编者按：肾癌是常见的泌尿系统恶性肿瘤之一，晚期肾癌主要依赖靶向或免疫药物治疗，其治疗有效率不高，容易出现治疗后耐药。近年来，新型靶向药物、免疫药物、HIF-2α抑制剂等的出现，为改善晚期肾癌患者预后提供新的可能性。在2023 ESMO优选论文专场（Proffered Paper session）上，公布了晚期肾癌领域多项重磅研究内容，包括Belzutifan相关多项临床研究以及我国首个晚期肾癌一线靶免联合治疗RENOTORCH研究等。《肿瘤瞭望》在会议现场特别邀请到该专场主席、奥地利维也纳医科大学肿瘤学家Manuela Schmidinger教授，对此进行点评和介绍。

 

Manuela Schmidinger教授

奥地利维也纳医科大学肿瘤学家、医学博士

 

 

Oncology Frontier：In this Proffered Paper session，the result of LITESPARK-003 is that the study and LITESPARK-005 were presented.How do you comment these two studies?And how do you think of the application prospects of HIF-2αinhibitors for RCC patients?

Schmidinger教授：我认为对RCC患者而言，这是一场非常有趣的会议。Tony Choueiri介绍了LITESPARK-003试验的数据。该研究旨在探讨Belzutifan联合卡博替尼在晚期透明细胞RCC(ccRCC)一线（队列1）及后线（队列2）患者中的疗效。队列1患者客观缓解率（ORR）达70%。我认为这个缓解持续时间（DOR）非常长，将近29个月。队列2患者ORR同样也很高，DOR甚至更好，达30个月。我认为这是一个非常有希望的组合。目前，这只是II期研究。我们需要看看这个组合的最佳位置在哪里，一线还是经免疫治疗后线？我们会看到这两个目标药物吗？但是数据确实非常令人鼓舞。

 

LITESPARK-005试验旨在评估Belzutifan单药对比依维莫斯在后线RCC患者中的疗效。当然，在这里，你可能会说，卡博替尼应该是一个更现实的比较者，但我们需要承认，80%患者不再处于二线治疗中，他们处于三线或以上环境。因此，这些都是经过大量预处理的患者，Belzutifan在主要生存终点进展和ORR方面明显优于依维莫斯。Belzutifan有望获批，我也很确定，这是我们真正需要的药物。你问我在肾癌中对Belzutifan的总体看法。我认为这是一个有趣的药物，原因有很多。首先，因为它的作用方式；其次，因为它的单剂活性；第三，因为它具有极好的耐受性；第四，因为它可以与其他靶向药物联用，也可以与免疫疗法联用。我们正在等待LITESPARK-011试验的数据，它是一项关于帕博利珠单抗和仑伐替尼加Belsutifan与卡博替尼的随机III期试验。

 

So，I think this was a very interesting session for patients with renal cell carcinoma.Tony Choueiri presented the data from the LITESPARK-003 trial.This was a combination of cabozantinib and Belzutifan，given in two different patient cohorts.One cohort was patients who had been treatment naive，and the other cohort were pre-treated patients.So，in the cohort one，in the treatment naive patients，response rates went up to 70%.And I think this is really very，it was a very long duration of response of almost 29 months.And in cohort two，the response rates were also very high，and it was an even better duration of response of 30 months.I think it’s a very promising combination.This is just a phase two trial for now.We will need to see where is the best place for this combination.Is it in first line?Is it maybe in the context of a triplet with immunotherapy?Is it in the context of just two targeted agents who will see that?But definitely the data were very encouraging.

 

With the respect to the Leitzbach 005 trial，Belsutifan versus Erolimus in patients who had failed prior treatments.Here，of course，you may argue，well，Cabozantinib should have been a more realistic comparator here，but we need to acknowledge that 80%of the patients who are no longer in a second line setting，they were in a third or beyond third line setting.So these were heavily pretreated patients，and Belsutifan clearly outperformed Erolimus in terms of the primary endpoint progression for survival and also in terms of response rates.Belsutifan is hopefully，and I’m pretty sure about it，going to be approved，and this is an agent that we really need.You were asking what is my general opinion impression about Belsutifan in the context of kidney cancer.And I think it’s an agent that is interesting for multiple reasons.First，because of the mode of action.Second，because of its single agent activity.Third，because of its excellent tolerance.Fourth，because it’s combinable with other targeted agents and also with immunotherapy.And we are waiting to see the data from the LITESPARK-011 trial，a randomized phase three trial on Pembrolizumab and Lenvatini plus Belzutifan versus Cabozantinib in the second line trial.

 

 

Oncology Frontier：The second question is Dr.Sheng Xinan also presented the results of the RenoTorch study.How do you comment the RenoTorch study based on the phase three studies and off the first line immunotherapy that have been reported so far?

 

Schmidinger教授：该研究评估了PD-1抑制剂特瑞普利单抗联合TKI阿昔替尼的治疗效果。该研究设计与在美国、欧洲和世界其他地区进行的KEYNOTE-426试验非常相似。我认为非常重要的是，在RENOTORCH试验中，没有低风险患者，只有中高危患者。该试验中的对照组是舒尼替尼。在中高危患者的一线治疗中，特瑞普利单抗与阿昔替尼的组合明显优于舒尼替尼。我认为，在这种背景下这项试验非常重要，因为这是将这些组合推向帕博利珠单抗未被批准的亚洲市场的最佳方式。帕博利珠单抗联合阿昔替尼是肾癌的标准一线治疗，但并非在所有地方都可获取，因此进行这项RENOTORCH研究非常重要，因为它将改变亚洲肾癌的治疗格局。

 

So this trial investigated the combination of Acetineep，very narrow TKI，in combination with Tori Palimab，PD1 inhibitor.The design has been very similar to the KEYNOTE-426 trial that was conducted in the US and the rest of the world in Europe.And I think it’s very important to know that the difference here was that in the RenoTorch trial there were no patients with favorable risk，just intermediate and poor risk patients.The comparator arm in that trial was Sunitineep and the combination of Tori Palimab and Acetineep clearly outperformed Sunitineep in the first line setting of intermediate and poor risk patients.And I think the trial was very important in that context that this is the best way to bring these combination to the Asian market where Pembroke Pembrolizumab is not approved.Pembrolizumab Acetinib is a standard of care in the first line setting of kidney cancer，but it’s not available everywhere，and therefore it’s very important to have this positive trial，this positive renal torch trial because it would change the treatment landscape in Asia.

 

 

Oncology Frontier：According to the topic of this session，management of IMDC，for variable risk patients in.So we know that the most of current studies show that the main benefits of combined immunotraplic and intermediate or poor risk patients，what do you think of the treatment strategy of EMDC for variable risk?

 

Schmidinger教授：从我的角度来看，我认为低风险患者大多数时候也应该接受免疫靶向联合治疗。因为与舒尼替尼相比，即使没有看到总体生存（OS）优势，但无进展生存（PFS）、缓解率和完全缓解率均显著提高。这些完全缓解率是促使我将免疫靶向结合作为低风险患者最佳治疗选择的主要因素。但当然有些患者只需观察就可以了，转移性肾癌患者需要立即接受治疗。当然，也有很多患者采用TKI单药治疗可能是合适的。但一般来说，应该给低风险患者提供免疫靶向联合治疗。然后，应该个体化讨论该患者是否需要联合用药或仅需观察、TKI单药。

 

So from my point of view，I’m the see favorable risk patients most of the time should also be treated with an IOTKI combination.The reason being that even if we don’t see an overall survival advantage for the moment when compared to Sunitinib，what we have seen however is a significant improvement of progression free survival response rates and also complete response rates.And maybe it’s because of these complete response rates as a main factor that drives my decision also in the favorable risk patients to consider IOTKI as the best treatment option.But of course there is patients who are also fine off just with observation or every kidney cancer patient with metastatic disease needs a treatment right away.And also there is certainly a good number of patients in whom a TKI monotherapy might be appropriate.But it should be in general be made available also for favorable risk patient，the IOTKI combination.And then it should be discussed on a patient by patient basis whether this patient needs the combo or just observation or a TKI.

 

 

Oncology Frontier：The last question.There are also some non-clear cell renouse cell carcinomas in clinical practice，which is lack of therapeutic targets could you introduce the progress of the treatment of nccRCC?

 

Schmidinger教授：过去几年，在nccRCC方面也取得了很大进展。例如，ASCO上展示了由我的好朋友Lawrence Albijes实施的KEYNOTE-B61试验。在这项试验中，仑伐替尼与帕博利珠单抗联合用药。仑伐替尼是一种VGF/FGF抑制剂。这项试验显示了非常好的结果，有非常高的缓解率，在非透明组织学患者中缓解率也高达约40%，即使在嫌色细胞癌中也是如此，嫌色细胞癌被认为免疫性较差，对免疫疗法不太敏感。另一个非常重要的组合是免疫疗法PD-1抑制剂联合VEGF-MET双重抑制剂卡博替尼。这种组合在非透明组织中也显示出超过40%的缓解率。但毫无疑问，这个领域是我们需要更多研究的领域。这是一项非常困难的研究，因为非透明组织学患者群体的异质性很大。

 

So in non-clear cell RCC we have also seen big advances in fact in the last few years.At ASCO for example was the presentation of the keynote B61 trial that was a trial that conducted by Lawrence Albijes，good friend of mine.And in this trial Lenvateneb was combined with Pembrolyzumap.Lenvateneb is a VGF and FGF inhibitor was combined with a PD1 inhibitor.And this trial showed really very nice results with a very high response rate，also in patient of non-cliosal histology response rate，about 40%，even in the setting of chromophobar，CC，which is believed to be less immune，less susceptible to immunotherapy.Another combination that I believe is quite important is combination of immunotherapy，PD1 inhibitor with kabosantinib，metaxl and VGF inhibitor.Also，this combination has shown a response rate above 40%in the non-cliosal setting.But certainly this field is the one where we need even more research.It’s a very difficult research because the group of patients with non-cliosal is very heterogeneous.