LUMINOSITY是一项单臂II期研究，在经既往治疗失败的EGFR野生型c-MET过表达晚期非鳞状非小细胞肺癌（NSCLC）患者中评估Teliso-V单药方案的有效性和安全性。2024 ASCO汇报的初步研究结果（摘要103）显示，Teliso-V在c-MET高表达患者中的客观缓解率（ORR）为34.6%，中位缓解持续时间（DOR）为9.0个月；在c-MET中等表达的患者中的ORR为22.9%，中位DOR为7.2个月。在生存期方面，Teliso-V在c-MET高表达患者中的中位无进展生存（PFS）为5.5个月，中位总生存（OS）为14.6个月，在c-MET中等表达的患者中的中位PFS为6个月，中位OS为14.2个月。最常见的治疗相关不良事件（TRAEs）是周围感觉神经病变（30.2%）、外周水肿（16.3%）和疲劳（14%）等，2例患者（1.2%）出现5级TRAEs（间质性肺病、呼吸衰竭）。

 

在《肿瘤瞭望》采访中，Dr.Camidge进一步解读LUMINOSITY试验对临床治疗的影响。

 

Dr.Camidge：我在2024 ASCO介绍了LUMINOSITY试验的结果，这是一项II期研究，研究一种名为Teliso-V的抗体-药物偶联物（ADC），Teliso-V是靶向c-Met表达的首创药物，采用微管蛋白抑制剂MMAE为弹头。

 

LUMINOSITY研究观察了二线或三线治疗中非鳞状组织学类型、EGFR野生型NSCLC患者，最重要的信息是，每个参与研究的患者都必须具有中度或高度Met表达（在肺癌人群约占25%）。如果Met水平较高，则Teliso-V的治疗反应率会更高，大约为34.6%（中等表达患者的ORR为22.9%）；但无进展生存期非常相似，中等表达组和高表达组均为约6个月；总生存期也非常相似，两组皆约为14-15个月。

 

LUMINOSITY试验：PFS和OS

 

Teliso-V的毒性主要以周围感觉神经病变为主，这是一种迟发性副作用，反映了剂量累积对于从药物治疗中获得实际长期获益患者的影响；还有某种程度上的间质性肺疾病（ILD），有三例死亡归因于ILD，ILD总体发生率为9.9%。综上，ADC药物也发生了这种程度ILD，用药时应谨慎，需要尽早识别ILD并采取处理措施。但总体而言，Teliso-V是一种有效的药物。

 

LUMINOSITY试验：不良事件

 

特别关注不良反应（包括ILD）

 

Dr.Camidge:Today I presented the results of LUMINOSITY，which was a phase II study looking at an antibody-drug conjugate called Teliso-V，which is the first-in-class directed against surface Met expression，and carries an MMAE warhead，which is a microtubule disrupting agent.

 

The study looked in patients who were EGFR wildtype with non-squamous histology in the second-or third-line setting.The headlines were that everybody to get into the study had to have either intermediate or high Met expression，which together represent about 25%of that lung cancer population.The response rate was higher if you had high Met-something like 34%versus around 22%for the intermediate-but the progression-free survival was very similar-about six months for both arms.The overall survival was also very similar at about 14-15 months.The toxicities were mostly dominated by peripheral neuropathy，which was a late onset side effect，reflecting cumulative exposure in patients who were actually deriving long-term benefit from the drug，and to some extent，interstitial lung disease.There were actually three deaths attributed to interstitial lung disease.The overall rate of interstitial lung disease was 9.9%.So this happened with antibody-drug conjugates，so we have to use them with caution and to recognize interstitial lung disease early and act on it.But this is a drug that works.

 

Dr.Camidge：ADC药物有很多种，在以下方面各不相同：ADC靶点、连接子和有效载荷。两种主要的有效载荷是MMAE（微管蛋白破坏剂）和以及拓扑异构酶1抑制剂，前者主要副作用是周围神经病变，后者主要副作用是骨髓抑制。然而，还有其他副作用，这些副作用取决于抗体靶标以及细胞毒素针对的位置。

 

一些TROP2 ADC已经显示出治疗活性，一种是Daiichi/AstraZeneca开发的Dato-DXd，另一种是Gilead开发的sacituzumab govitecan，但毒性肯定有点令人担忧，会导致口腔炎和脱发。根据2024 ASCO报道的结果，Gilead开发的TROP2 ADC对比多西他赛的EVOKE-01研究在技术上是一项阴性研究——两组几乎没有区别；其耐受性略好一些，所以该药物看起来不太有前景。Daiichi最近发布了一份新闻稿，表明尽管Dato-DXd治疗使经治局部晚期/转移性非鳞状NSCLC患者的无进展生存PFS略有改善，但总生存OS并未提高（非鳞状NSCLC患者中OS有获益趋势）。TROP2 ADC的研发正在苦苦挣扎。

 

我认为问题是，这类ADC是否只需要针对不同的靶标，因此导致不同的毒性模式，既不涉及脱发和口腔炎，又能改变疗效。目前这些药物获得20%的反应率和3~4个月的中位PFS，还不足以击败多西他赛。

 

Dr.Camidge:There are many antibody-drug conjugates，and they vary in terms of:what they are directed against;to some extent，the linker;and to some extent，the payload.The two dominant payloads are MMAE(microtubule disrupting agent)，which has a major side effect of peripheral neuropathy，and topo-1 inhibitors，which have a major side effect of myelosuppression.However，there are other side effects that are derived by what the antibody is directed against and where else that toxin is directed.

 

TROP2 agents，one by Daiichi/AstraZeneca and the other by Gilead，have shown some activity，but certainly the toxicity is a little concerning，with stomatitis and alopecia.What we saw this year at 2024 ASCO is that the Gilead drug，when compared to docetaxel was technically a negative study-there was very little difference.It was somewhat better tolerated.So that is not looking very promising.The Daiichi study had a press release recently that showed although there was a minor PFS benefit in the non-squamous population，the overall survival was not improved.So I think TROP2 agents are struggling.

 

I think the question is，do they just need a different target to be directed to so we get a different pattern of toxicity that doesn’t involve alopecia and stomatitis，but also will be able to change the efficacy.A 20%response rate，and a median progression-free survival of 3 or 4 months is not good enough to beat docetaxel at present.

 

Dr.Camidge：在安全性方面，我认为，未来将在一定程度上根据安全性选择ADC所靶向的表位。现在ADC药物攻击的部分与正常组织重叠太多，以至于患者或医生都无法接受。我认为，关于与弹头类型相关的一些副作用（MMAE型弹头的周围神经病变、拓扑异构酶1型弹头的骨髓抑制），当这些ADC应用于患者并使用较长时间后，我们会逐渐学会如何管理用药相关的副作用。

 

下面谈一谈两种不良反应的管理策略：(1)对于间质性肺疾病，我们必须学会在严重程度为1级时识别这种副作用，当间质性肺疾病只是在扫描中发现但没有症状时，不要将其误认为其他疾病，并积极使用类固醇进行干预，我认为间质性肺疾病管理领域正在经历一个学习曲线；(2)另一个是与微管蛋白破坏剂相关的周围神经病变，也许在患者获得良好治疗反应之后、发生周围神经病变之前，需要安排治疗中断，或减少剂量，或增加治疗间隔，因为当患者情况良好时，可能不需要每两周或每三周继续推入这种药物。

 

Dr.Camidge:In terms of safety，I think we are going to pick the epitope that these antibodies are directed against to some extent based on safety.I think we will find things that have too much overlap with normal tissues for them to be acceptable to patients or to physicians.I think some of the things that we are perceiving as class effects associated with the warhead-peripheral neuropathy with the MMAE-type warheads，myelosuppression with the topo-1-type warheads-we will learn as we get people on these drugs and they are on them for a long time，to manage how we give them.

 

Two things come to mind.Certainly，for interstitial lung disease，we have to learn to recognize it when it is Grade 1，when it is just showing up on the scans and there are no symptoms，not mistake it for something else，and actively intervene with steroids.I think there is a learning curve going on in the field for that.The other is peripheral neuropathy associated with the microtubule disruption agents.Maybe after you have had a good response and before you have got peripheral neuropathy，we need to have scheduled breaks from treatment，or reduce the dose，or more gaps between it，because maybe we don’t need to keep pushing this drug in every two weeks or every three weeks when the patient is doing well.

 

参考文献：Camidge，D，et al.Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC:Primary analysis of the LUMINOSITY trial.2024 ASCO，abstract 103.