year at ASCO, the subcohort of the CHRYSALIS-2 trial showed the expected median OS of 42 months (3.5 years). That is very impressive data, because compared to the previous data which showed less than 2 years with the second generation TKI, which was the standard of care for some uncommon EGFR mutations, I think this will have a practice changing result in the future. Also, it is a phase II study, not a randomized phase III trial, but I think this has very meaningful results to change the first line treatment for this kind of uncommon EGFR mutations.
And lastly, for exon 20 insertions, there was already a previous study called the PAPILLON study, which combined amivantamab plus chemotherapy, and it showed promising data and has been published in NEJM. But this year at ASCO, sunvozertinib, an EGFR TKI from China, also showed very promising efficacy and has also been published in NEJM. So there are many competitors in this field, and there are some advantages of TKIs over the chemotherapy containing regimens. We do not know which drug is better because we do not have any head to head data. But as data accumulate, I think there should be some defined sequence to treat this kind of patient in the future.
给药方式革新与AE管理
皮下注射提升患者体验，主动预防护航联合治疗
《肿瘤瞭望》：请您结合最新研究进展，谈谈您认为皮下注射剂型相较于传统静脉输注，在优化靶向治疗“以患者为中心”的体验方面带来了哪些实质性改变？
任胜祥教授：从2026年ASCO会议报告的COPERNICUS研究结果来看，埃万妥单抗皮下注射的疗效非劣于静脉输注。更重要的是，COPERNICUS研究数据显示，在皮下给药联合皮肤及VTE预防方案下，注射相关反应（ARRs）发生率为9%，静脉血栓栓塞（VTE）发生率为7%，因AE停用埃万妥单抗的比例仅为5%[9]。与既往静脉给药相比，皮下给药的安全性表现有了显著提升。此外，静脉给药的患者需在医院长时间停留，单次输注耗时3至6小时；而皮下注射仅需在门诊完成，无需住院。PALOMA-3研究显示，皮下给药组85%的患者认为治疗"非常方便"或"方便"，而静脉给药组为52%[10]。
这种便利性的提升显著优化了治疗策略。EGFR突变晚期NSCLC患者需每日口服EGFR-TKI，皮下制剂的使用使患者可居家生活，仅需定期门诊注射，极大方便了患者及其家属。目前，皮下制剂已在中国获批，绝大多数患者已从静脉输注转为皮下注射。
ONCOLOGY FRONTIER: Based on the latest research, how do you think the subcutaneous formulation substantively changes the "patient-centered" treatment experience compared to traditional intravenous infusion?
Prof. Ren: I believe the different formulation, from intravenous to subcutaneous, is a big change for routine use in the clinic. We know from the articles at this year’s ASCO meeting, together with the COPERNICUS trial, that when amivantamab is used subcutaneously, the efficacy is a little bit better than when used intravenously, because the progression free survival is a little bit longer. I believe the very important issue is that when you use amivantamab by subcutaneous injection, the side effects, especially the injection related reactions, are significantly lower compared with the intravenous formulation. Besides that, we also find that for patients using intravenous administration, they must stay in the hospital for a long time, maybe 3 hours, 5 hours, or 6 hours.
However, if patients just have a subcutaneous injection, they only need to stay in the outpatient clinic and do not need to be admitted to the hospital. I believe the convenience also changes the whole strategy. As we all know, for patients with EGFR mutated advanced non small cell lung cancer, the TKI is taken orally every day, and if they use the subcutaneous formulation, they can just stay at home and only need to come to the clinic. That would be much more convenient for the patients and their relatives. Also, we know that the subcutaneous formulation is approved in China, and the majority of patients have already switched from intravenous to subcutaneous injection.
《肿瘤瞭望》：在您的临床实践中，您如何看待埃万妥单抗联合治疗相关的皮肤不良反应和血栓风险对患者的生存获益的影响？针对这些不良反应，您有哪些值得推广的预防性管理经验？
Beung-Chul Ahn教授：目前，相关管理策略已逐渐成为标准实践。MARIPOSA方案问世初期，尚无系统的管理方案，既缺乏强化的皮肤管理措施，也缺乏预防性输注相关反应管理方案。
SKIPPirr研究和COCOON研究结果公布后，临床医生对这些强化管理措施的信心显著增强。COCOON研究显示，加强皮肤管理组≥2级皮肤AE的发生率为38.6%，标准管理组为76.5%（OR=0.19; 95% CI, 0.09-0.40; P<0.0001）；在亚洲人群中，这一获益同样得到验证（OR=0.22; 95% CI, 0.10-0.47）[11-13]。基于此，对于皮疹，严格采用COCOON方案中列出的强化皮肤管理措施，包括根据个人皮肤状况在面部和身体每日至少涂抹2次保湿霜（软膏）；患者避免阳光直射皮肤；外出时采取物理防晒措施；头皮皮疹使用温和的去屑洗发水和外用皮质类固醇等。上述措施已在我院常规配备，可在启动埃万妥单抗联合兰泽替尼方案时同步开具。
对于输注相关反应，SKIPPirr研究表明，预防性口服地塞米松8mg可将IRR发生率从67.4%降至22.5%[14]。对于VTE，FDA推荐在埃万妥单抗联合兰泽替尼治疗前4个月内预防性抗凝，PALOMA-2研究显示预防性抗凝治疗可将VTE发生率从20%降至11%[15]。
采用上述缓解策略后，埃万妥单抗联合方案相关不良反应显著减少，该结果与2026年ASCO大会报告的美国真实世界研究COPERNICUS数据高度一致。基于此，临床医生应更有信心使用这些缓解策略来处理相关不良反应。
ONCOLOGY FRONTIER: In your clinical practice, how do you view the impact of skin adverse events and thrombotic risk associated with amivantamab-based combination therapy on patients' survival benefits? What preventive management strategies for these adverse events would you recommend?
Prof. Ahn: I think it is becoming more like standard practice nowadays. Because when the MARIPOSA regimen first came out, there were no management protocols. There were no enhanced dermatology management protocols, no prophylactic IRR management protocols. But after the SKIPPER and the COCOON study results came out, we are having more confidence in using those enhanced managements for those adverse events.
So therefore, for skin rashes, I definitely use enhanced dermatology management that has been listed in the COCOON regimen: giving the Topical clindamycin, Chlorhexidine 4% on the nails, Ceramide-based moisturizer to prevent the skin from becoming dry, and also giving oral antihistamines and antibiotics to prevent folliculitis. All those kinds of starter packs are already in our hospital, ready to be prescribed when we start the MARIPOSA regimen. Also, for infusion related reactions, we give prophylatic steroids.
So when the patient decides to use the MARIPOSA regimen, I immediately give dexamethasone 8 mg for 2 days. I reserve the admission for patients; after 3 days, when the patient comes to the room, or if the patient has complied with the dexamethasone and says he has taken it, we start the MARIPOSA regimen right away. After using these mitigation strategies, the adverse events that have been presented in the MARIPOSA regimen have been dramatically reduced. And it is very consistent with the COPERNICUS data that was presented at this year’s ASCO, which was a real world study from the US. I think it is very consistent data, and I think most physicians should be more confident in using these mitigation strategies for these MARIPOSA adverse events.
耐药谱差异与脑转移破局
基于机制的序贯策略，大分子药物颅内显效
《肿瘤瞭望》：请您结合最新研究进展谈谈，不同一线方案对耐药谱的影响有何差异？这种差异是否会直接影响患者的后续治疗选择和预后？在临床实践中，当患者出现疾病进展后，您通常如何根据初始治疗方案和耐药机制制定后续策略？
任胜祥教授：目前，EGFR突变晚期NSCLC的一线治疗主要分为单药EGFR-TKI治疗和联合治疗（EGFR-TKI联合化疗或埃万妥单抗联合兰泽替尼）两种策略。当患者对一线治疗产生获得性耐药时，其耐药机制因初始治疗方案的不同而存在差异。
接受TKI单药治疗后进展的患者，常见的耐药机制包括C797S突变（7%）、MET扩增（15%）、其他旁路信号通路的激活以及小细胞肺癌转化，且约39%的患者存在多个耐药机制。相比之下，接受埃万妥单抗联合兰泽替尼治疗的患者中，特定耐药事件的发生率显著降低。MARIPOSA研究的耐药分析显示，埃万妥单抗联合兰泽替尼使MET扩增发生率从13.1%降至3.4%（p=0.002），EGFR继发突变从7.6%降至1.4%（p=0.01）。该研究还显示，埃万妥单抗联合兰泽替尼组68%的患者在进展时未检测到已知耐药机制，奥希替尼组为59%；且埃万妥单抗联合兰泽替尼显著降低了耐药复杂性和整体突变异质性（p=0.0073）。这一差异直接影响了后线治疗的结局。一线埃万妥单抗联合兰泽替尼组的患者接受二线治疗的中位PFS为8.4个月，奥希替尼组为5.3个月（HR=0.72; 95% CI, 0.54-0.95; p=0.02）[16]。
针对一线治疗后的耐药管理，目前已有多种治疗选择。在中国，针对MET扩增或MET过表达的患者，相应的MET抑制剂已获得批准。2026年ASCO大会上，来自美国及中国的第四代EGFR-TKI在C797S突变患者中显示出令人鼓舞的抗肿瘤活性，客观缓解率（ORR）介于44%～60%之间，因此该类患者参与临床研究是合理的治疗选择。对于不存在上述特定耐药机制的患者，埃万妥单抗联合化疗、TROP2 ADC药物Sac-TMT、HARMONi-A方案及ORIENT-31方案等已在中国获批临床应用。
治疗策略应根据耐药机制进行个体化制定。对于一线接受单药EGFR-TKI治疗后进展的患者，若再次活检证实存在MET扩增或过表达，联合MET抑制剂是合理的治疗选择；若检测到C797S突变，则优先推荐参加第四代EGFR-TKI的临床研究。对于一线接受埃万妥单抗联合兰泽替尼治疗后进展的患者，由于MET扩增和C797S突变的发生率较低，临床上可考虑含铂双药化疗、ADC药物或化疗联合抗PD-1/VEGF等方案。
对于疾病进展模式的评估同样至关重要。当患者出现耐药后，应首先通过全身影像学检查明确进展模式。若为寡进展（即局限性、少数病灶进展），局部治疗（包括立体定向放疗或手术）是一种有效的处理策略。在中国及韩国，许多肿瘤内科及放射肿瘤科医生对寡进展患者采用局部治疗，此类患者的中位PFS可达6至8个月。若为系统性广泛进展，则需更换全身治疗方案。
ONCOLOGY FRONTIER: Based on the latest research, how do different first-line regimens influence the resistance mutation spectrum? Does this difference directly affect subsequent treatment choices and prognosis? In clinical practice, when patients progress, how do you usually determine subsequent strategies based on the initial treatment and resistance mechanisms?
Prof. Ren: As you mentioned, nowadays, for first line treatment, we have two different kinds of choices: monotherapy and combination therapy. So when patients just become resistant to frontline treatment, they will have different mechanisms regarding monotherapy and combination therapy. As we know, when patients receive TKI monotherapy, they will have C797S mutation, MET amplification, other kinds of bypass signaling pathways, and also small cell lung cancer transformation. However, if patients receive combination therapy, for example, from the FLAURA2 study, the incidence of C797S mutation is significantly decreased. Also, when patients receive lazertinib plus amivantamab, MET amplification is also significantly decreased. Another point is that we know when patients become resistant to frontline treatment, they have a lot of choices.
In China, there is an approved therapy for patients with MET amplification or MET overexpression. At this year’s ASCO meeting, for patients who had C797S mutation, we know that fourth generation EGFR TKIs from a US company and a Chinese company showed promising results, with objective response rates as high as 60% or 44%. So in this setting, if patients have C797S mutation, participating in a clinical trial is a good choice.
Besides that, for the general population, we know that in China, the TROP2 ADC Sac-TMT has been approved in China for second line treatment. Also, the MARIPOSA-2 study has been approved in China, and the HARMONi-A and ORIENT-31 regimens have also been approved in China. So according to clinical practice and the different mechanisms, I believe for patients who received monotherapy, if a rebiopsy shows MET amplification or overexpression, adding a MET inhibitor would be a choice. And if patients have C797S mutation, participating in a clinical trial might be a good choice.
For those patients who received combination therapy, the incidence of MET amplification and C797S mutation is lower. In this setting, when I suggest using chemotherapy, ADC, chemo plus amivantamab, or chemo plus anti PD-1/VEGF, those are kinds of choices. However, in China, and I think also in Korea, many oncologists and radiation oncologists perform local therapy. They use radiotherapy, and we use surgery, for patients who just have oligoprogressive disease. In this setting, the median progression free survival is about 6 to 8 months. I believe when patients just become resistant to monotherapy or combination therapy, they should have a whole body examination. If the patient just has oligoprogression, local therapy is a kind of choice.
《肿瘤瞭望》：针对临床上极为棘手的脑实质转移和软脑膜转移，本次会议有一项基于双抗单药及联合方案的多中心真实世界研究，显示出积极的颅内控制率和症状改善。您如何看待这类药物在控制中枢神经系统病灶方面的临床价值？其潜在的作用机制又是什么？
Beung-Chul Ahn教授：在埃万妥单抗或ADC药物问世之前，EGFR-TKI是唯一能够穿透血脑屏障并有效控制脑转移的药物。然而，随着患者生存期的不断延长，中枢神经系统转移的长期管理需求日益凸显。
近年来，以埃万妥单抗为代表的大分子药物在颅内显示出良好的抗肿瘤活性。MARIPOSA研究显示，在基线有脑转移史的患者中，埃万妥单抗联合兰泽替尼组36个月时仍有36%的患者存活且无颅内进展，奥希替尼组为18%，颅内PFS曲线持续分离[5]。其作用机制可能与脑转移导致血脑屏障局部破坏或功能紊乱有关，从而使大分子药物得以进入中枢神经系统发挥治疗作用。CHRYSALIS研究中观察到埃万妥单抗治疗期间颅内进展罕见，提示大分子药物可能通过受损的血脑屏障进入中枢神经系统[17]。
既往观点认为，免疫检查点抑制剂（ICIs）及大分子靶向药物在颅内疗效有限。然而，包括真实世界研究在内的最新证据表明，埃万妥单抗在脑转移患者中具有确切的临床获益。因此，上述证据提示有必要重新审视大分子药物在中枢神经系统转移治疗中的临床价值。未来研究应进一步探索其确切的作用机制或递送途径，例如通过检测脑脊液中的药物浓度来验证中枢神经系统的药物暴露水平。目前，多数机制假说仍主要归因于脑转移后血脑屏障的物理破坏。
ONCOLOGY FRONTIER: For the clinically challenging conditions of brain parenchymal metastases and leptomeningeal metastases, a multicenter real-world study at ASCO 2026 on bispecific antibody monotherapy and combination therapy showed promising intracranial control rates and symptom improvement. How do you view the clinical value of such agents in controlling CNS lesions? What are the potential mechanisms of action?
Prof. Ahn: The intracranial response of many agents is now coming out at international conferences. But before bispecific antibodies or ADCs came out, the TKI was the only holy grail that could penetrate the BBB and work well in brain metastases. But as patients live longer and expect lifelong extension, we need to control brain metastases for a very long time. Now, combination therapies are coming, and agents such as amivantamab, a bispecific antibody, can work well in the brain. The mechanism for that is that if the patient has brain metastases, the BBB can be destroyed or disrupted, so those large molecules, such as ADCs or bispecific antibodies, can also work in the brain.
However, long ago, ICIs and amivantamab and other ADCs seemed not to work well in the brain, but recent studies including ADCs and bispecifics show they work in the real world. So I think it is now time for a global community to have a consensus that these large molecules do work in the brain. We should look for a new mechanism of action or mechanism of delivery to find out how they really work in the brain, because there are many studies measuring drug dosage or drug concentration levels in the CSF. So in future studies, I think those kinds of questions should be answered. But currently, most of the mechanisms are explained by the disruption of the BBB after brain metastasis.
生物标志物驱动全程决策
突变亚型与ctDNA动态指导精准分层
《肿瘤瞭望》：请您结合最新研究进展，分享下在您看来，目前哪些生物标志物（如突变亚型、共突变状态、ctDNA动态变化等）对于指导一线联合治疗的选择最具临床实用价值？
任胜祥教授：针对不同的EGFR突变类型（包括exon20ins、19del、21号外显子L858R点突变以及PACC突变），需要采取差异化的治疗策略。对于经典突变，埃万妥单抗联合兰泽替尼（MARIPOSA研究方案）以及第三代EGFR-TKI联合化疗（FLAURA2研究方案）是目前优选的一线治疗方案。对于exon20ins，埃万妥单抗联合含铂化疗已获得适应证批准，是目前的标准治疗选择之一。此外，中国已有多款口服EGFR-TKI可供临床使用。对于PACC突变，多项第三代EGFR-TKI已进入III期临床试验阶段，其治疗价值有待进一步验证。
其次，共突变状态亦具有重要临床意义。TP53及RB1等伴随突变目前被视为预后性生物标志物，而非预测性标志物。伴有TP53共突变的晚期EGFR突变 NSCLC患者可以从强化治疗的联合方案中获益。MARIPOSA亚组分析显示，伴有TP53突变的患者从埃万妥单抗联合兰泽替尼方案中的PFS获益显著（HR=0.58）[4]。
此外，既往研究显示，89%的EGFR突变NSCLC患者基线存在高风险因素，这些患者预后较差，中位PFS仅9.1-14.8个月。例如，伴有脑转移的患者可能从化疗联合方案或埃万妥单抗联合方案中获得更大的生存获益[6]；有肝转移病史的患者，埃万妥单抗联合兰泽替尼的PFS HR低至0.58[6]。
对于一线治疗后出现耐药的患者，建议进行再次活检以明确耐药机制，包括C797S突变、MET扩增以及其他驱动基因融合（如ALK、RET）。上述分子事件均可作为后续靶向治疗的干预靶点。需要特别指出的是，约40%的患者在疾病进程中会发生小细胞肺癌（SCLC）转化，在此情况下，组织再活检（而非仅依赖液体活检）对于准确识别转化具有关键作用。
ONCOLOGY FRONTIER: From your perspective, which biomarkers (e.g., mutation subtype, co-mutation status, ctDNA dynamics) currently have the greatest clinical utility in guiding first-line combination therapy selection?
Prof. Ren: I think biomarkers are very important for patients with EGFR mutations. For frontline therapy, for different EGFR mutations such as exon 20ins, exon 19 deletion, exon 21, and also PACC mutations, we have different kinds of treatment. For classic EGFR mutations, I think the third generation TKI, like the FLAURA2 study, and the MARIPOSA study combining with chemo or with amivantamab, are the best choices. However, for patients with exon 20 insertions, we know that chemotherapy plus amivantamab has the indication.
In China, we also have three other kinds of TKIs, sincluding sunvozertinib and furmonertinib, are available for clinical use in China. For PACC mutations, I believe a lot of pan EGFR TKIs, such as furmonertinib, are already in phase III clinical trials. Besides that, we usually have other kinds of gene testing. For example, concurrent co mutations like TP53, RB1, those kinds of biomarkers may not be predictive biomarkers but are prognostic biomarkers.
Besides that, clinical features such as brain metastases and liver metastases will also affect what choice we make for frontline therapy. For example, if a patient has brain metastases, they might benefit more from combination with chemotherapy or amivantamab. And for patients who become resistant to frontline therapy, as I just mentioned, we do rebiopsy to know C797S mutation, MET amplification, and other kinds of fusions such as ALK, RET, and these kinds of fusions also benefit from targeted therapy. Also, I need to mention that nearly 40% of patients will transform to small cell lung cancer. In this setting, tissue rebiopsy, not just liquid biopsy, will be pivotal for identifying small cell lung cancer transformation.
《肿瘤瞭望》：未来随着检测技术的进步，您认为基于生物标志物的治疗策略在EGFR突变NSCLC的哪些临床环节（如一线方案选择、疗效动态评估、耐药机制识别、后线决策等）最具应用价值？
Beung-Chul Ahn教授：血液循环肿瘤DNA（ctDNA）检测目前已在中国和韩国广泛应用于临床常规，主要用于识别高风险患者。在日常实践中，我们通过ctDNA检测评估血液中是否存在肿瘤细胞，从而向患者提供预后判断。因此，基线ctDNA检测具有重要的临床价值。
在动态监测方面，治疗早期肿瘤来源ctDNA水平的迅速下降通常提示良好的预后。我们可以向患者解释，ctDNA水平的下降或清除意味着更佳的长期生存预期。然而，目前ctDNA的动态变化尚不能直接指导治疗决策的调整，治疗方案的选择及疾病进展的判断仍然主要依赖于影像学评估。对于无法获得组织活检的患者，液体活检是识别耐药机制的有效替代手段。因此，ctDNA检测在当前临床实践中更多扮演辅助性工具的角色，而非决策的决定性依据。
ONCOLOGY FRONTIER: With advances in detection technologies, at which clinical steps in EGFR-mutant NSCLC do you see the greatest value for biomarker-based treatment strategies?
Prof. Ahn: Like detecting ctDNA in the blood. Nowadays, it is very routinely done, I think, in China and Korea as well, to find out whether a patient is high risk or not. As already mentioned, combination regimens have a better hazard ratio in patients with ctDNA positivity. So now, in our routine practice, we usually do ctDNA testing to detect whether there are tumor cells in the blood or not, to define and explain to the patient whether they have a better or worse prognosis. So I think nowadays it is very crucial to do that.
But for dynamic purposes, to see the changes during treatment, we can assume that if the patient’s ctDNA level, tumor derived ctDNA level, rapidly decreases, that patient seems to have a very good prognosis compared to a patient without such a response in ctDNA. Therefore, we can explain to the patient that they may have a better prognosis if the ctDNA levels decrease or disappear. However, it does not determine the final treatment decision. The regimen or the definition of progression is still based on radiological assessment right now. So I think it is more complementary rather than definitive for decision-making.
真实世界启示与未来方向
从个案到全局，联合免疫调变实现长期生存
《肿瘤瞭望》：请您分享一个您在EGFR突变NSCLC诊疗中印象深刻的真实病例？重点谈谈其中的临床决策考量、所面临的挑战以及相应的应对策略？
任胜祥教授：我曾接诊一例对多代EGFR-TKI原发耐药的患者。患者初诊为IV期肺腺癌，19del突变。阿法替尼一线治疗1个月后即出现疾病进展，换用另一种二代TKI同样在1个月后进展。患者因工作原因对化疗有所顾虑。我们采用了化疗联合抗VEGF及抗PD-1治疗，患者获得PR，但6个月后再次出现疾病进展——影像学评估显示仅为骨寡进展，其余病灶控制良好。经与放疗科协作，我们对所有进展灶实施了SBRT，患者再次获得约6个月的疾病控制。后续换用化疗联合个体化疫苗，3个月后再次进展。最终患者接受埃万妥单抗单药治疗，获得长期缓解，至今仍存活。因此，个人认为，埃万妥单抗对于EGFR-TKI原发耐药的患者是一种有效的治疗选择，且可与ADC或免疫治疗联合应用。
ONCOLOGY FRONTIER: Could you share a memorable real-world case of EGFR-mutant NSCLC that impressed you? Please focus on the clinical decision-making considerations, challenges encountered, and corresponding management strategies.
Prof. Ren: The most impressive case for me was a patient with primary resistance to first, second and third generation EGFR-TKIs. The patient was male and was diagnosed with stage IV lung adenocarcinoma harboring an exon 19 deletion. I started afatinib as first‑line therapy, but disease progression occurred just one month later. I then switched to another second‑generation TKI, and progression recurred after another month. Since the patient was reluctant to receive early chemotherapy because of concerns about its impact on his normal work, I tried a combination of chemotherapy, anti-VEGF and anti-PD‑1 therapy. The patient achieved a partial response, but progressed again six months later. Whole‑body imaging showed only oligoprogressive bone disease, while other lesions remained well controlled. After consultation with radiation oncologists, I delivered stereotactic body radiotherapy (SBRT) to all progressive lesions. The patient then had another six months of disease control before progressing again. Subsequent chemotherapy combined with an individualized vaccine was ineffective, and progression occurred three months later.
Eventually, the patient received amivantamab monotherapy and achieved a long‑lasting response. He remains alive to date. During amivantamab treatment, he experienced a local relapse, which was managed with local ablation therapy. Currently, TROP2 ADC, amivantamab and ivonescimab are available in China. Therefore, in my opinion, amivantamab is an effective treatment option for patients with primary resistance to EGFR TKIs, and it can be combined with ADC or immunotherapy. This is the most impressive case in my clinical practice.
Beung-Chul Ahn教授：令我印象最为深刻的病例是全球首例接受埃万妥单抗治疗的exon20ins突变患者。当时，大多数临床医生认为EGFR抗体在EGFR突变肺癌中无效，因为既往研究未能证实其疗效。恰逢韩国国家癌症中心参与了一项I期临床试验，旨在评估埃万妥单抗单药治疗经治失败的exon20ins突变患者。该研究首例入组患者即表现出极为显著的治疗反应，持续缓解超过10个月，这对于exon20ins突变患者而言极为罕见。在国际学术会议上报告这一结果时，许多同行对该药物的作用机制提出质疑，认为可能仅为偶然或巧合。然而，正是这一病例开启了后续一系列研究。
自首例患者之后，埃万妥单抗现已广泛应用于经典突变及exon20ins突变的一线治疗，并在多种其他适应证及癌种中获得批准，相关临床研究仍在持续推进。这段经历是我深耕肿瘤内科领域的重要原因。当年作为专科培训医师，我亲自参与了该患者的治疗及不良反应管理。这些看似微小的个案，最终推动了全球标准治疗方案的变革。因此，即使某些药物在初始阶段不被看好，肿瘤内科医师仍应关注那些微弱的线索或假说，从而推动更大规模的全球临床研究。
Prof. Ahn: I have many interesting cases. As Dr. Ren mentioned, I also have a case that was on afatinib after a second generation TKI and had a very good response, because it was not a typical mutation. It was exon 19 deletion and insertion, a very uncommon mutation, not an exon 20 insertion. So I think I have a similar case, but my most impressive case was the first case of amivantamab in an exon 20 insertion patient. It was the world’s first case, because amivantamab was a rather promising agent at that time.
Most physicians thought that an EGFR antibody would not work in EGFR mutant lung cancer because some previous results had failed. But coincidentally, there was a phase I trial that our National Cancer Center and some other cancer centers were involved in. They used amivantamab monotherapy for treatment failure exon 20 insertion patients. And the first case had a very dramatic response. At that time, when it was presented at an international conference, some colleagues from the US and others said, "What is the mechanism of this?" Nobody could explain, and they thought it was a fluke or a coincidence, or that this agent did not have any effect. But that was the start. I am very impressed because that was our institution’s first patient, and the world’s first patient, using amivantamab long term as monotherapy.
Now, it is used in combination in the first line setting, and it has improved outcomes; those patients had a dramatic response lasting more than 10 months, which is very unusual for exon 20 insertion patients. After that, the patient underwent other chemotherapy and finally expired. But anyway, I thought that amivantamab, from the first patient to now, has fully bloomed to cover conventional mutations, exon 20ins, and even has been approved for many other indications, cancer types, and ongoing trials. That is the reason I became more obsessed with this medical oncology field. At that time, I was a fellow; I treated that patient and managed those adverse events. But now, from the beginning of my memory, I think those small things could change the world’s standard of care. Even though some agents seem not to have any potential, I think medical oncologists should focus on those small clues or small hypotheses to generate more global wide clinical trials.
《肿瘤瞭望》：基于这些经验，您对EGFR突变晚期NSCLC的长期全程管理有哪些核心建议？
任胜祥教授：在多学科团队协作模式下，我们应广泛采用局部治疗手段（如SBRT、手术等），并综合运用所有可及的治疗方案，包括已获批适应证的药物以及临床研究中具有潜力的新药，积极为患者争取最佳治疗机会。同时，需根据突变亚型、共突变状态及临床特征进行风险分层，强化不良反应的主动管理，以保障长期治疗的依从性。MARIPOSA研究亚洲数据显示，埃万妥单抗联合兰泽替尼对比奥希替尼可降低死亡风险26%，预测中位OS可延长超12个月[5]。我相信，随着精准治疗策略的不断优化，EGFR突变晚期非小细胞肺癌患者的生存时间将在不久的将来进一步延长。
ONCOLOGY FRONTIER: Based on your experience, what are your core recommendations for long-term comprehensive management of advanced EGFR-mutant NSCLC?
Prof. Ren: I think in MDT, we use a lot of local therapy, and we cooperate quite well with industry. Some drugs already have the indication, and others are still in earlier drug development. So we use all those kinds of things. And we already observed from the MARIPOSA study that nearly half of the patients could live longer for 5 years. I think in the near future, the survival time will be much longer.
Beung-Chul Ahn教授：对于EGFR突变NSCLC的未来治疗方向，我认为单一靶向治疗的时代已经过去，当前已进入基于EGFR-TKI联合策略（如埃万妥单抗、化疗或ADC）的新阶段。
MARIPOSA研究证实埃万妥单抗联合兰泽替尼是首个在EGFR突变NSCLC一线治疗中显著改善疗效（包括OS）的chemo-free方案[4]。延长患者长期生存的关键机制之一在于肿瘤微环境的免疫调节，这一作用独立于癌细胞本身的驱动信号。即使在过去，我们认为化疗对EGFR突变NSCLC疗效有限，但越来越多的证据提示，联合治疗可改变肿瘤的免疫状态。埃万妥单抗可募集免疫效应细胞，引起依赖NK细胞的抗体依赖性细胞毒性和依赖巨噬细胞的胞啃作用，成为具备免疫调节潜力的药物之一。未来研究应进一步探索如何将EGFR突变NSCLC从免疫学上的"冷"肿瘤转化为"热"肿瘤，从而最终实现OS的持续延长。
Prof. Ahn: For the future of EGFR mutant lung cancer, I think the era of using a single targeted therapy has passed. Now is the era of adding another agent to the TKI. I think the crucial mechanism to extend long term survival is immune modulation of the tumor microenvironment, also independent of the cancer cells. Even before this era, we thought immunotherapy does not work in EGFR driven lung cancers. But nowadays, more and more people are focusing on how to make this cold tumor into a hot tumor in the future. Therefore, amivantamab is also one clue, one agent that could modulate the microenvironment. As a start, innovative biotech companies should focus on how to turn EGFR mutant lung cancer into a hot tumor and achieve long term extension of overall survival.
专家简介
任胜祥 教授
同济大学附属上海市肺科医院 肿瘤科 科行政主任
同济大学附属上海市肺科医院 I期临床研究病房 主任
同济大学附属上海市肺科医院 肺癌与免疫实验室 主任
主任医师 教授 博士生导师
国家优秀青年医师，上海市先进工作者
世界免疫协会亚洲分会（WIC-Asia）临床委员会主任委员
国际肺癌研究协会（IASLC）教育委员会委员
中国医促会胸部肿瘤分会主任委员
CSCO非小细胞肺癌专委会副主任委员
上海市医师协会肿瘤医师分会副主委
上海市抗癌协会转化研究委员会副主委
上海市抗癌协会肺癌分子靶向免疫治疗委员会副主委
Beung-Chul Ahn教授 (韩国)
韩国国家癌症中心（National Cancer Center, Korea）肺癌中心助理教授
研究方向：
非小细胞肺癌（NSCLC） 的靶向治疗与免疫治疗
肺癌脑转移及软脑膜转移的综合管理
基于患者来源细胞（PDC）的药物反应预测及耐药机制研究
液体活检与循环肿瘤DNA（ctDNA）基因组分析
新型免疫联合治疗策略（AXL抑制剂、抗PD-1/PD-L1、化疗联合方案）
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