编者按：免疫治疗的出现，使晚期三阴性乳腺癌（mTNBC）患者看到了更多获益。SYNERGY研究是一项随机、多中心、开放Ⅱ期临床研究，探索了度伐利尤单抗（Durvalumab）+紫杉醇+卡铂±抗-CD73单克隆抗体Oleclumab在晚期三阴性乳腺癌（TNBC）一线化疗联合免疫治疗的疗效与安全性。《肿瘤瞭望》记者特邀采访了该项研究PI——比利时布鲁塞尔自由大学朱尔斯博尔德研究院Laurence Buisseret教授，请她介绍该项研究的相关数据结果。

 

△比利时布鲁塞尔自由大学朱尔斯博尔德研究院Laurence Buisseret教授

 

肿瘤瞭望：请您为我们介绍一下SYNERGY研究数据结果如何，oleclumab是否能给患者带来更多获益？该研究为我们带来了哪些启示？

 

Could you please tell us about the SYNERGY data and whether oleclumab provides more benefit to patients?What implications does this study bring to us?

 

Laurence Buisseret教授：SYNERGY研究旨在探究化疗-免疫疗法治疗三阴性乳腺癌的疗效和安全性。目前，在晚期三阴性乳腺癌患者的一线治疗中，对于PD-L1阳性的肿瘤患者，治疗方案是化疗联合PD-1免疫检查点抑制剂。

 

在SYNERGY试验中，我们将化疗-免疫疗法与腺苷靶向药物（Oleclumab）相结合。Oleclumab是一种针对CD73的单克隆抗体，而CD73负责在肿瘤微环境中产生免疫抑制性腺苷。PD-1/PDL-1免疫检查点抑制剂和腺苷靶向抑制剂的组合旨在增强免疫反应。

 

研究共纳入127例符合标准的患者。入组患者按照1∶1随机分组，在12周内接受紫杉醇和卡铂化疗，同时接受抗CD73的Oleclumab和抗PD-L1的Durvalumab单抗进行治疗。A组（63例）：Oleclumab+度伐利尤单抗+紫杉醇+卡铂，B组（64例）：度伐利尤单抗+紫杉醇+卡铂。在12周的免疫治疗后，患者继续接受免疫治疗，主要研究终点是第24周的临床获益率（CBR）。次要终点包括客观缓解率（ORR）、持续缓解时间（DOR）、无进展生存期（PFS）、总生存（OS），根据不同PD-L1和CD73表达水平的CBR等。

 

 

试验没有显示出两组之间的临床获益率差异，主要研究终点显示，A组采用双重免疫疗法的临床获益率为43%，B组单用Durvalumab的临床获益率为44%。

 

 

次要研究终点：A组患者的中位PFS为6个月，B组患者的中位PFS为7.7个月。两组安全性相似，不良事件可控。

 

 

这项研究表明，在未经遴选的TNBC患者中，Oleclumab的加入并没有给化疗-免疫治疗的组合带来获益。在我看来，我们必须对生物标志物进行更好的研究，并选择TNBC这种异质性疾病作为研究对象，或许能够发现TNBC中部分患者可能会从腺苷靶向药物中获益。

 

The SYNERGY clinical trials aim to investigate a new combination of chemo-immunotherapy.Currently，in the first-line setting for patients with advanced triple-negative breast cancer(TNBC)，treatment is chemotherapy with PD-1/PD-L1 immune checkpoint blockade in patients whose tumors are PD-L1-positive.

 

In the SYNERGY trial，we combined this chemo-immunotherapy with an adenosine targeting agent，oleclumab.This is a monoclonal antibody directed against CD73.CD73 is responsible for the generation of immunosuppressive adenosine in the tumor microenvironment.So the combination of a PD-1/PD-L1 immune checkpoint blocker and this adenosine targeting agent is aimed at enhancing the immune response.Patients were randomized to chemotherapy with paclitaxel and carboplatin received over 12 weeks，and oleclumab，the anti-CD73，with durvalumab，an anti-PD-L1.And in the other arm，patients received the same chemotherapy，but with durvalumab alone.After the 12 weeks of immunotherapy，patients continued with immunotherapy maintenance.The primary endpoint was the clinical benefit at week 24.The trial didn’t show a difference in clinical benefit between the two arms，showing 43%CBR in Arm A with the double immunotherapy，and 44%in Arm B with durvalumab alone.

 

In this study，we show that in unselected TNBC，oleclumab didn’t add benefit to the combination of chemo-immunotherapy.But in my opinion，we have to do better research for biomarker and to select TNBC as it is an heterogeneous disease.And it might that we will be able to identify a subset of TNBC patient that might benefit of adenosine targeting agents.

 

肿瘤瞭望：您是否看好免疫治疗+靶向治疗+化疗在晚期三阴性乳腺癌患者中的治疗前景？

 

Are you optimistic about the treatment prospects of immunotherapy+targeted therapy+chemotherapy in patients with advanced triple-negative breast cancer?

 

Laurence Buisseret教授：近期，使用抗体-药物偶联物的（ADCs）在mTNBC中已经显示出了良好的治疗疗效。我很期待ADC联合免疫疗法的治疗疗效，这可能会提高TNBC的治疗效果。

 

Recently，targeted therapies with antibody-drug conjugates(ADCs)have shown promising results.I am looking forward to the results of combining ADCs with immunotherapy that might improve the benefits of treatment for TNBC.

 

肿瘤瞭望：对于“免疫+靶向”进展的患者，后线治疗又应该如何选择？

 

How should we choose the treatment regimen for patients who progress after immune combined targeted therapy?

 

Laurence Buisseret教授：目前，对于“免疫+靶向”治疗进展的患者，后线治疗可选择的方案是ADC，ADC联合免疫疗法未来可期。我们将探索在新辅助和辅助治疗中使用化疗联合免疫治疗的方案。对于未经遴选的TNBC PD-L1阳性和阴性患者来说，在早期阶段进行免疫治疗是标准的临床管理策略。因此，现在需要确定疾病复发患者的治疗方案，并明确既往接受过免疫检查点抑制剂治疗的患者。

 

This is a good question.Currently，the treatment option would be ADC，and in the future，ADC plus immunotherapy.We will have to investigate the treatment options for patients who were treated with chemotherapy and immune checkpoint blockers in the neoadjuvant and adjuvant setting.As you may know，the standard-of-care for unselected TNBC who are PD-L1-positive and-negative，is to give immunotherapy in the early setting.We now need to define the treatment options for those patients who relapse and were previously treated with immune checkpoint blockers.