编者按
2026年欧洲肺癌大会（ELCC）于3月25日至28日在丹麦哥本哈根盛大召开。作为全球肺癌领域最具影响力的学术盛会之一，本届大会在罕见靶点诊疗领域释放了诸多重磅信号：从HER2突变一线治疗格局的重塑，到KRAS G12D抑制剂的崭露头角，再到抗体药物偶联物（ADC）向一线治疗的战略前移，罕见靶点正从“边缘”走向“中心”。
会议期间，《肿瘤瞭望》特邀2026 ELCC大会科学委员会主席、英国皇家马斯登医院Sanjay Popat教授与国际肺癌研究协会（IASLC）主席、同济大学附属东方医院周彩存教授，立足大会最新进展，围绕“肺癌罕见靶点精准诊疗”热点话题进行深度探讨，以期为临床实践提供前沿洞见。
肿瘤瞭望
本届ELCC大会上，针对肺癌罕见靶点的专题讨论数量显著增加。从临床诊疗的角度来看，近年来这一领域取得了哪些突破性进展？
HER2领域：Zongertinib确立一线地位，颅内活性成亮点
Sanjay Popat 教授
罕见驱动基因突变非小细胞肺癌（NSCLC）的诊疗始终是我们面临的重大挑战，而精准的基因分型是识别这些患者的关键所在。近年来，个体化治疗取得了显著进展。在2026年ELCC大会上，我们看到了一系列极具影响力的数据更新，尤其是在HER2领域。Beamion LUNG-1研究的最新数据为Zongertinib在HER2酪氨酸激酶结构域（TKD）突变的晚期NSCLC中的美国食品药品监督管理局（FDA）获批提供了有力支持。该药物在初治患者中展现出快速且深度的缓解，确认客观缓解率（ORR）达76%，中位无进展生存期（PFS）为14.4个月，中位缓解持续时间（DoR）为15.2个月，均显示出持久的疗效。更为重要的是，我们首次观察到该药物在活动性脑转移患者中的颅内活性。研究显示，在伴有活动性脑转移的患者中，颅内ORR达47%，中位颅内PFS为8.2个月；而在未接受过脑部放疗的患者中，颅内ORR更是高达59%[1]。这一数据意义重大，因为此类患者群体通常被排除在临床试验之外。基于如此确切的全身及颅内疗效，我认为，在药物可及的前提下，Zongertinib应成为HER2突变晚期NSCLC一线治疗的标准。
Prof. Sanjay Popat：The rare driver diagnoses within non-small cell lung cancer are an ongoing problem, and it's very important that we try and identify these patients accurately with appropriate genotyping. We continue to make huge advances in personalized therapy over the years. At ELCC 2026, we saw updates on these and for me, the most impactful data sets were for HER2. We had updated data which supports the FDA approval for Zongertinib for tyrosine kinase domain (TKD) mutant, advanced non-small cell lung cancer, here demonstrating very rapid responses, very deep responses, PFS in excess of 1 year. And for the first time, we've seen intracranial activity of the drug in patients with untreated, asymptomatic brain metastases, demonstrating very good response rates. And I think really, this is a standard first-line drug if available. I understand it's available in China. I'm not sure about the regulatory environment, but from my viewpoint, the efficacy data is suitable for first-line treatment.
周彩存 教授
确实如此。对于携带罕见驱动基因的患者，我们目前已有多种靶向药物可供选择。这些酪氨酸激酶抑制剂（TKI）不仅肿瘤缓解率高、无进展生存期长，且具备良好的中枢神经系统活性。我非常赞同Sanjay Popat教授的观点，TKI应成为HER2突变NSCLC一线治疗的标准。但当前的关键在于如何精准筛选出合适的患者。在中国，我们高度重视活检，通过超声支气管镜（EBUS）或穿刺获取足量组织进行检测。以往我们较多采用PCR检测，虽速度快但覆盖有限；如今我们更应推行大panel检测，这一点至关重要。
Prof. Caicun Zhou：That's great. For patients with uncommon oncogenic drivers, nowadays we have targeted therapies for several of them. We have TKIs that are very good, with high tumor response rates and longer PFS. They also have CNS activity. I could totally agree with you: the TKI should be standard of care for first-line treatment of HER2 mutation, but nowadays we need to find the right patients with uncommon mutations. So in China we do a lot of biopsies. We try to get tissue. For us, we can do EBUS, we can do core needle biopsy, try to get enough tissue. Next, we need the test. Usually we perform a lot of PCR-based tests. PCR is faster, but we cannot do a panel. So nowadays we should do panel testing.
精准检测：NGS是识别罕见靶点的“金标准”
Sanjay Popat 教授
完全正确。尤其是在EGFR 20外显子插入突变（EGFR ex20ins）领域，目前已发现数百种不同的插入变异，基于PCR的技术只能捕获极少部分。如果不采用二代测序（NGS），可能根本无法发现这类患者。
Prof. Sanjay Popat：It's very true. And I think especially when it comes to something like EGFR exon 20 insertion, right? For example, we know in EGFR we have many hundreds of EGFR exon 20 insertion variants, and the PCR-based technologies will only pick up a very small number of these insertions. So if you're not using NGS, you're not going to find your patient.
周彩存 教授
检测的重要性贯穿诊疗全程，不仅在基线，在疾病进展时同样需要再次检测。
Prof. Caicun Zhou：The testing is very important. Not only at the baseline, we also need to test at the time of disease progression. I think that's correct.
Sanjay Popat 教授
我们在临床中观察到患者可能出现脱靶驱动基因。例如，若考虑继续使用EGFR或ALK抑制剂，但在进展时发现了脱靶驱动基因，则继续使用TKI已无意义，患者需转向化疗或抗体药物偶联物（ADC）为基础的策略。因此，了解患者在初诊和复发时的生物学背景，对临床决策至关重要。
Prof. Sanjay Popat：One of the things we're noticing is that patients have off-target drivers. So for example, if we're thinking about giving another EGFR inhibitor or another ALK inhibitor, it's pointless if there's an off-target driver; those patients need a chemo-based strategy or ADC-based strategy to try and improve their outcomes. So understanding the biology of the patient at diagnosis and at relapse is, I think, critical to the decision making.
KRAS靶点：G12D崛起，联合治疗面临毒性挑战
周彩存 教授
除了HER2突变，KRAS G12D领域也有令人兴奋的进展。一些化合物显示出约40%的缓解率和较长的PFS，但截至目前，我们尚无这些药物在中枢神经系统中是否有效的数据。在中国和美国均是如此。
Prof. Caicun Zhou：Right. So except for HER2-mutant lung cancer, we also have very interesting compounds for KRAS G12D. There are some compounds showing benefit, with around 40% response rates and quite longer PFS for survival. So far, we do not have any data on whether these compounds work or not in the CNS. In China and the United States, that's right.
Sanjay Popat 教授
KRAS G12D领域确实非常令人期待。在亚洲，KRAS G12D突变NSCLC的发生率远高于西方，而西方以KRAS G12C突变更为常见。这是一个非常重要的领域，不仅关乎胰腺癌，也关系到从不吸烟者和吸烟者中的KRAS G12D突变肺癌患者。该领域正快速发展，涌现出多种不同的药物。
Prof. Sanjay Popat：The KRAS G12D space, I think, is a very exciting space. In Asia, you see a lot more G12D non-small cell lung cancer than we do in the West, where G12C is more common. But this is a very important area. It's a big problem for pancreatic cancer, but also for never-smoker and smoker populations with G12D KRAS-mutant lung cancer. And this area, I think, is evolving very, very quickly with many different agents.
周彩存 教授
我们特别关注联合治疗，尤其是与免疫治疗的联合。但毒性问题，特别是肝毒性，不容忽视。部分患者无法耐受KRAS G12C抑制剂联合免疫治疗。
Prof. Caicun Zhou：Especially we talk a lot about combination therapy. We talk about combining with IO, but toxicity is a kind of problem, especially liver toxicity. Some patients could not tolerate the combination of a KRAS G12C inhibitor plus IO.
Sanjay Popat 教授
我完全同意。KRAS G12C抑制剂活性很强，但要推向一线，必须与免疫检查点抑制剂联合，有时甚至需要联合化疗。我们观察到高发的腹泻、转氨酶升高，部分源于免疫激活，部分来自药物本身。这些患者常需使用激素，如何确保他们安全完成全程治疗是一大挑战。随着KRAS G12D抑制剂的开发，我们同样需要关注其不良反应谱。
Prof. Sanjay Popat：I think this is completely correct. KRAS G12C inhibitors are very active, but we need to combine them with checkpoint inhibitors to move to first line. And sometimes perhaps even with chemo as well. We see very high rates of diarrhea, we see high rates of ALT/AST rise. Sometimes it's due to immune activation, sometimes it's due to the drug itself. These patients often need steroids. It can become very problematic to make sure they get the right treatment all the way through. We're starting to see signals of that with some types of G12D inhibitors as well. And we have to be mindful of the adverse event profile as these drugs continue to be developed.
周彩存 教授
因此，我们需要研发更有效的KRAS G12C和HER2抑制剂。要开发更有效的KRAS抑制剂，可以利用新技术，如蛋白降解剂。
Prof. Caicun Zhou：So another way is we should produce more potent KRAS G12C and HER2 inhibitors. To produce more potent KRAS inhibitors, we can use new technology such as protein degraders.
Sanjay Popat 教授
没错。KRAS药物开发有多种途径，我们需要思考是水平抑制、垂直抑制，还是使用分子胶或其他形式的蛋白降解剂。许多不同的靶点正在被开发。我认为未来几年KRAS领域的研发将非常精彩。在KRAS G12C已确立、新一代药物和KRAS G12D抑制剂即将涌现的同时，泛RAS抑制剂也初现端倪。问题在于，我们应选择突变特异性抑制剂、泛RAS抑制剂，还是需要联合治疗？
Prof. Sanjay Popat：That's right. And I think there are many different approaches to drugging KRAS. We need to think about whether we drug it horizontally, vertically, whether we use a molecular glue or some other form of protein degrader. Many different targets are being developed. There are many different approaches to this. I think the next few years in the development space of KRAS, in general, is going to be very, very interesting. Because in the space that we have already established with G12C, we have next-generation G12C coming. We have first-generation G12D nearly around the corner, but we also have pan-RAS inhibitors as well. The question is, how do we then work out which is the right strategy to use? Do we use a mutation-specific inhibitor, pan-RAS, or do we even need combinations?
ADC时代：从后线前移，与TKI如何共舞？
周彩存 教授
这正是关键问题，我完全同意。但我们将目光投向ADC时代。现在我们有了ADC联合化疗、ADC联合免疫治疗、ADC联合双特异性抗体。如果ADC联合免疫治疗比KRAS G12C抑制剂联合免疫治疗疗效更好，我们还需要开发更有效的TKI吗？TKI毒性更小，更易于给药。
Prof. Caicun Zhou：I totally agree with you. But we look forward to the ADC era. Now we have ADC plus chemo, ADC plus IO, ADC plus bispecifics. If ADC plus IO produces better efficacy compared with KRAS G12C inhibitor plus IO, do we still need to develop more potent TKI? TKI is less toxic and easier to administer.
Sanjay Popat 教授
我认为这非常正确。ADC领域发展迅速，尤其在中国。我对中国正在开发的众多ADC非常感兴趣，你们在临床试验招募和展示这些药物的疗效与安全性方面做得非常出色。但有趣的是，在某些情况下，这些ADC可能会进入一线治疗，无论是单药还是联合免疫检查点抑制剂。现在关键问题是，如果这些药物进入一线，那么靶向治疗的位置在哪里？特别是对于KRAS？我认为对于EGFR突变肺癌，我们仍然需要某种TKI作为基础。但我可以看到未来EGFR领域一线TKI联合ADC的局面。在这种情况下，罕见突变亚型该如何应对？在罕见领域生成数据将非常困难。但这就是我们前进的方向，或许在EGFR领域，这将对更广泛的驱动基因阳性领域产生深远影响。
Prof. Sanjay Popat：I think this is very true. The field of ADCs is moving very, very quickly, especially in China. I'm very interested in the number of ADC compounds which are being developed in China, and you are doing a great job, I have to say, in recruiting to trials and demonstrating the efficacy and safety profile of these. But what is becoming very interesting is, in some scenarios, these ADCs, I think, may move to first line, either as monotherapy or probably in combination with a checkpoint inhibitor. Now, the key issue is, if these are moving to frontline, then where do the targeted therapies fit in? Particularly when it comes to KRAS? I think for EGFR-mutant lung cancer, we're still going to need to have some sort of TKI; that's still going to be the backbone. But I can see a world where it's going to be first-line TKI plus ADC in the future for EGFR. What do we do about rarer mutation subtypes in that scenario? It's going to be very hard to generate data in that rare space. But this is the way we're moving, perhaps in EGFR, and that has broader implications for the wider oncogene-addicted field.
周彩存 教授
我完全同意。在中国，我们有多个III期试验在比较EGFR抑制剂联合，尤其是第三代EGFR-TKI联合ADC。我们将在不久的将来获得数据。如果PFS能够进一步改善，这种联合治疗将成为新的标准治疗。
Prof. Caicun Zhou：I totally agree with you. In China, we have several phase III trials comparing EGFR inhibitor plus, especially the third-generation EGFR TKI plus ADC. We have so many such kinds of trials. We will know the data in the near future. If the PFS could be further improved, that combination will become the new standard of care.
ADC选择：有效载荷 vs. 靶点，孰轻孰重？
Sanjay Popat 教授
我认为是的。我们需要确定的关键问题之一是，在一线应该使用哪种类型的ADC？我们有许多正在开发的TROP2 ADC，它们的疗效特征略有不同，毒性特征也截然不同。我们如何选择正确的ADC与TKI联合？这是一个持续的挑战。
Prof. Sanjay Popat：I think so. One of the key issues we need to establish is what is the right type of ADC to be using upfront? We have many TROP2 ADCs in development. They all have a slightly different efficacy profile. They definitely have a different toxicity profile. How do we then choose the right ADC to partner with whichever TKI? This is an ongoing challenge.
周彩存 教授
我认为是的。尤其在中国，我们有多种ADC。我们有EGFR ADC，有双特异性ADC（EGFR-MET ADC），也有许多HER2 ADC。
Prof. Caicun Zhou：Especially in China, we have so many kinds of ADCs. We have EGFR ADC, we have bispecific ADC (EGFR-cMET ADC), EGFR-HER3 ADC, we also have so many HER2 ADCs.
Sanjay Popat 教授
我认为一个仍然非常相关的问题是，到底是有效载荷（payload）更重要，还是靶点更重要？
Prof. Sanjay Popat：One of the questions I think is still really relevant is, is it really the payload that's more important, or is it the target that's more important?
周彩存 教授
我认为，对于ADC来说，如果靶点没有差异，那么有效载荷就成为关键。所以在中国，我们正在开发混合有效载荷的ADC。我们可以在一个ADC中放入两种有效载荷。我们也有混合靶点ADC，如TROP2联合另一个靶点。这种双靶点ADC的研究正在进行中，目前尚无数据。这是一个非常有趣的问题。
Prof. Caicun Zhou：I would say, for an ADC, if there is no difference in the target, then the payload becomes the key. So in China, we are developing mixed payload ADCs. We can do two payloads in one ADC. We also have mixed ADCs such as TROP2 plus another target. This kind of dual-target ADC study is just ongoing. So far, we do not have any data.That's a very kind of problem.
Sanjay Popat 教授
我非常期待这方面的进展，因为我认为双有效载荷和生物有效载荷非常有趣，可能会占据主导地位。但ADC有许多不同的优化需求需要解决：我们是否获得了足够的靶点覆盖？我们是否具有足够的细胞毒性？最重要的是，我们是否获得了足够的脑穿透性？因为我们不能忘记，在肺癌领域，我们积累到的经验是：脑部控制等于最佳生存。
Prof. Sanjay Popat：I'm very much looking forward to this, because I think dual payloads and biological payloads are very interesting, and may take over. But there are so many different optimization needs for ADCs that we have to work out. Are we getting enough target coverage? Are we really having enough cytotoxicity? And above all, are we getting adequate brain penetration? Because we can't forget that at the end of the day, one lesson we've learned, I think, in lung cancer is brain control equals best survival.
周彩存 教授
尤其当患者生存期延长时，脑转移成为我们需要解决的更重要的问题。所以现在我们正试图开发具有中枢神经系统穿透性、中枢神经系统活性的化合物与ADC联合。我认为这是一种控制中枢神经系统转移的双重化合物策略。相关研究正在进行中，目前尚无数据可分享。
Prof. Caicun Zhou：Especially if patients survive longer, brain metastasis becomes a more important question we need to answer. So nowadays we try to develop CNS-penetrative, CNS-active compounds combined with ADC. So I would say that is a dual compound approach to control CNS metastasis. So the study is ongoing; so far, do not have any data to tell you.
未来展望：多药联合时代的机遇与挑战
Sanjay Popat 教授
我认为我们可以达成共识，未来几年药物开发领域将非常令人兴奋。我们有许多正在开发的药物，包括靶向药物（TKI）、多种RAS抑制剂，还有许多免疫治疗双特异性化合物正在开发。新型免疫检查点正在建立。在此背景下，我们有新型ADC，包括传统ADC、新型有效载荷ADC和双特异性ADC。我们如何将这些组合起来，真正为患者最大化获益？这将是一个巨大的挑战。
Prof. Sanjay Popat：I think we can agree that the next few years are going to be very exciting in the world of drug development. We have many drugs being developed, both targeted agents (TKIs), both RAS inhibitors in many different aspects, and we have many IO bispecific compounds being developed. We have novel types of IO checkpoints being established. And on the background of that, we have novel ADCs, both traditional ADCs and novel payloads, and bispecific ADCs. How do we combine all of these to really maximize the outcomes for our patients? This is going to be a big challenge.
周彩存 教授
这是一个非常重要的问题。如果ADC联合免疫治疗成为标准治疗，门槛会更高。下一个ADC很难再与之联合。我不确定下一个ADC能否超越这一标准。
Prof. Caicun Zhou：A very important question we need to answer. If ADC plus IO becomes standard of care, the bar becomes higher. It's difficult for the next ADC to combine with it. I'm not sure the next ADC could beat that standard.
Sanjay Popat 教授
这确实是个问题。也许在未来几年内，我们会在疗效上达到某种平台期。我认为这将是一个“幸福的烦恼”。所以让我们继续推进临床试验，确保患者能够接触到新治疗，最重要的是，确保我们拥有精准、准确的基因分型。没有准确的基因分型，我们就无法恰当地对患者进行分层，为他们提供正确的治疗。
Prof. Sanjay Popat：Maybe we are in a position where over the next few years we reach a sort of plateau in activity. I think this would be a nice problem to have. So let's carry on recruiting to trials, making sure that our patients get exposure to new treatments, and above all, ensure we have very good and accurate genotyping. Without accurate genotyping, we cannot properly stratify our patients to get them the right treatment.
周彩存 教授
我完全同意。生物标志物始终重要。我们需要生物标志物，我们需要组织，我们需要检测。但到目前为止，我们还没有非常好的ADC生物标志物，尤其是对于TROP2 ADC。TROP2 ADC在我们的市场上可用于EGFR突变肺癌。我认为TROP2 ADC将可用于治疗野生型晚期NSCLC。
Prof. Caicun Zhou：I totally agree. Biomarkers are always important. We need biomarkers, we need tissue, we need to test. But so far, we do not have any very good biomarker for ADCs, especially for TROP2 ADC. TROP2 ADC is available in our market for EGFR-mutant lung cancer. I would say the TROP2 ADC will be available in the market to treat wild-type advanced non-small cell lung cancer. That's true.
Sanjay Popat 教授
确实如此。一些ADC正在开发预测性免疫组化评分，利用数字病理平台评估TROP2或HER2表达。另一些ADC则在开发中不要求靶点表达。我们需要观察实施的障碍是什么、生物标志物检测的疗效获益是什么、安全性平衡如何。但随着这些药物不断进化和发展，我认为未来几年将非常有趣。我们密切关注这一领域。毫无疑问，TROP2对于EGFR突变人群和野生型人群都是一个非常可行的靶点。关键问题是，对于野生型人群，我们是否需要生物标志物分层？这是一个持续的关键问题。
Prof. Sanjay Popat：That's true. And some ADCs are being developed with a predictive immunohistochemistry (IHC) score, looking at TROP2 or HER2 expression using digital pathology platforms. Other ADCs are being developed without a requirement for target expression. We have to see what the barriers to implementation are, what the efficacy benefits are for biomarker testing, and what the safety balances are. But I think it's going to be very interesting over the next few years as these drugs continue to evolve and develop. We keep a very careful eye on this space. Certainly, TROP2 is a very, very viable target for the EGFR-mutant population and a very viable target for the wild-type population. The key issue is, do we need biomarker stratification for the wild-type population or not? This is a key ongoing question.
周彩存 教授
所以我们需要共同努力解决这个问题，为未来的精准医学找到正确的生物标志物。
Prof. Caicun Zhou：So we need to work together to solve the problem, to find the right biomarker for future precision medicine.
Sanjay Popat 教授
我完全同意。
Prof. Sanjay Popat：I would totally agree.
肿瘤瞭望
面对多种治疗选择，对于EGFR ex20ins患者，在一线和后线治疗中应如何选择治疗策略，以实现患者获益最大化？
EGFR ex20ins：埃万妥单抗仍是基石，TKI蓄势待发
周彩存 教授
这是一个非常好的问题。目前，埃万妥单抗（amivantamab）联合化疗是全球标准。我们必须使用埃万妥单抗联合化疗治疗晚期EGFR ex20ins突变患者。未来，我们可能会有像WU-KONG研究这样的靶向药物。我们正在等待该研究的数据。但从目前这些TKI在后线治疗中的数据来看，PFS并不长。所以可能需要联合治疗。埃万妥单抗联合化疗已被PAPILLON研究验证可行。那么TKI联合化疗呢？TKI联合埃万妥单抗呢？您怎么看？
Prof. Caicun Zhou：That's a very good question. So far, amivantamab plus chemotherapy is the standard of care worldwide. We have to use amivantamab plus chemotherapy to treat advanced patients with EGFR exon 20 insertion. In the future, maybe we will have targeted agents like the WU-KONG studies.We are just waiting for the data of that study. But when we look at the duration of these TKIs so far in the second-line setting, the PFS is not so long. So maybe we need combination. The combination of amivantamab plus chemotherapy is already feasible, approved by the PAPILLON study. How about TKI plus chemotherapy? TKI plus amivantamab? What's your idea?
Sanjay Popat 教授
我认为这完全正确。目前，埃万妥单抗联合化疗是获批方案，有III期数据支持，但TKI也显示出非常好的活性。所以毫无疑问，未来我们将有舒沃替尼、zipalertinib等选择，还有许多其他药物正在开发。一个非常有趣的领域是，我们是否需要根据exon 20的基因型进行个体化治疗？因为其中一些药物可能对某些loop区或C-螺旋区突变类型显示出更好的疗效。我认为这是一个不断发展的领域。我们目前还没有足够大的样本量来对基因型-疗效关系做出有信心的预测。但在未来几年，随着这些数据集的积累，我们将不得不开始考虑个体突变状态。这又回到了我们之前讨论的一点：在exon 20领域，我们必须使用NGS，因为如果只做PCR，我们无法捕获这些个体基因型。展望未来，我们将面临埃万妥单抗、TKI单药或化疗联合TKI等多种选择。我们如何序贯？如何考虑联合？我们甚至可能看到ADC在这一领域的数据。TKI联合ADC无疑是合理的组合。我们需要思考如何设计这些试验。周教授，我相信这方面有很多正在进行的探索。
Prof. Sanjay Popat：I think this is completely a correct statement. At the moment, amivantamab plus chemo is the approved regimen. We have phase III data supporting its usage, but the TKIs are showing very good activity. So undoubtedly, I think in the future, we will have options like sunvozertinib, zipalertinib, and there are many others that are being developed as well. One of the really interesting areas is, do we need to individualize based on the genotype for exon 20? This is a very interesting topic, because some of these drugs are perhaps showing greater efficacy for certain loop or C-helix types of mutations than others. I think this is an evolving area. We don't have such large numbers to be able to confidently make predictions about genotype-efficacy relationships at this point. But over the next few years, as these data sets evolve, we're going to have to start thinking about individual mutation status. And this goes back to one of the points we were saying beforehand: in the exon 20 space, we have to use NGS, because we won't pick up these individual genotypes if we're doing PCR. Now, if we think about the future, we are going to have a future where the options will be amivantamab, TKI monotherapy, or chemo plus TKI. How do we then sequence? How do we then think about combinations? We may even have some data coming through on ADCs in this space as well. A combination of TKI plus ADC would make absolute sense. We need to think about how we generate these trials. Doctor Zhou, I'm sure there's a lot of activity ongoing.
周彩存 教授
我们对埃万妥单抗联合TKI的探索非常感兴趣。有一个小样本量的I期试验正在进行中，目前尚无数据。TROP2 ADC在EGFR突变肺癌中非常敏感。那么TROP2 ADC联合埃万妥单抗，或TROP2 ADC联合TKI呢？我们正在等待这些研究的数据。
Prof. Caicun Zhou：We are quite interested in the combination of amivantamab plus TKI. There is a small sample size phase I trial ongoing. So far, we don't have the data. TROP2 ADC is very sensitive in EGFR-mutant lung cancer. How about TROP2 ADC plus amivantamab, or TROP2 ADC plus TKI? We just wait for the data of the studies.
肿瘤瞭望
面对“TKI与ADC并驾齐驱”的局面，对于初治的HER2突变晚期NSCLC患者，您在选择一线治疗方案时，会基于哪些临床因素或生物标志物（如突变亚型、脑转移状态等）进行决策？
HER2一线选择：TKI优先，但需考量突变亚型与脑转移
Sanjay Popat 教授
我们目前面临的情况是，TKI在一线治疗中可用，这在美国FDA管辖范围内已经是事实。而且我们很快将拥有支持HER2 ADC一线应用的数据。那么我们如何选择？我认为必须个体化。需要考虑很多因素。患者生物学上的突变类型是否可能从两类药物中同等获益？我们看到，经典的HER2 20外显子插入YVMA突变对这类TKI非常敏感。激酶结构域突变也表现出非常好的活性。但对于非激酶结构域突变，例如细胞外结构域突变、跨膜结构域突变，可能存在疑问。也许这些情况我们需要考虑使用ADC。另一个需要考虑的是每种药物的毒性特征。一些正在开发的ADC，例如deruxtecan衍生物，有相当比例的间质性肺炎风险，我们需要积极管理并为患者考虑。其他一些ADC则没有那么大的间质性肺炎风险。一些HER2 ADC有更多EGFR抑制相关副作用，如皮肤毒性和腹泻。我们还需要考虑脑穿透性。ADC的脑穿透性与TKI不同。周教授，我很想听听您的看法。
Prof. Sanjay Popat：We have a scenario where we have TKIs available in the first-line setting, which is already the case in the FDA jurisdiction. And we also will very shortly be having HER2 ADCs approved for use in the front-line setting with data to support them. So how do we choose which to use? I think we have to think about individualizing for the patient. There are many factors to consider. Does the patient biologically have a mutation that is likely to benefit equally from both classes? What we've seen is that the HER2 classical exon 20 insertion, YVMA, is very sensitive to these TKIs. The kinase domain mutations have very good activity. We have some questions about non-kinase domain mutations, for example, the extracellular domain mutations, the transmembrane domain mutations. Maybe these are ones where we need to think about using ADCs in this situation. The other thing we need to think about is the toxicity profile of each of these drugs. Some of the ADCs that are being developed, for example, the deruxtecan derivatives, have a reasonable rate of pneumonitis that we need to manage actively and consider for our patients. Some of the other ADCs don't have so much of a pneumonitis risk. Some HER2 ADCs have more EGFR inhibitory side effects such as cutaneous toxicity and diarrhea. We need also to think about brain penetration. The ADC brain penetration is different to the TKI brain penetration. I'm interested in your views, Doctor Zhou.
周彩存 教授
我完全同意您的观点。对于HER2 20外显子突变NSCLC，TKI应作为一线标准治疗，但非激酶结构域突变除外。对于HER2突变肺癌，我们需要考虑HER2表达水平。对于HER2 IHC 3+人群，我们能否使用ADC治疗？目前有一些数据显示DS-8201在这一人群中非常活跃。有一些研究正在进行，比较ADC联合埃万妥单抗与化疗。是的，这也是我们需要研究的重要领域。
Prof. Caicun Zhou：So I totally agree with you. TKI should be standard of care as first-line treatment for HER2 exon 20-mutant non-small cell lung cancer, except for non-kinase domain mutations. For HER2-mutant lung cancer, we need to consider HER2 expression. For the HER2 IHC 3+ population, can we use ADC to treat such a kind of population? Nowadays, we have some data to demonstrate that DS-8201 is quite active in this population. There are some kinds of studies ongoing, comparing ADC plus amivantamab versus chemotherapy. Yes, that's also an important area we need to investigate.
HER2表达与扩增：超越突变的生物标志物
Sanjay Popat 教授
没错。不仅仅是HER2突变，不能孤立地看待。我们还需要考虑拷贝数增加、HER2扩增，尤其是现在新出现的生物标志物HER2 IHC 3+。我认为这是一个非常令人兴奋的领域，正在开展ADC联合免疫治疗的研究。HER2 IHC 3+是一组异质性很强的患者，有些是驱动基因阳性，有些则不是。我们需要更大的数据集来明确哪些亚型能从ADC中获得最大获益。
Prof. Sanjay Popat：That's right. It's not just HER2 mutation. You can't take that out by itself. We have to consider copy number gain, HER2 amplification, and especially now the emerging biomarker of HER2 IHC 3+. I think this is a very exciting area where you have ongoing studies in this space with ADCs and IO. HER2 IHC 3+ is a heterogeneous group of patients. It's sometimes oncogene-addicted positive, sometimes it's not. We need to really get bigger data sets to work out what are the subtypes of HER2 IHC 3+ that are really driving the greatest benefit.
周彩存 教授
非常好。HER2扩增也是EGFR-TKI的获得性耐药机制之一。在疾病进展时，我们应检测HER2扩增甚至突变。在这种情况下，您是否愿意用ADC联合TKI治疗？
Prof. Caicun Zhou：So that's great. HER2 amplification is also an acquired resistance mechanism to EGFR-TKIs. At the time of disease progression, we should check for HER2 amplification, even mutation. In that case, would you like to treat them with ADC plus TKI?
Sanjay Popat 教授
我认为这是一个悬而未决的问题。我们确实有相关I期研究的数据，显示T-DXd单药在HER2 IHC 3+患者中有效，其中一些是EGFR突变阳性并在TKI治疗后进展的患者。所以问题是，单药治疗是否足够？单药是否具有足够的颅内活性？还是需要联合TKI？这是一个持续的问题。无论HER2表达状态如何，我们可能都想这么做。但可能是HER2表达状态为控制持续时间带来了额外获益。
Prof. Sanjay Popat：I think this is an ongoing question. We definitely have data from the initial Daiichi phase I studies of trastuzumab deruxtecan showing activity as monotherapy in HER2 IHC 3+, some of which are patients who were EGFR mutation-positive and then progressed on TKI. So the question is, is monotherapy adequate? Do we have enough intracranial activity with an agent as monotherapy? Or do we combine with a TKI? This is an ongoing question. We might want to do that anyway, regardless of HER2 expression status. But it may be that HER2 expression status gives us additional benefit for duration of control.
周彩存 教授
是的，我完全同意。所以在未来，我们需要更多的检测。不仅仅是EGFR通路、MET通路，我们还需要检测旁路通路，如HER2扩增。
Prof. Caicun Zhou：Yeah, I totally agree with you. So in the future, we need even more testing. Not only the EGFR pathway, MET pathway, we also need to test bypass pathways, such as HER2 amplification.
Sanjay Popat 教授
耐药机制越来越复杂。我们需要更全面的生物学信息，了解肿瘤在复发时发生了什么，以便更好地判断最佳治疗方案。
Prof. Sanjay Popat：The resistance setting is becoming increasingly complex. We need more comprehensive biological information about what happens to the tumor at relapse to better make judgment decisions on what the optimal treatment should be.
耐药与适应性治疗：从持续性细胞到ctDNA动态监测
周彩存 教授
所以我们追踪TKI治疗下的肿瘤演化。在获得性耐药后，肿瘤对我们来说变得更加复杂。耐药机制目前尚未完全阐明。这只是其中一部分，并非全部。所以我们能否超越仅关注突变？您怎么看？关于持久的、药物耐受的持续性肿瘤细胞，我们能否在这个阶段采取一些措施？在持续性阶段，也许我们可以有所作为。
Prof. Caicun Zhou：So we follow the tumor evolution on TKI therapy. After acquired resistance, tumors become even more complicated to us. The resistance mechanism is so far not fully understood. That's just part of them, not all of them. So can we move beyond mutation only? What do you talk about? Talk about persistent drug-tolerant persister cancer cells. Can we do something at that stage? At the persister stage, maybe we can find something.
Sanjay Popat 教授
这是一个非常好的问题，周教授。我认为我们面临的挑战之一是，哪些患者仅用TKI单药治疗就足够了？因为我们都有少数患者仅用单药治疗多年仍然很好，而另一些患者因为药物耐受的持续性细胞而快速复发。我们能否使用一些适应性策略？我们是否需要将所有治疗都前置？还是需要基于监测这些持续性细胞来调整策略，例如通过ctDNA清除，并在那个时间点加入ADC？这些是不断发展的领域，我认为中国非常有条件引领这些探索，因为中国EGFR突变高发、治疗可及性强，并且有设计临床试验的能力。我们需要更聪明地考虑患者的整体纵向策略，而不是将所有治疗都前置。也许有一些适应性策略我们可以考虑。
Prof. Sanjay Popat：This is a very good question, Doctor Zhou. And I think one of the challenges that we have is in whom is TKI monotherapy adequate, because we all have a small number of patients who are doing very well for many years just with monotherapy, and other patients who relapse very quickly, because of these drug-tolerant persister cells. Can we use some adaptive strategies? Do we need to do everything up front? Or do we need to adapt our strategy on the basis of monitoring these persister cells, for example, through ctDNA clearance, and add in an ADC at that point? These are evolving areas that I think China is very well poised to take the lead on because of the prevalence of EGFR mutations that you have, the access to the therapies, and the ability to design trials. We need to think a bit more cleverly about the whole longitudinal strategy for our patients, rather than everything up front. Maybe there are some adaptive strategies we can think about.
TP53共突变：强化治疗的价值与精细分层需求
周彩存 教授
我完全同意。在本次ELCC上，有一项来自中国的III期研究，即TOP研究[2]，他们使用TKI联合化疗治疗EGFR突变合并TP53突变的患者。您如何看待这项研究？
Prof. Caicun Zhou：So I totally agree with you. At this ELCC, there was one phase III study from China, the TOP study. They used TKI plus chemo to treat patients with EGFR mutation plus TP53 mutation. Do you think what's your idea about the study?
Sanjay Popat 教授
这是一项非常有趣的研究。它清楚地表明，在TP53突变人群中，联合化疗带来了额外的PFS和总生存期（OS）获益。然而，关键问题是，这种获益是否与TP53状态无关？因为在我看来，TP53是预后因素而非预测因素。另一个问题是，TP53之外可能还有其他因素影响预后。它只是患者旅程中需要考虑的多个变量之一。所以我很高兴看到这些数据，因为它独立验证了FLAURA2和MARIPOSA研究中关于TP53突变状态的多变量分析结果，表明针对不良预后因素（如TP53）进行强化治疗确实能带来获益。然而，关键问题是，是否所有TP53患者都能获得这种获益？可能不是。是否有患者不需要强化治疗？可能有。我们如何更好地在前线EGFR治疗中选择需要强化治疗的患者？我认为我们还没有从这些试验中获得足够精细的数据。但我很想知道您的看法。
Prof. Sanjay Popat：A very interesting study. And it clearly demonstrates that adding chemotherapy to the TP53 mutant population has additional progression-free survival and overall survival benefit. However, the key issue is, is that going to happen anyway, regardless of the TP53 status? Because TP53, to my mind, is prognostic rather than predictive. The other issue is that with TP53, there may be other factors that influence prognosis outside of it. It's only one of several multivariables that we need to think about for the patient journey. So I was very pleased to see that data because it independently verifies the multivariable analysis from TP53 mutation status, both from FLAURA2 and also from MARIPOSA, suggesting that intensification therapy for patients with poor prognostic factors, such as TP53, does derive a benefit. However, the key issue is, do all patients with TP53 derive that benefit? Probably not. Are there patients that don't need it? Probably. How do we better select our patients in the front-line EGFR setting for intensification or not? I don't think we really have that granularity of data from these trials as well. But I'm interested in your thoughts.
周彩存 教授
我完全同意。TP53突变不是单一的变异。有这么多不同的变异，可能具有不同的生物学行为。到目前为止，我们不知道哪种变异能获得更多获益，哪种变异不能。目前尚无相关数据。
Prof. Caicun Zhou：I totally agree with you. TP53 mutation is not one variant. There are so many different variants, maybe with different biology. So far, we do not know which variant could get more benefit and which variant could not. So far, we do not have any data.
Sanjay Popat 教授
非常正确。有些TP53突变导致蛋白失活，即无效变异。有些TP53变异导致蛋白在核内蓄积，在免疫组化上表现为TP53阳性。它们的生物学行为非常不同。所以我们需要更好地理解这一点，这可能有助于我们做出一些决策。当然，目前尚不清楚每项试验是如何对其TP53突变状态进行分类的。当我们深入挖掘数据的细节时，这也会影响我们对试验结果的解读。
Prof. Sanjay Popat：That's very true. We have TP53 mutations which cause inactivation of the protein, the null variants. We have the TP53 variants which cause overaccumulation within the nucleus that lead to TP53 positivity on immunohistochemistry. They behave very differently. So we need to better understand this, and maybe that might help us in some of the decision making. Certainly, it's not clear how each of the trials have classified their TP53 mutation status. And when we start drilling down to the granularity of the data, that also affects our interpretation of the trial.
周彩存 教授
所以现在，正如您之前提到的，适应性治疗应该是最佳选择。
Prof. Caicun Zhou：So nowadays, as you mentioned earlier, adaptive therapy should be the best.
全程管理：疗效最大化与毒性最小化的平衡之道
Sanjay Popat 教授
我认为，如果我们认为患者的生存期现在将以年为单位来衡量，我们需要使疗效和安全性尽可能达到最佳。必须在管理疗效和减轻及最小化毒性之间取得平衡。那么，我们如何以一种有意义的方式实现这一点，同时为我们的医疗系统和患者保持经济可行性？所以也许我们需要考虑“开-关”策略。也许我们需要为此寻找生物标志物。我们需要开始生成这类数据。否则，我们将陷入将所有治疗前置、然后再将所有治疗后置的局面，从患者耐受性角度来看这是不可能的。
Prof. Sanjay Popat：I think if we are thinking that our patient's lifespan is now going to be measured in years, we need to make the efficacy and safety as optimal as possible. And there has to be a balance between managing efficacy and mitigating and minimizing toxicity. So how do we achieve that in a meaningful way that's also economically viable for our health systems and for our patients? So maybe we need to think about on-off strategies. Maybe we need to think about biomarkers for that. We need to start generating this type of data. Otherwise, we're going to be in a situation where we're front-loading every treatment up front, and then front-loading every treatment after, which is just not possible from a patient tolerability viewpoint.
周彩存 教授
我同意。毒性会增加。TKI毒性加上另一种治疗的毒性。我们还需要考虑经济毒性，尤其是现在。并非所有患者都需要联合治疗。有些患者单药治疗就能生存超过十年。我们会有这样的患者。
Prof. Caicun Zhou：I agree with you. Toxicity will be increased. TKI toxicity plus another treatment's toxicity. We also need to consider economic toxicity, especially nowadays. Not all patients need combination. Some patients could be treated with monotherapy and survive more than 10 years. We will have these patients.
Sanjay Popat 教授
那么，我们如何前瞻性地识别他们，以确保我们为他们匹配正确的治疗？我认为这是一个正在进行的工作，我们需要在研究中更好地识别这些患者。
Prof. Sanjay Popat：So how do we prospectively identify them to ensure that we are matching them to the right therapy? I think this is work ongoing, and we need to work better in our studies to better identify these patients.
总结与展望：罕见靶点治疗的未来方向
2026年ELCC大会传递出的核心信号是：肺癌罕见靶点治疗已从“单药突破”迈入“精准分层、联合优化、全程管理”的新阶段。
在HER2领域，TKI与ADC并驾齐驱，一线治疗迎来“双轨”时代。Zongertinib凭借卓越的颅内活性和深度缓解，已确立一线治疗地位，而T-DXd等ADC则在HER2 IHC 3+及耐药人群中持续拓展边界。临床决策需综合突变亚型、脑转移状态、毒性谱及患者个体特征，实现真正意义上的个体化治疗。
在KRAS领域，G12C抑制剂已成功突破“不可成药”的困境，新一代G12D抑制剂及泛RAS抑制剂正在崛起。联合治疗虽为一线探索方向，但免疫联合带来的肝毒性等挑战不容忽视，如何平衡疗效与安全性、如何筛选联合治疗的最佳人群，仍是亟待回答的核心问题。
在EGFR ex20ins领域，埃万妥单抗联合化疗仍是当前标准，但以舒沃替尼为代表的新型TKI正蓄势待发。未来，根据具体插入亚型进行“基因型指导”的治疗选择，将成为临床新常态。
贯穿全程的，是对精准检测的更高要求。从基线到耐药，从组织到液体活检，NGS已成为不可或缺的工具，唯有精准分型，才能为患者匹配最适宜的治疗路径。
展望未来，随着ADC与TKI的深度融合、适应性治疗策略的探索、以及基于ctDNA动态监测的“开-关”模式的推进，罕见靶点肺癌正从“不可治”走向“可管理”，从“晚期”走向“全程”。正如两位教授所言，下一阶段的核心任务，是在疗效最大化与毒性最小化之间找到平衡点，通过多学科协作与精细化管理，让每一位罕见突变患者都能在精准医学的时代浪潮中，收获更长、更高质量的生存。
专家简介
周彩存 教授
上海市东方医院
主任医师，教授，博士生导师
上海市东方医院肿瘤科主任
同济大学医学院肿瘤研究所 所长
国际肺癌研究协会(IASLC)主席
中国医促会胸部肿瘤学分会主任委员
中国临床肿瘤学会转化医学专家委员会主任委员
中国抗癌协会非小细胞肺癌专委会主任委员
中国抗癌协会肿瘤药物临床研究专业委员会主任委员
上海市抗癌协会肺癌分子靶向和免疫治疗专委会主任委员
中国医师协会肿瘤分会常委
上海市抗癌协会副理事长
上海市医师协会肿瘤分会副会长
上海市医学会肿瘤分会 副主任委员
Sanjay Popat 教授
英国皇家马斯登医院（The Royal Marsden Hospital）肺癌中心主任、肺癌研究负责人
英国癌症研究院（Institute of Cancer Research）胸科肿瘤学教授
英国胸科肿瘤学组（BTOG）研究组主席
英国国家卫生与临床优化研究所（NICE）药物评审临床专家
英国国家卫生研究院（NIHR）伦敦南部临床研究网络癌症分部联合主席
英国国家癌症研究所（NCRI）肺癌组晚期疾病亚组前主席
西伦敦基因组肿瘤咨询委员会主席
欧洲肿瘤内科学会（ESMO）科学委员会委员
欧洲胸科肿瘤学平台（ETOP-IBCSG Partners Foundation）理事会成员及科学委员会委员
国际肺癌研究协会（IASLC）科学委员会委员
欧洲药品管理局（EMA）临床专家
参考文献：1. John Heymach, et al. Zongertinib in treatment-naïve patients with HER2-mutant NSCLC, including those with active brain metastases: Beamion LUNG-1. 2026 ELCC, 6MO.2. Yunpeng Yang, et al.Osimertinib (osi) with or without chemotherapy (CTx) as first-line treatment in EGFR-mutant (EGFRm) advanced NSCLC with concurrent TP53 mutations (TOP study).2026 ELCC.2O.
（来源：《肿瘤瞭望》编辑部）
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