根据2024年ASCO年会上公布II期BrUOG 354试验（NCT03355976）的数据，与纳武利尤单抗（nivolumab）单药治疗相比，纳武利尤单抗+伊匹木单抗（ipilimumab）的缓解率更高，并且改善了卵巢透明细胞癌患者的预后。研究作者、罗德岛医院Lifespan癌症研究所Don S.Dizon在《肿瘤瞭望》访谈中对研究结果以及卵巢癌免疫治疗相关不良反应的处理策略予以解读。

 

BrUOG354试验共招募了44名患者，包括36名卵巢癌患者，6名子宫癌患者，2名其他肿瘤类型患者。患者的中位年龄为57岁，大多数为白种人。在单药治疗组（n=14）中，患者每2周静脉注射240 mg纳武利尤单抗。在联合治疗组（n=30）中，每2周静脉注射240mg纳武利尤单抗，每6周静脉注射1mg/kg伊匹木单抗。数据截止时间为2023年12月31日，中位随访时间为11.3个月。主要终点是总体缓解率（ORR），次要终点是PFS、OS和不良反应（AE）。

 

在免疫联合组和免疫单药组，完全缓解（CR）率分别为16.7%和0%，部分缓解（PR）率分别为16.7%和14.3%。综合CR和PR，ORR分别为33.3%和14.3%。此外，免疫联合组和免疫单药组分别有33.3%和35.7%的患者病情稳定（SD），33.3%和50%的患者病情进展（PD）。联合组的中位缓解持续时间为22.4个月±11.8个月，单药组为30.6个月±4.5个月。

 

图1.肿瘤缓解情况

 

免疫联合组的中位无进展生存期（PFS）为5.6个月（95%CI:1.6-29.1），而单药治疗组为2.2个月（95%CI:1.2-3.4）。中位总生存期（OS）分别为24.7个月（95%CI:5.9-未达到）和17.3个月（95%CI:2.1-42.7）。

 

图2.无进展生存

 

图3.总生存

 

在接受免疫疗法治疗的妇科透明细胞癌患者中，没有发现新的安全信号。在免疫联合组中，任意级别的不良反应（AE）主要包括疲劳（22.5%）、瘙痒（26.7%）和甲状腺功能减退（20.0%）。在单药治疗组中，任意级别AE包括甲状腺功能减退（35.7%）、斑丘疹（14.2%）、血栓栓塞（7.1%）和腹泻（7.1）。一名患者因3级肌酐升高而退出研究。进行了肾脏活检，发现间质性肾炎，与药物治疗反应一致。患者接受了类固醇治疗，治疗6周后CT扫描显示PR。

 

图4.不良反应

 

Dr.Dizon:BrUOG 354是一项II期非对比临床试验，研究了纳武利尤单抗单独使用或与伊匹木单抗联合使用对透明细胞癌患者（不包括肾脏肿瘤）群体的影响。所有参与试验的患者都患有妇科癌症，其中超过80%（36/44）患者患有卵巢透明细胞癌。BrUOG 354试验得出的最重要的结论是，免疫疗法是透明细胞癌患者重要且可用的治疗选择，需要的人应该获得和使用这种疗法。

 

BrUOG 354试验的主要结果是，纳武利尤单抗组的ORR约为14.3%，其中包括两名患者达到部分缓解，但没有患者出现完全缓解。联合伊匹木单抗的方案使缓解率飙升至33.3%，其中包括5名完全缓解的患者。

 

比较单一免疫治疗和两种免疫药物联合使用的生存数据：中位PFS分别为2.2个月和5.6个月，中位PFS分别为17.3个月和24.7个月。重要的是，对纳武利尤单抗+伊匹木单抗联合治疗有应答的患者，其治疗反应具有持久性，并且有几名患者仍在参加临床试验，并且能够继续接受治疗超过两年。

 

对透明细胞癌患者进行免疫治疗时，没有发现新的安全信号。BrUOG 354试验中的主要毒性是甲状腺功能减退症，单药组和联合组的发生率分别为35.7%和20%。所以，从安全性考虑，我希望BrUOG 354试验数据能让临床医生在治疗这些罕见透明细胞肿瘤时更有信心地使用免疫疗法。

 

Dr.Dizon:BrUOG 354 was a phase II non-comparative clinical trial that looked at nivolumab alone or in combination with ipilimumab in a population of patients who have clear cell cancers outside of the kidney.Everyone who was enrolled had a gynecological cancer，with 85%of our patients enrolled having ovarian clear cell cancers.The top-line conclusion is that immunotherapy is important and available for people with clear cell cancers，and should be accessed and used by people who need it.

 

The top-line results of the trial were that nivolumab is associated with an overall response rate of about 13%，and that included two partial，but no complete responses.With the combination，the response rate shoots up to 33%，and that included five people who did have a complete response.The median progression-free survival if you look at single agent versus the combination was 2.2 and 5.6 months respectively.And median overall survival was 17 and 24 months respectively.Now importantly，people who did respond to the combination of nivolumab and ipilimumab had durability in that response，and there are several people who still remain on the clinical trial and who had been able to stay on treatment for over two years.

 

There are no new safety signals that were seen when you give immunotherapy to people with clear cell cancers.The major toxicity we saw was hypothyroidism in about 30%and 20%of people respectively.So I think at this point，it hopefully will enable clinicians to utilize immunotherapy with a bit more confidence when they are treating people with these rare tumors，called clear cell.

 

Dr.Dizon：2024 ASCO介绍的另一项研究免疫疗法的试验是AGO-OVAR 2.29/ENGOT-ov34。该试验是在铂耐药卵巢癌受试者中进行的。ENGOT-ov34试验采用的对照标准治疗是抗血管生成抑制剂贝伐珠单抗联合化疗以及安慰剂。研究组包括化疗、贝伐珠单抗和免疫检查点抑制剂阿替利珠单抗。ENGOT-ov34的主要结论是，在all comers人群中，加用阿替利珠单抗治疗并没有生存获益（未改善PFS和OS）。有人认为（这也许是未来试验的基础），阿替利珠单抗的益处与紫杉醇的使用和之前使用贝伐珠单抗有关。这些都不是结论性的，只是一种提示。

 

将阿替利珠单抗与化疗和贝伐珠单抗一起使用时，副作用肯定更高。我看到的ENGOT-ov34试验中的主要副作用是，使用阿替利珠单抗相比使用安慰剂发生疲劳的几率更高，胰腺炎发病率更高。有趣的是，疲劳可能是化疗和使用贝伐珠单抗造成的，而且这些患者往往因疾病而更加虚弱。同样，接受治疗的人群患有铂耐药卵巢癌，这是一种更有症状的癌症，因此患者可能出现疲劳的叠加。

 

首先，不管我们能否处理免疫治疗相关的疲劳，了解疲劳严重程度也很重要。就胰腺炎而言，在应用免疫疗法时观察到的胰腺炎可以是任何症状（从无症状的胰腺指标升高，到胰腺指标升高且胰腺炎疼痛，或发生糖尿病症状血糖升高）。其次，除了观察不良反应的严重程度，早期干预也很重要。如果患者有发生免疫治疗毒性的迹象（就像研究人员在BrUOG 354试验中所做的那样），则需要更仔细地检查，早期干预，以免毒性变得更严重。

 

Dr.Dizon:The other trial that looked at immunotherapy that was presented here was ov34，which was done in volunteers with platinum-resistant ovarian cancer.The standard treatment in that trial was chemotherapy with the angiogenesis inhibitor，bevacizumab，and a placebo.The investigational arm was chemotherapy，bevacizumab and the checkpoint inhibitor，atezolizumab.The major take home point there was that if you look at all comers，there was no survival advantage to the use of atezolizumab.There was a suggestion(and maybe the basis of a future trial)that the benefit of atezolizumab was tied to the use of paclitaxel，and the prior use of bevacizumab.Those are not conclusive，just suggestive.

 

The side effects profiles were definitely higher when you use atezolizumab with chemotherapy and bevacizumab.The main ones that I saw were higher rates of fatigue，higher rates of pancreatitis in the population who got atezolizumab versus those who got placebo.What is interesting about that is that the fatigue is something that may have been due to the chemotherapy anyway and the use of bevacizumab，as well as these patients are often times much sicker due to the disease.Again，the population treated had platinum-resistant ovarian cancer.These tend to be a bit more symptomatic of cancer.But it appears there was an additive fatigue.

 

Whether or not we were able to treat that and the grade of the fatigue is important to understand as well.In terms of pancreatitis，when we look at it with immunotherapy，it can be anything from an asymptomatic rise in the pancreas levels to the associated rise in pancreas levels with pain consistent with pancreatitis，or with an elevated glucose consistent with the onset of diabetes.Again，looking at the severity of that is important，but also early intervention is important.If people are showing signs of toxicity to immunotherapy(as they did in 354 as well)，it requires closer inspection so that the toxicities don’t become more severe.

 

Dr.Dizon：我认为，以下是这次ASCO报告的多项研究得出的非常有趣的结论。首先，如果仅添加一种免疫检查点抑制剂，不太可能成为卵巢癌的有效临床策略。卵巢癌免疫治疗有一个关键问题，我们需要研究将免疫疗法与另一种药物或治疗策略相结合，以期最大限度地发挥双重作用机制带来的获益。例如，可以尝试免疫疗法和贝伐珠单抗联合。联合治疗策略的标准相当高，特别是考虑到研究人员还没有一致确定单用免疫疗法是有效的治疗方法。

 

但另一种策略也很重要：我们需要能够预测哪些卵巢癌患者会从免疫治疗中获益。我在ASCO报告的BrUOG 354研究表明，对于具有透明细胞组织学类型的卵巢癌，免疫治疗很重要。事实上，透明细胞癌患者的反应率最高，可以在双免疫治疗中达到完全缓解。

 

所以，我们需要更好地了解卵巢癌免疫治疗领域，尤其是上皮性卵巢癌，因为很明显，有些亚群会对免疫治疗有反应，而其他亚群则不会。

 

Dr.Dizon:I think it is a very interesting conclusion made at this meeting.First，if you add a single agent immune checkpoint inhibitor，that is not likely to be an effective clinical strategy in ovarian cancer.One of the take-home messages here is that we need to be looking at combining immunotherapy with perhaps another agent or strategy to see if we can maximize the benefit of dual action;for example immunotherapy and bevacizumab could be tried.That is a fairly high bar，especially if you consider we haven’t consistently seen immunotherapy itself being an effective treatment.

 

But the other way is also important.We need to be able to predict who is going to benefit from immunotherapy in ovarian cancer.The study I presented suggests that there is that group of people who have a clear cell histology in whom this is important.In fact，the highest response rate was seen in people with clear cell.The complete responses were seen in people with clear cell.

 

We need a better understanding of the field，especially in epithelial ovarian cancer，because it is clear that there are subpopulations who will respond to treatment where others will not.

 

参考文献

Dizon DS，et al.Final results of BrUOG 354:a randomized phase II trial of nivolumab alone or in combination with ipilimumab with ovarian and extra-renal clear cell carcinomas.J Clin Oncol.2024;42(suppl 17):LBA5500.doi:10.1200/JCO.2024.42.17_suppl.LBA5500