在2025年欧洲肺癌大会（ELCC）上，ESMO前任主席、瑞士洛桑大学医院肿瘤科主任Solange Peters教授以“双特异性抗体和T细胞衔接器：对抗免疫荒漠”为题发表专题报告。《肿瘤瞭望》就这些创新疗法及当前免疫治疗领域的热点问题对Peters教授进行了独家专访。

 

Dr.Peters：双特异性抗体同时针对两个靶点，令人惊讶的是，其疗效竟然优于两种单抗联合使用。需要记住，双特异性抗体的定义很广泛，这类药物靶向两种肿瘤相关抗原，但大多靶向两个免疫检查点，通过抑制或刺激免疫反应发挥抗肿瘤作用。例如，双特异性抗体的两个靶点可能是PD-1/PD-L1与CTLA-4，可能是VEGF与PD-1。这是一种免疫反应的调节剂（刺激或抑制）。

 

2025 ELCC发布了首批靶向PD-1和LAG-3两种通路的双特异性抗体的数据（摘要7MO：Tobemstomig/含铂化疗对比帕博利珠单抗/含铂化疗一线治疗局部晚期或转移性NSCLC患者的II期临床研究）。我们希望联合PD-1和LAG-3治疗，理想情况下是使用双特异性抗体，或使用两种药物分别治疗。但罗氏研发的双特异性抗体Tobemstomig联合化疗对比帕博利珠单抗/化疗是阴性结果，所以以上概念可能并不成立。

 

目前尚不清楚CTLA-4/PD-1双特异性抗体为何比CTLA4单抗联用PD-1单抗更有效，可能是同步靶向两个免疫检查点可以增强肿瘤内部的协同效应，从而有效整合免疫反应的各个组成部分（向肿瘤细胞抗原呈递的细胞、T细胞衔接器等），我们希望这种机制产生作用，但尚缺乏研究数据支持。

 

T细胞衔接器是不同作用机制的药物，它通过结合CD3激活T细胞，促进其细胞增殖并分泌细胞因子。这是T细胞的启动过程。T细胞衔接器不依赖于预先存在的免疫反应。虽然T细胞衔接器可能引发一些副作用，例如细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS），但它为针对性治疗策略带来了巨大的希望，通过激活T细胞并招募免疫细胞大军来攻击肿瘤。

 

制药行业正在针对这类药物进行大量研发，临床试验覆盖多种肿瘤和疾病不同阶段，其中200个双特异性抗体正在II期临床试验阶段。

 

Dr.Peters:My name is Solange Peters.I am Director of Oncology at the University Hospital of Lausanne in Lausanne，Switzerland.

 

First of all，it is quite surprising to see how a bispecific with two targets might potentially be more active than two drugs together.Remember，bispecifics define many things.You could target two tumor-associated antigens，but most of these bispecifics target two checkpoints，inhibitory or stimulatory.For example，PD-1 and PD-L1/CTLA4，VEGF/PD-1–modulators of the immune response，stimulatory or not.Why does it work better to give a bispecific CTLA4/PD-1 compared to giving both drugs together?We still don’t know.We think that when you target two checkpoints，you may promote collaboration within the tumor to bring together components of the immune response–antigen presenting cells to tumor cells，and T-cell engagers in the immune response.We hope it will work.Do we have data?Yes and no.Today，we saw the first data on a bispecific targeting PD-1 and LAG-3，two pathways.We would like to combine them together，ideally as a bispecific or maybe one-by-one，but the bispecific from Roche has failed already with chemotherapy versus chemo/pembrolizumab.So，we think maybe the whole concept is not valid.T-cell engagers are completely different.They activate T-cells by binding onto CD3 making the cell proliferate and produce cytokines.It is a switching on of the T-cells.You don’t need a pre-existing immune response.There are some side effects like CRS(cytokine release syndrome)and some ICANS(immune effector cell-associated neurotoxicity syndrome)，but it brings wonderful hope for a specifically targeted therapy.Activating T-cells creates an army of immune cells against the tumor.The amount of further developments by the pharmaceutical industry is huge.Across diseases and various phases of clinical trials，we currently have around 200 bispecifics in clinical trials in phase II.

 

Dr.Peters：这个问题的核心在于明确免疫检查点抑制剂（ICI）在伴致癌驱动基因晚期非小细胞肺癌（NSCLC）中的有效性。首先，我们应该谨慎地看待已知信息（我们所知最多的是将EGFR和ALK阳性肺癌系统性地排除在免疫治疗之外），而EGFR和ALK两个靶点非常重要。

 

ALK：免疫检查点抑制剂在ALK阳性肺癌中的活性非常低，也没有任何令人信服的疗效数据，我确实不会为这类患者开免疫疗法的处方。RAF1和MEK相比ALK的研究更少，这类肺癌的特点也是免疫原性极低、PD-L1表达低以及肿瘤突变负荷（TMB）低。与ALK家族一样，RAF1和MEK也不适合免疫治疗。

 

EGFR：免疫治疗是否适用于EGFR突变型肺癌，并非非黑即白的问题。来自中国台湾的Gee-Chen Chang教授一直告诉我，免疫疗法对EGFR突变体有一定的治疗活性，可能需要将其留到后线治疗与化疗/抗血管生成药物联用。当免疫疗法与化疗联用不足以产生效果时，联用抗血管生成药物可提升疗效并产生获益（例如IMpower150、ATTLAS和HARMONi-8研究）。因此，当免疫疗法联用其他疗法（抗血管生成药物，未来可能联用双特异性抗体或T细胞衔接器）时，在EGFR突变型肺癌治疗中仍有应用价值。我认为免疫疗法在这类患者中是有发展空间的。

 

其他靶点：KRAS G12C变异对免疫疗法非常敏感。如果患者是吸烟者，且携带BRAF和MET外显子14，患者可能也会对免疫治疗敏感，而非吸烟者则不那么敏感。因此，在伴有EGFR/ALK以外的其他致癌驱动基因时，免疫疗法可能在一线治疗中没有用武之地，但临床医生需要与医疗机构和患者进行知情讨论，因为目前尚不清楚免疫治疗能否产生影响。

 

Dr.Peters:The question is how much is immunotherapy valid in the oncogenic addiction setting of advanced NSCLC.First of all，I think you need to be very cautious about what we know.What we know the most is the systematic exclusion of EGFR and ALK.These are the two important targets.For ALK，we have seen very little activity and haven’t seen any convincing data that immune checkpoints are valid in ALK-positive disease.I would really not prescribe in this disease setting.Similar to ALK and even less studied，RAF1 and MEK are also diseases with very low immunogenicity，low PD-L1，low mutational burden.We know that with the ALK family，RAF1 and MEK are the same types of tumors，but EGFR is not so black and white.My colleague from Taiwan，Gee-Chen Chang keeps telling me that it has some activity in EGFR mutant，but you probably need to keep it in reserve for late lines in combination with chemo and probably antiangiogenics.When combining with chemo is not sufficient to make a difference，in IMpower150，in ATTLAS，in HARMONi-8，giving an anti-angiogenic gives rise to a benefit.So，there is room for immunotherapy in EGFR when you combine immunotherapy and something else，maybe an anti-angiogenic，or maybe another bispecific in the future，maybe T-cell engagers too.I think there is room in this setting.Remember that KRAS G12C is very sensitive to immunotherapy.When you are a smoker with BRAF and MET exon 14，you might be sensitive too，less for non-smokers.So，in other oncogenic settings，maybe not useful in frontline，but you need to have this informed discussion with your institution and your patient because it is not clear that it has no impact.

 

Dr.Peters：免疫治疗的停止时机仍存在争议。很多国家的患者别无选择，因为大多数晚期肺癌免疫治疗的临床试验通常设定2年为治疗期限，因此医疗报销到时停止，患者只能停药。然而，有些国家不考虑这个问题，可支付持续治疗的费用。

 

KEYNOTE-024和KEYNOTE-189模拟了接受2年免疫治疗后停药的患者与继续治疗患者的长期结局。若肺癌完成2年免疫治疗后停药，病情得到控制，仍有超50%的患者会在后续3年内复发；如果对复发速度进行模拟，免疫停药后可能存在"复发加速"现象，因此疾病进展的风险会增加，这一现象值得临床医生与患者进行讨论。目前尚不清楚持续免疫治疗能否改变这些动力学数据，但可能性很高（50%是很高的概率）。虽然无法确定延长免疫治疗能否阻止上述不利情况，但医患共同决策很重要。基于个人经验，我的大多数患者更倾向持续治疗直到疾病进展，而非主动停药。

 

Dr.Peters:The time to stop immunotherapy is a matter of debate.Basically，in many countries，you have no choice.Most of the trials stopped at three years，so reimbursement stops at three years.But some countries don’t look at it and can afford to continue.Otherwise，we don’t know.We simulated from the KEYNOTE-24/KEYNOTE-189 what would happen after stopping versus if you continued.If you stop at two years and the patient is controlled，more than 50%will relapse in the next three years.If you simulate the pace of relapse，it looks like an acceleration.When you stop，there is an acceleration in simulations，so an increased risk of progression.This is what you need to discuss with your patient.I don’t know if continuing will change these kinetics，but you need to know that there is a high probability(50%is a high probability).I don’t know that continuing would prevent it，but you can make that decision together.In my experience，most of my patients continue until they experience progression，but most of my patients don’t want to stop.

 

Dr.Peters：我非常欣赏此次会议的内容，因为2025 ELCC展示的一系列II期临床试验为解决耐药和探索生物学机制提供了新机遇。2025 ELCC发布了一系列令人惊叹的靶向疗法研究数据，例如在KRAS抑制领域，我们获得了更多关于调节KRAS抑制的信息。

 

2025 ELCC最重要的讨论是对于EGFR突变NSCLC患者，如何通过MARIPOSA方案延长生存期，尽管毒性增加带来挑战。此外，对于发生MET扩增（一种常见耐药机制）的患者，如何使用埃万妥单抗（amivantamab）靶向治疗来解决问题。

 

我认为，EGFR突变NSCLC治疗正在重新定义，这非常重要。在瑞士，EGFR突变阳性肺癌的占比相对较低，但在亚洲这类患者约占一半，因此这一话题具有非常重要的临床意义。2025 ELCC发布的关键信息将重新定义EGFR突变NSCLC治疗，推动共识和指南的更新，进一步优化EGFR突变NSCLC的一线及后线治疗策略。

 

Dr.Peters:This is a Congress that I like because they present some phase II trials，new opportunities for addressing resistance，of addressing biological questions.I think we have seen today an amazing range of targeted therapies.KRAS inhibition-how you can modulate KRAS inhibition.The most important debate we had at this meeting was how to prolong the life of EGFR mutated patients with the improvement in survival of MARIPOSA，although toxicity is a challenge.MET amplification–this is often encountered，and how to address it with targeted therapy with amivantamab.I think we are redefining these diseases，which is extremely important.I am from Switzerland where it is not so important，but this is half of the patients in Asia，so it is a hugely important topic.I think this meeting has been key in trying to redefine the journey of these patients with EGFR mutants.If I had to pick one key message，with redefinition，we need to work on consensus and guidelines，what to do first，and what to do next in EGFR mutant NSCLC.

 

《肿瘤瞭望》在ELCC现场报道