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.

 

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.

 

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.

 

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.

 

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.

 

 

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

 

 

 

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.