ESMO 2022丨Laurence Buisseret教授：SYNERGY研究——双免联合化疗在mTNBC患者中的探索

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编者案：免疫治疗的呈现，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，摸索了度伐利尤单抗（Durvalumab）+紫杉醇+卡铂±抗-CD73单克隆抗体Oleclumab在晚期三阴性乳腺癌（TNBC）一线化疗结合免疫治疗的疗效与平安性。《肿瘤瞭看》记者特邀摘访了该项研究PI——比利时布鲁塞尔自在大学墨尔斯博尔德研究院Laurence Buisseret传授，请她介绍该项研究的相关数据成果。

△比利时布鲁塞尔自在大学墨尔斯博尔德研究院Laurence Buisseret传授

01

肿瘤瞭看：请您为我们介绍一下SYNERGY研究数据成果若何，oleclumab能否能给患者带来更多获益？该研究为我们带来了哪些启迪？

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传授：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平安性。目前，在晚期三阴性乳腺癌患者的一线治疗中，关于PD-L1阳性的肿瘤患者，治疗计划是化疗结合PD-1免疫查抄点按捺剂。

在SYNERGY试验中，我们将化疗-免疫疗法与腺苷靶向药物（Oleclumab）相连系。Oleclumab是一种针对CD73的单克隆抗体，而CD73负责在肿瘤微情况中产生免疫按捺性腺苷。PD-1 /PDL-1免疫查抄点按捺剂和腺苷靶向按捺剂的组合旨在加强免疫反响。

研究共纳进127例契合原则的患者。进组患者根据1∶1随机分组，在12周内承受紫杉醇和卡铂化疗，同时承受抗CD73的Oleclumab和抗PD-L1的Durvalumab单抗停止治疗。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，患者陆续承受免疫治疗，次要研究起点是第24周的临床获益率（CBR）。次要起点包罗客看缓解率（ORR）、继续缓解时间（DOR）、无停顿保存期（PFS）、总保存（OS），根据差别PD-L1和CD73表达程度的CBR等。

试验没有展现出两组之间的临床获益率差别，次要研究起点展现，A组摘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%。

次要研究起点：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。两组平安性类似，不良事务可控。

那项研究表白，在未经遴选的TNBC患者中，Oleclumab的加进并没有给化疗-免疫治疗的组合带来获益。在我看来，我们必需对生物标记物停止更好的研究，并抉择TNBC那种异量性疾病做为研究对象，或许可以发现TNBC中部门患者可能会从腺苷靶向药物中获益。

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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.

02

肿瘤瞭看：您能否看好免疫治疗+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传授：近期，利用抗体-药物偶联物的（ADCs）在mTNBC中已经展现出了优良的治疗疗效。我很等待ADC结合免疫疗法的治疗疗效，那可能会进步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.

03

肿瘤瞭看：关于“免疫+靶向”停顿的患者，后线治疗又应该若何抉择？

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

Laurence Buisseret传授：目前，关于“免疫+靶向”治疗停顿的患者，后线治疗可抉择的计划是ADC，ADC结合免疫疗法将来可期。我们将摸索在新辅助和辅助治疗中利用化疗结合免疫治疗的计划。关于未经遴选的TNBC PD-L1阳性和阴性患者来说，在早期阶段停止免疫治疗是原则的临床治理战略。因而，如今需要确定疾病复发患者的治疗计划，并明白既往承受过免疫查抄点按捺剂治疗的患者。

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.

（来源：《肿瘤瞭看》编纂部）

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