海德堡大学曼海姆医学院Frederik Marmé教授在2024 ASCO汇报了III期AGO-OVAR 2.29/ENGOT-ov34研究（NCT03353831）的最终分析结果：对于复发性卵巢癌患者，在单药非铂类化疗+贝伐珠单抗治疗中添加阿替利珠单抗时，未观察到生存获益增加（摘要LBA5501）。阿替利珠单抗加化疗和贝伐珠单抗组的中位无进展生存期（PFS）为6.4个月，而安慰剂加化疗和贝伐珠单抗的中位PFS为6.7个月（HR=0.87；P=0.12）；中位总生存（OS）分别为14.2个月和13.0个月（HR=0.83；P=0.06）；客观缓解率（ORR）分别为39.6%和43.5%；中位缓解持续时间分别为8.6个月和6.1个月。在《肿瘤瞭望》现场采访中，Dr.Marmé进一步分析了卵巢癌免疫治疗的研究方向。

 

Dr.Marmé：我是海德堡大学曼海姆医学院妇科肿瘤学教授Frederik Marmé，担任AGO研究小组的联合主席，也是欧洲妇科肿瘤学试验组网络（ENGOT）的成员。我们在2024 ASCO展示了一项随机III期研究AGO-OVAR 2.29/ENGOT-ov34的最终OS和PFS结果。

 

ENGOT-ov34是在铂耐药复发性卵巢癌患者中开展的安慰剂对照、随机III期研究，评估了PD-L1抑制剂阿替利珠单抗与化疗和贝伐珠单抗的组合。研究纳入了先前最多接受过三种治疗的患者，需要有患者近期和存档的活检标本。试验包括四个分层因素：先前治疗的线数；计划使用的化疗（患者可以接受紫杉醇或脂质体阿霉素[PLD]）；之前是否使用过贝伐珠单抗（研究中也允许使用）；以及PD-L1状态。主要终点是OS和PFS。大部分统计效能被分配给OS分析，OS是最重要的指标，结果也在2024 ASCO展示。

 

ENGOT-ov34研究：无进展生存

 

ENGOT-ov34研究：总生存

 

ENGOT-ov34研究发现，在88%的事件成熟度下，在化疗和贝伐珠单抗中添加阿替利珠单抗并没有改善无进展生存期：中位PFS在阿替利珠单抗组为6.4个月；在安慰剂组中为6.7个月，差异没有统计学显著性。在中位随访27个月时，添加阿替利珠单抗并没有显著改善总生存，OS呈现获益趋势，但p值为0.06，里程碑式24个月OS分析数据显示，阿替利珠单抗组和安慰剂组的2年OS率差异为8%（31%vs 23%），但OS曲线在观察结束前一直保持分离。

 

ENGOT-ov34没有达到其主要终点，这有点令人失望，但ENGOT-ov34结果与其他III期试验中看到的情况一致。这是在铂耐药卵巢癌患者中探索化疗、贝伐珠单抗和免疫检查点抑制剂联合治疗的最大规模的试验。综合单一免疫检查点抑制剂治疗卵巢癌的所有数据，及其与化疗、贝伐珠单抗联合，甚至与PARP抑制剂联合的研究数据，我认为这些都不是卵巢癌免疫治疗前进的方向，我们无法识别或利用预测标记物来选择可真正获益的少数患者（确实有一些），而且这种联合方案是以更大毒性为代价的。

 

阿替利珠单抗组确实观察到更多的副作用，严重不良事件（SAE）在阿替利珠单抗组和安慰剂组分别为63.7%和51.4%；免疫介导的不良事件也是如此，与阿替利珠单抗或安慰剂相关的≥3级不良事件（AE）分别为23.5%vs 11.9%，在阿替利珠单抗组更高。最常见的AE事件是甲状腺疾病、肝炎、肝酶升高、结肠炎、胰腺炎和腹泻，这些都与阿替利珠单抗有关。

 

总体而言，ENGOT-ov34试验结果是阴性的，未达到其主要终点，该试验确实看到了获益的信号，但这不足以真正使其成为一项改变临床实践的研究。重要的是，我们在几项不同的研究中看到了阿替利珠单抗联合化疗/贝伐珠单抗的获益信号，包括不久前发布的一项类似的III期ATALANTE/ENGOT-ov29研究。ATALANTE研究不是在铂耐药患者中开展，而是在铂敏感复发卵巢癌（PSROC）患者中评估了阿替利珠单抗联合铂类化疗和贝伐珠单抗方案，结果与ENGOT-ov34类似，两个治疗组的PFS没有差异。不幸的是，OS不是ATALANTE研究统计分析计划的主要终点，但研究中呈现明显的OS改善趋势，一小部分患者确实有可能获益。然而，我们研究过的所有生物标志物（无论是PD-L1状态还是其他生物标志物）都无法识别获益患者。

 

因此，我认为卵巢癌免疫治疗的进步之路实际上是获得更好的IO（免疫肿瘤学）组合，不仅仅是将IO与化疗、贝伐珠单抗或PARP抑制剂相结合，而是将IO与不同的IO方法相结合，包括疫苗或基因工程细胞因子，甚至采用双免疫检查点抑制剂进行阻断，这方面有一些有前景的研究数据。这种IO组合显然会增加毒性，但我认为也会提高疗效；也许还有机会将这些免疫检查点抑制剂与正在进入卵巢癌治疗领域的新型ADC联合。

 

Dr.Marme:My name is Professor Frederik Marmé.I am Professor of Gynecologic Oncology at the Mannheim Faculty of Medicine of the University of Heidelberg.I am the Co-chair of the AGO study group，and member of the ENGOT study network as well.Today here at ASCO，we have presented the final overall and progression-free survival results of a randomized phase III study，the AGO 2.29/ENGOT-ov34.

 

The study was conducted in the setting of platinum-resistant ovarian cancer，and it investigated a combination of atezolizumab，a PD-L1 inhibitor，combined with chemotherapy as well as bevacizumab.It is a placebo-controlled，randomized，phase III study.It included patients with up to three prior lines of therapy.Patients needed to have a recent，as well as an archival biopsy，for inclusion，and then we stratified by:number of prior lines;planned chemotherapy(they could have received either paclitaxel or liposomal doxorubicin);as well as the prior use of bevacizumab，which was also allowed in the study;and by PD-L1 status.These were the four stratification factors.The primary endpoints were overall survival and progression-free survival.Most power was allotted to overall survival analysis，so that was the most important and that is what we presented today.

 

What we found is that at a maturity of 88%of events，the addition of atezolizumab to chemo and bevacizumab did not increase the progression-free survival.In the atezolizumab arm，the median profession-free survival was 6.4 months;in the placebo arm，it was 6.7 months.That was not statistically significant of course.Likewise also，at a median follow-up of 27 months，the addition of atezolizumab did not significantly improve overall survival.This actually had a trend，but the p-value was 0.06.At a landmark analysis of 24 months，there was an 8%difference in OS favoring atezolizumab，but the curves remained separate until the end of observation.So it did not meet its primary endpoint，which is somewhat disappointing，but is in-line with what we have seen with other phase III trials.This is the largest trial combining chemotherapy，bevacizumab and an immune checkpoint inhibitor in the platinum-resistant setting.I think summarizing all the data of single immune checkpoint inhibitors，even combined with chemotherapy，with bevacizumab，or even with PARP inhibitors，is not the way to move forward.We have not been able to identify and predictive markers to select those few patients(and there are some)that would really benefit from the therapy.And it comes at a cost of toxicity.We do see more side effects.Serious adverse events were more frequently observed-64%versus 51%-in patients receiving atezolizumab.The same holds true if you look at the immune-mediated adverse events.Looking at Grade 3 or greater events，they were more frequent in the atezolizumab arm compared to the placebo arm.The most frequent events were thyroid disorders，hepatitis，elevated liver enzymes，colitis，pancreatitis and diarrhea attributed to atezolizumab.

 

Overall，the trial results are negative.The trial didn’t meet it’s primary endpoint.We do see a signal，but that is not enough to really make this a practice-changing study.What I think is important is that we see the signal in several different studies.A similar study，not conducted in the platinum-resistant setting but in the platinum-sensitive setting，was presented some time ago.It is the ATALANTE study.It showed something similar-there is no difference in PFS.Unfortunately，due to the statistic analysis plan，they were not able to actually look at the OS formally，but there is a clear trend in the study that there is an improvement in OS.Potentially，a minor fraction of patients do actually gain benefit，but none of the biomarkers we have investigated，be it PD-L1 status or other biomarkers，have been able to identify these patients.

 

So，I think the way to move forward with immunotherapy in ovarian cancer is really to get better IO(immuno-oncology)combinations，just not to combine IO with chemotherapy，bevacizumab or maybe PARP inhibitors，but to combine IO with different IO approaches，including vaccines or maybe genetically engineered cytokines or even go for dual checkpoint inhibitor blockade.There is some promising data on that.Obviously，this will increase toxicity，but I think it will also increase efficacy.Maybe there is also an opportunity to combine these immune checkpoint inhibitors with the novel ADCs that are coming into ovarian cancers as well.

 

Dr.Marmé：对于ENGOT-ov34试验的特别关注不良事件（AESIs），可归因于阿替利珠单抗或安慰剂的AESIs发生率在阿替利珠单抗组确实更高（18.5%vs 8%）。贝伐珠单抗相关的AESIs在两个治疗组中相当（6.8%vs 5.2%）。阿替利珠单抗组因副作用而停药的比例仅为16.4%，安慰剂组达到14.3%。与阿替利珠单抗相比，更多患者不得不停用贝伐珠单抗。总体而言，ENGOT-ov34试验的毒性特征相当可控。

 

ENGOT-ov34研究：安全性

 

在ENGOT-ov34试验中，我们看到一些免疫治疗相关不良事件（AE），管理免疫治疗相关副作用的基础用药是皮质类固醇：暂停治疗，使用皮质类固醇，就会看到AE症状有所改善；如果没有改善，则必须使用二线免疫抑制剂。但对于一些特定的副作用，比如甲状腺疾病，通常不需要使用皮质类固醇，甚至可能不必暂停治疗，可以采用抗甲状腺药物来治疗甲状腺功能亢进；如果患者有甲状腺功能减退症，则只需要更换甲状腺激素。这是我们在过去许多年里学到的管理免疫相关副作用的方法，简单明确。

 

我想强调的一件事是，临床医生必须进行患者教育，告知患者，提高患者的意识，让患者知道与免疫疗法有关的副作用种类繁多。当患者发生了这些免疫相关副作用，他们就会回来找你，而不是在家里等一周直到病情恶化。此外，还需要对医院的工作人员进行相关教育。

 

Dr.Marme:I think what we have seen is really that there were more side effects in the atezolizumab arm，if you look at the side effects that were attributed to atezolizumab.If you look at the side effects that were related to bevacizumab，they were equally distributed in both treatment arms.The discontinuation rate of atezolizumab due to side effects was just 16%in the atezolizumab arm，and even 14%in the placebo arm.More patients had to discontinue with bevacizumab compared to atezolizumab.So overall，the toxicity profile is quite manageable.

 

We encounter immune-related adverse events，like，as I said，thyroid disorders.The cornerstone of managing side effects related to immunotherapies is corticosteroids.You stop the treatment，you give corticosteroids，and you see that the symptoms improve.If they don’t，you have to go to second-line immunosuppressive agents.But there are specific side effects，like the thyroid disorders，where you usually don’t give corticosteroids.You may not even have to halt the treatment.You can treat the hyperthyroidism with blocking the thyroid;or in the case that you have hypothyroidism，you just need to replace the thyroid hormones.It is something that we have learned over the last many years actually how to manage these immune-related side effects.It is quite straight-forward.

 

One thing I want to point out is that you really have to educate the patients，inform them，raise awareness that this is a very diverse picture of side effects that could be related to immunotherapies，so if they encounter some of these problems，they will actually come back to you and not just wait for a week at home until things get worse.Also，you need to educate your staff in the hospital obviously.

 

Dr.Marmé：关于2024 ASCO报道的妇科癌症治疗进展，其中一项研究是这项ENGOT-ov34试验，没有达到其主要终点，但传递了重要信号，与我对卵巢癌免疫治疗发展方向的设想一致。

 

2024 ASCO还有一项非常有趣的研究探索了双重免疫检查点抑制剂（伊匹木单抗和纳武利尤单抗）治疗透明细胞癌（80%为卵巢透明细胞癌）患者的BrUOG 354试验。这是一项II期随机研究，也是非比较性的研究。结果发现伊匹木单抗联合纳武利尤单抗方案确实显著提高了ORR（摘要LBA5500）。

 

另一项双免疫疗法的研究是抗TIGIT单克隆抗体Vibostolimab联合PD-1抑制剂帕博利珠单抗治疗错配修复缺陷（dMMR）晚期子宫内膜癌经治患者的II期KEYVIBE-005研究队列B1的结果。帕博利珠单抗和TIGIT抑制剂的组合产生了非常令人信服的反应率（摘要5502）。2024 ASCO发布的是单组研究结果，我们仍需等待该方案在随机试验中转化为更好的获益，但我认为该方案确实值得进一步研究。

 

GOG-0724研究发现接受根治性子宫切除术的高危早期宫颈癌患者同步放化疗（CRT）后进行辅助化疗没有获益（摘要5504）。我认为这也是一个重要的信息。

 

前期我们在Lion试验中了解到，对于临床淋巴结阴性的晚期上皮性卵巢癌，腹膜后盆腔和主动脉旁淋巴结清扫术（RPPL）在初始肿瘤细胞减灭术中缺乏获益，但新辅助化疗后间歇性肿瘤细胞减灭术中RPPL的作用仍缺乏数据。法国学者在2024 ASCO展示了这方面的数据：III期CARACO结果表明，在接受新辅助化疗和间歇性肿瘤细胞减灭术的患者中，如果淋巴结临床阴性，也应省略系统性淋巴结清扫术（摘要LBA5505）。

 

Dr.Marmé:So far，what we have seen today was our study，which has not met it’s primary endpoint，but there were also some signals that I think were important that go along the lines of what I have envisioned of where to go with immunotherapy in ovarian cancer.

 

There was a very interesting study on a dual immune checkpoint inhibitor blockade with ipilimumab and nivolumab that was targeted at clear cell cancers，not just of the ovary but the gynecologic clear cell cancers.It was a randomized study and it was non-comparative，but we see that the combination of ipilimumab and nivolumab does significantly increase the overall response rate.

 

Similarly，we have seen signals of a dual immune checkpoint blockade in mismatched repair-deficient endometrial cancer，where a combination of pembrolizumab and a TIGIT inhibitor created really compelling response rates.It is a single arm study，and we still have to wait and see if this will translate into a better benefit in a randomized trial，but I think that will really be worthwhile going forward.

 

And then，we have also seen some results on adjuvant chemotherapy in intermediate-risk cervical cancer after chemoradiotherapy，which did not improve the outcomes.I think that is also an important message.

 

Another study I wanted to point out is a study of lymphadenectomy in ovarian cancer at interval debulking surgery.We have only known so far from data in the upfront setting，so primary debulking surgery，that if the nodes are clinically negative，there is no benefit from doing a systematic lymphadenectomy in these patients at upfront surgery.This data was lacking from interval debulking surgery，and we have seen that data presented today by our French colleagues.

 

参考文献：MarméF，Harter P，Redondo A，et al.Atezolizumab versus placebo in combination with bevacizumab and non-platinum-based chemotherapy in recurrent ovarian cancer:final overall and progression-free survival results from the AGO-OVAR 2.29/ENGOT-ov34 study.J Clin Oncol.2024;42(suppl 17):LBA5501.