在2024年美国临床肿瘤学会（ASCO）年会上，英国皇家马斯登医院NHS基金会信托Sanjay Popat教授报告了随机Ⅲ期BEAT-meso（ETOP13-18）试验中阿替利珠单抗-贝伐珠单抗-卡铂-培美曲塞（ABC）vs贝伐珠单抗-卡铂-培美曲塞（BC）一线治疗不可切除的恶性胸膜间皮瘤（MPM）患者的疗效（摘要号LBA8002）。

 

关于BEAT-meso试验的主要终点总生存（OS），ABC组vs BC组的中位OS为20.5个月vs 18.1个月（HR=0.84，P=0.14），2年OS率分别为40%vs 38%，差异未达到统计学显著性。亚组分析显示，非上皮样亚型（HR=0.50）、PD-L1 TPS≥1%（HR=0.66）、EORTC评分预后差（HR=0.60）的患者可从ABC治疗中获得OS显著获益。在非上皮样亚型患者中，ABC组vs BC组的中位OS为17.9个月vs 10.0个月（HR=0.50，P=0.0022），2年OS率分别为29%vs 14%。在无进展生存（PFS）方面，ABC组较BC组显著延长患者的PFS，中位PFS分别为9.2个月vs 7.6个月（HR=0.72，P=0.0020）。

 

在《肿瘤瞭望》现场采访中，Dr.Popat进一步对BEAT-meso试验发现予以点评。

 

Dr.Popat：BEAT-meso（ETOP13-18）试验是一项针对不可切除的胸膜间皮瘤患者的随机III期试验，评估了阿替利珠单抗联合化疗加贝伐珠单抗（ABC）是否优于最佳对照组的化疗加贝伐珠单抗。ABC方案是有效的，但不幸的是，整体方案没有达到预先设定的OS主要终点，生存优势并不具有统计学意义。然而，这可能是由于间皮瘤有两种主要组织学类型——上皮样亚型和非上皮样亚型。

 

BEAT-meso试验：不同组织学亚型患者的OS

 

我们在BEAT-meso试验通过多变量分析来调查研究方案有效的因素，结果发现ABC方案在非上皮样亚型中最有效，具有非常强的OS优势，风险比为0.5，OS差异具有统计学意义。相比之下，在上皮样亚型患者组中没有看到生存优势，尽管我们确实看到了小的PFS获益，但存在交叉，这减弱了生存优势。

 

BEAT-meso试验：不同组织学亚型患者的PFS

 

总而言之，ABC方案不能说是胸膜间皮瘤的标准一线方案，因为整体试验未达到主要终点。然而，在双相型、肉瘤样型这种非上皮样亚型患者中，ABC方案存在强大的生存优势，风险比为0.5。

 

Dr.Popat:The BEAT-meso trial，the ETOP 13-18 trial，a randomized phase III trial for patients with unresectable pleural mesothelioma，evaluated whether combination chemotherapy with bevacizumab/atezolizumab(ABC)was superior to the best control arm of chemotherapy plus bevacizumab.The regime was active，but unfortunately the overall regime did not meet the pre-specified primary endpoint of overall survival with a survival advantage that was not statistically significant.However，this was probably driven by the fact that mesothelioma is two main histologies-epithelioid and non-epithelioid.

 

When we look at multivariable analysis to investigate factors where the investigational regime was active，we identified that the regime was most active in the non-epithelioid subtype，but here we had a very strong survival advantage with a hazard ratio of 0.5，which is statistically significant in the non-epithelioid tumors，and a median survival of 22 months.By comparison，in the epithelioid group，we didn’t see a survival advantage，although we did see a small PFS benefit，but there was crossover which mitigated the survival advantage.

 

In summary，the regime of ABC cannot be said to be standard because the overall trial did not meet the primary endpoint.However，in the biphasic sarcomatoid non-epithelioid group，there was a strong survival advantage with a hazard ratio of 0.5 with a median survival of 22 months.

 

Dr.Popat：这个问题实际上是ABC方案（化疗/阿替利珠单抗/贝伐珠单抗）是否比纳武利尤单抗（nivolumab）/伊匹木单抗（ipilimumab）更有优势。我认为，在上皮样亚型的间皮瘤患者中，我们不能说ABC方案能带来获益，尽管这是一种间接比较，因为纳武利尤单抗/伊匹木单抗不在BEAT-meso试验范围内。但是，对于上皮样亚型，起始治疗采用铂类和贝伐珠单抗是非常合理的（如果临床医生希望采用这种方案的话），以期将免疫检查点抑制剂作为二线治疗。当然有生存数据支持这是一种合理的策略。然而，非上皮样亚型患者确实需要首先使用免疫检查点抑制剂。个人认为我们实际上可以为这组患者考虑两种选择。

 

在Checkmate 743试验中，一线治疗方案采用纳武利尤单抗/伊匹木单抗，但这是一种PFS曲线和OS曲线交叉的方案，并且会发生早期事件，并且该方案具有明显的毒性特征。关于BEAT-meso试验的ABC方案，对于非上皮样亚型患者，ABC具有很强的生存优势，并且我们没有看到PFS曲线或OS曲线交叉，不良事件发生率相当。我们可以说，ABC将是非上皮样亚型患者的潜在方案。

 

Dr.Popat:The question really is whether the ABC regime of chemotherapy/atezolizumab/bevacizumab has a benefit over nivolumab/ipilimumab.I think in the epithelioid group of mesothelioma patients，we cannot say there is a benefit for that，although we are making indirect comparisons because nivolumab/ipilimumab was not within the trial.However，for the epithelioid group，I think it is very reasonable to start with platinum and bevacizumab if you wanted to do that，with a view to going to checkpoint inhibitors second-line.There certainly are survival data which would support that as a reasonable strategy.However，in the non-epithelioid group，these patients do need checkpoint inhibitors upfront.I think we have really two options we can think about for this group of patients.

 

We have nivolumab/ipilimumab upfront as per the Checkmate 743 trial，but it is a regime with crossing of the PFS curve and also the OS curve with early events occurring.And it has an appreciable toxicity profile.With the BEAT-meso regime，the ABC regime，there was a strong survival advantage with ABC for the non-epithelioids，and we did not see the PFS curve or the OS curve crossing over.The adverse event rate was much more comparable to the chemo/IO regime than the IO/IO doublet.One could make the argument that that would be a potential regime for the non-epithelioid group.

 

Dr.Popat：关于2024 ASCO报道的胸膜间皮瘤研究进展，大家对BEAT-meso试验结果翘首以待，想看看这项试验能否影响胸膜间皮瘤的临床实践。我认为你的提问可能提出一个论点，即BEAT-meso试验结果可能会影响非上皮样亚型的临床治疗，也可能会影响上皮样亚型，因为临床医生可能不一定希望为这些患者选择纳武利尤单抗/伊匹木单抗作为一线治疗。纪念斯隆-凯特琳癌症中心的专家小组研究了纳武利尤单抗/化疗在间皮瘤手术前的作用，有一些非常好的转化数据，但是我认为该数据集确实让我们担心一些患者可能无法接受手术，但它仍然是一个很好的转化数据集。

 

我的同事Dean Fennell教授在2024 ASCO上报告了MIST5单组试验（摘要号8017）。这项多中心IIa单组试验将尼拉帕利与dostarlimab联合用于先前接受过铂类双药一线化疗且疾病控制时间>6个月的复发性间皮瘤患者。MIST5试验达到了主要终点12周时疾病控制率（DCR12w为65.4%，总体疾病控制率为80.8%），并且有大约15.4%的治疗反应率。我认为MIST5试验的治疗方案值得关注，并且已经有了一些非常好的转化研究数据，表明肠道微生物群可能会影响免疫检查点抑制剂治疗对间皮瘤的敏感性。

 

Dr.Popat:In terms of pleural mesothelioma at this Congress，I think the BEAT-meso trial was the trial that everybody was waiting for to see whether it impacted on their practice.I think you may make an argument that it could impact on your practice for the non-epithelioid group，and it may impact on the epithelioid group insofar as you may not want to necessarily go for nivolumab/ipilimumab in frontline for those patients.The other dataset we had from the Memorial Sloan Kettering group was looking at the role of nivolumab/chemotherapy prior to surgery for mesothelioma.It has some very nice translational data，however，I think that dataset really did give us the concern we have that patients might not get to surgery，but is still a nice translational dataset.

 

My colleague，Professor Dean Fennell，reported the MIST5 single arm trial at ASCO，which is a single arm cohort of combination niraparib together with dostarlimab in patients with relapsed mesothelioma who have relapsed with more than six months of benefit from their first-line therapy.This trial met the primary endpoint of disease control rate，and there were also around 15%responses.I think this is a regime to keep an eye on，and there was some very nice translational data coming out of this，suggesting that the role of the gut microbiome may influence the impact of immune checkpoint inhibitor sensitivity in mesothelioma.

 

参考文献

 

Popat S，et al.BEAT-meso:A randomized phase III study of bevacizumab(B)and standard chemotherapy(C)with or without atezolizumab(A)，as first-line treatment(TX)for advanced pleural mesothelioma(PM)—Results from the ETOP 13-18 trial.Abstract#LBA8002.Presented at the 2024 American Society of Clinical Oncology Annual Meeting;May 31-June 4，2024，Chicago，Illinois.