抗体偶联药物（ADC）是肺癌治疗领域备受瞩目的新兴力量，正在变革肺癌治疗的格局。在2025年欧洲肺癌大会（ELCC）"下一代ADC"教育专场上，西班牙巴塞罗那医院Noemi Reguart教授就"ADC治疗非小细胞肺癌的当前挑战"进行了专题报告。会后，Reguart教授接受《肿瘤瞭望》独家专访，深入解析了ADC治疗肺癌的临床应用策略、当前挑战及安全性管理等关键议题。

 

Dr.Reguart：我是西班牙巴塞罗那医院的肿瘤内科医生Noemi Reguart，正在美丽的巴黎参加2025年欧洲肺癌大会。

 

ADC虽然本质上仍属于化疗，但它采用不同的靶向递送细胞毒性药物到细胞内的技术。ADC是胸部肿瘤治疗领域的最新进展之一，但在肺癌中的应用目前落后于其他肿瘤类型。研究人员正在肺癌不同阶段检验和探索ADC的作用，目前已批准用于肺癌的ADC药物是德曲妥珠单抗（trastuzumab deruxtecan），适用于HER2突变型肿瘤患者。除此之外，虽然ADC尚未获批用于驱动基因阴性肺癌，但根据2025 ELCC的报道，去年开展的研究在一线治疗探索了ADC联合免疫疗法，在驱动基因阳性患者靶向治疗进展后评估了ADC二线治疗。显然，ADC领域即将迎来变革，可以确定在未来一两年内，我们有望看到越来越多的试验推动ADC取代目前使用的化疗。

 

ADC药物在肺癌治疗中面临的挑战之一是“具有不同毒性特征”。ADC具有不同于化疗的特异性毒性，其毒性谱非常复杂，取决于有效载荷、抗体选择以及靶蛋白的表达水平。由于ADC通过与细胞表面蛋白结合来发挥作用，而这些蛋白并非肿瘤独有，可能同时存在于健康组织中，因此可能导致特定脱靶毒性，具体取决于靶蛋白在肿瘤中的表达分布。

 

临床医生需要学习如何安全地处理ADC的毒性，结合预防措施和恰当的随访方案。在肿瘤学领域，我们正在深入了解ADC新药及其独特毒性谱，在证实某种ADC可为患者带来显著获益时，我们会继续想方设法减轻其毒性。

 

Dr.Reguart:Hello everyone.I am Noemi Reguart.I am a medical oncologist at the Hospital Clinic Barcelona，Spain.We are here at the European Lung Cancer Conference 2025 in the beautiful city of Paris.

 

ADCs are one of those technologies that，although it is chemotherapy，has a different way of delivering the cytotoxic payload into the cells.It is one of the newest developments in the field of therapy for thoracic tumors.In lung cancer，the use of ADCs has lagged behind other oncological diseases，but we are now seeing ADCs being tested and explored in different settings.There is one approval in lung cancer with ADCs，which is trastuzumab deruxtecan，approved for patients with HER2 mutant tumors.Beyond that，right now，we don’t have approvals in the non-oncogenic addicted settings，but we have seen at this conference that during the last year，ADCs are being explored in the first-line setting in combination with immunotherapy，and also in the second-line setting in those patients with oncogenic alterations after progression.So，it is a field that is going to change.For sure，in the next one or two years，we are going to see more and more trials incorporating these specific ADCs in place of current chemotherapy.One of the challenges is how we are going to approach the different toxicities with these drugs.These drugs have a really specific toxicity profile which is very different to chemotherapy.It is very complex issue—it depends on the payload，the antibody used，and the level of target expression protein.As you know，the ADCs bind to the protein on the surface cells，and sometimes these proteins are not exclusive of the tumor—they can also be expressed in healthy tissues.So，sometimes ADCs are associated with specific off-target toxicities，depending on the expression of these proteins within the tumor.We will need to learn how to handle these safely and how to integrate prophylactic measures and appropriate follow-up for these patients.This is what we do in oncology–we are learning more about new drugs and their unique toxicity profiles，and we always find ways to mitigate these toxicities when we see that these drugs are providing clear benefits for our patients.

 

Dr.Reguart：ADC代表着一项新技术，将抗体、有效载荷进行链接，是一种巧妙的化疗递送方式，抗体与肿瘤细胞上表达的蛋白结合，并将细胞毒药物直接递送到细胞内，最终杀死细胞。ADC面临的最大挑战之一是靶蛋白可以在肿瘤外的非肿瘤组织表达，如果靶蛋白对于肿瘤特异性不高，就会产生脱靶毒性（这种毒性本不应该存在）。ADC的毒性取决于几个因素——有效载荷的稳定性、细胞靶蛋白、抗体和有效载荷的化疗类型。ADC毒性管理需要学习曲线。

 

不同类型的ADC具有特定的安全性特征，其毒性谱可能存在显著差异。在不久的将来，随着ADC被整合到更多肺癌治疗方案中，我们将不得不学习ADC毒性管理并采取预防措施。预防性毒性管理非常重要，也是我们正在积极学习的内容，已在COCOON试验和MARIPOSA试验中得到验证——COCOON试验将预防性管理措施纳入患者管理，从而减轻了双特异性抗体埃万妥单抗联合兰泽替尼方案的毒性。这就是未来的探索方向。相信随着时间推移和学习曲线效应，我们能够管理好ADC的安全性。

 

Dr.Reguart:As I mentioned earlier，ADCs represent a novel technology.It is an antibody that has a link to which a payload is bound.The way to think of it is as a clever way to deliver chemotherapy:the antibody binds to the protein that is expressed on the tumor cell，and it carries the toxic drug that is delivered directly into the cell，ultimately killing it.One of the most important challenges with these ADCs is that those target proteins can be expressed in non-tumor tissues(off-tumor)，and that’s why they can produce off-target toxicity–toxicities that should not be there，but if the protein is not highly specific to the tumor，you will find them.Each antibody has its own specific toxicity.It depends on several factors–the stability of the payload，the cell target protein，the antibody，and the type of chemotherapy used in the payload.It’s a learning curve.You have to remember that，depending on the ADC you are looking at，you are going to have a specific safety profile，which can vary significantly between different ADCs.In the near future，if we have these antibodies integrated into more lung cancer scenarios，we will have to learn to handle these toxicities and implement prophylactic measures.This is very important，and something that we are actively learning.We have seen this with the use of the bispecific amivantamab，in the COCOON trial and the MARIPOSA trial—that if you integrate prophylaxis into patient management，you can mitigate the toxicities.This is the future.I am sure，with time，the learning curve will allow us to manage the safety profiles of ADCs.

Dr.Reguart：III期MARIPOSA试验的最终总生存期（OS）数据非常精彩，这是我们一直期待的研究结果。在EGFR突变型非小细胞肺癌一线治疗中，几种治疗策略正在被探索。当前标准治疗方案是奥希替尼，每日一片口服非常方便，安全性良好，中位OS约为38个月。我们希望在此基础上更进一步，这意味着必须探索一线联合治疗策略，已开展的探索包括正在进行中的TROPION-Lung14试验（奥希替尼联合ADC）、FLAURA2研究（奥希替尼联合化疗）以及MARIPOSA试验（双特异性单克隆抗体埃万妥单抗联合兰泽替尼）。

 

MARIPOSA试验结果为阳性，早期已证实埃万妥单抗+兰泽替尼可显著改善无进展生存期（PFS），尽管那时只有OS初步数据。本次ELCC报道的MARIPOSA更长时间随访数据显示，虽然埃万妥单抗/兰泽替尼方案的中位OS尚未达到，但对OS产生了积极影响，OS曲线早期即分离，且随着时间推移分开程度变大。这是首次证明奥希替尼单药治疗以外的其他联合策略改善一线OS的研究。但需特别注意，埃万妥单抗方案存在较高的毒性发生率，具有特定的毒性特征。

 

2025 ELCC还展示了COCOON试验结果（摘要10MO），该试验旨在整合多种策略来降低埃万妥单抗联合兰泽替尼的毒性。通过预防性强化管理方案（主要针对指甲和皮肤护理），3级不良事件的发生率显著降低。患者个体化用药至关重要——未来仍需探索哪些患者能从这种联合治疗策略中获益最多，将这种预防措施整合到临床实践中以改善毒性特征也至关重要。

 

Dr.Reguart:I would have to say the final overall survival data from the phase 3 MARIPOSA trial was a really nice presentation.This was one of the things we were expecting，because we know there are several strategies being explored in the first-line setting of EGFR mutant NSCLC.We had osimertinib as standard-of-care—an oral drug，one pill per day.It was very easy to take，the safety profile was very good and it showed an overall survival of 38 months.What we wanted，though，was to improve on that.Improving on that meant having to explore combination strategies—and there are several being investigated right now.One of them，TROPION-Lung14，is combining the ADCs we have been talking about with osimertinib in the first-line setting.This trial is currently ongoing.Another strategy is the FLAURA2 study，which combined chemotherapy with tyrosine kinase inhibitors.Then we had the MARIPOSA trial，which evaluated a different type of drug—amivantamab，a bispecific monoclonal antibody—combined with lazertinib.This trial was positive，demonstrating a significant improvement in progression-free survival，although at the time we had only preliminary data on overall survival.At this ELCC Conference，they presented longer follow-up on overall survival.Although the median overall survival for amivantamab/lazertinib has not been reached，it is already having a positive impact on overall survival.The curves separated early and then widened over time.It is the first study demonstrating that another combination strategy beyond the tyrosine kinase inhibitors can indeed improve overall survival in first-line setting.Very importantly，though，amivantamab is associated with a higher rate of toxicity.It has a specific toxicity profile.Here at the ELCC 2025，they have also presented the COCOON trial，which is a way of integrating strategies to mitigate the toxicity of amivantamab.With this intensive prophylaxis regimen，looking mainly at nail and skin care，we saw how the incidence of Grade 3 adverse events decreased dramatically.It is important to individualize patients–we still need to know which patients will benefit most from these combination strategies.It will also be very important to integrate this prophylaxis into clinical practive to improve the toxicity profile of new therapies.

 

《肿瘤瞭望》在ELCC现场报道