编者按：第14届欧洲乳腺癌大会（EBCC-14）于当地时间3月20～22日在意大利米兰召开，会上，KEYNOTE-756最新研究结果、ALEXANDRA/IMpassion030研究最终分析数据都进行了公布。美国德克萨斯大学西南医学中心西蒙斯癌症综合中心Heather McArthur教授同时参与了这两项研究，并在会上报道了KEYNOTE-756研究的最新数据，肿瘤瞭望特邀采访了Heather McArthur教授，请她就相关内容进行介绍。

Heather McArthur教授：KEYNOTE-756研究招募了Ⅱ期或Ⅲ期、组织学分级为3级的ER+/HER2-乳腺癌患者，并将她们1∶1随机分配接受至新辅助化疗联合安慰剂或帕博利珠单抗（pembrolizumab）治疗组。接受帕博利珠单抗治疗的患者在辅助治疗阶段继续使用帕博利珠单抗+ET，以完成共计一年的治疗。在这次会议上我们更新了该研究的相关数据，主要集中在年龄和绝经状态的病理学完全缓解方面。我们报告了新辅助化疗结束后到手术治疗的时间以及手术后到辅助治疗的时间，雌激素受体状态＜10%和≥10%患者的残余肿瘤负荷（RCB），以及手术后30天内的不良事件发生情况。

 

 

Oncology Frontier：Please give us an update on the KEYNOTE-756 study that you reported at this conference.

 

Heather McArthur：The KEYNOTE-756 study is a study that enrolled women in stage 2 or 3，estrogen receptor positive，grade 3 breast cancer，and randomized them to receive neoadjuvant chemotherapy with either placebo or pembrolizumab.And for those assigned to receive pembrolizumab，they continued pembrolizumab as well in the adjuvant setting to complete a total of one year.We provided an update of that study at this meeting.We provided a pathologic complete response updates by both age and menopausal status.We reported on time from completion of neoadjuvant therapy to surgery and time from surgery to adjuvant therapy.We reported on residual cancer burden by estrogen receptor status less than 10%versus greater than or equal to 10%.And we reported on adverse events within the first 30 days after surgery.

 

Heather McArthur教授：KEYNOTE-756研究有两个主要研究终点，即病理学完全缓解（pCR）和无事件生存（EFS）。目前为止，我们只得到了pCR的结果——pCR率提高了8.5%。EFS数据尚未成熟，但希望pCR的提高最终能够转化为EFS的改善，就像KEYNOTE-522研究中治疗三阴性乳腺癌一样，使患者获益。

 

 

Oncology Frontier：What is the significance of the publication of the latest progress data of KEYNOTE-756 study，and what important implications will it bring to the treatment of early ER+/HER2-patients?

 

Heather McArthur：So the KEYNOTE-756 study importantly has two primary endpoints，pathologic complete response and event-free survival.To date，we’ve only seen the results on pathologic complete response with an improvement in pathologic complete response of 8.5%.The event-free survival data is not yet mature，but it’s hoped that this improvement in pathologic complete response will ultimately translate into improvements in event-free survival and thereby curability as it did with KEYNOTE-522，triple negative breast cancer experience.

 

Heather McArthur教授：我对使用免疫治疗药物治疗激素受体阳性乳腺癌患者持乐观态度。从KEYNOTE-756研究中我们看到pCR率提高8.5%便是一个有力的数据支持。此外，我们从I-SPY2研究中也看到了类似的结果，通过联合帕博利珠单抗，pCR率从13%提高到了34%。因此，我对这种治疗方法抱有信心。

 

假设KEYNOTE-756研究中患者pCR获益能够转化为EFS获益，我认为未来我们也将面临其他治疗方案的挑战，包括使用卡培他滨治疗等（我们在CREATE-X研究中也看到了残余肿瘤）。我们也会面临一些其他数据的挑战，包括辅助治疗中使用CDK4/6抑制剂进行治疗的数据。目前，高危ER+患者辅助治疗中使用阿贝西利（Abemaciclib）已获得许多卫生机构的批准。不过，KEYNOTE-756研究中患者并未使用CDK4/6抑制剂治疗。此外，OlympiA研究中也包含使用奥拉帕利（Olaparib）治疗高危ER+患者的数据，而KEYNOTE-756研究中也没有接受奥拉帕利治疗的患者。因此，未来我们必须解决的是，这些药物的联合应用或先后使用顺序。

 

Oncology Frontier：Are you optimistic about the prospects of immunotherapy in the treatment of patients with ER+/HER2-early stage breast cancer?What do you see as the current challenges and opportunities in this area?

 

Heather McArthur：I’m very optimistic about the opportunity for treating selected patients with hormone receptor positive disease with immunotherapy.And I think that the improvement that we’ve seen on KEYNOTE-756 with the 8.5%improvement in pathologic complete response supports that.We’ve seen similar results from I-SPY2，for example，where an estimated pathologic complete response was improved from 13%to 34%with the addition of pembrolizumab.So I’m very much encouraged about this approach.I think we will be challenged in the future，assuming that the benefits from KEYNOTE-756 translate into event-free survival advantages by other data sets，including the use of Capecitabine，which we see not only in CREATE-X for residual disease.

 

Going forward，I think we will be challenged by some of the other data sets，including the adjuvant CDK4/6 inhibitor data set.So currently，adjuvant Abemaciclib is approved by many health authorities.And of course，CDK4/6 inhibitors were not permitted on KEYNOTE-756.And then you have the OlympiA data set as well with adjuvant olaparib for high-risk hormone receptor positive patients with olaparib also not being administered on KEYNOTE-756.So we will have to reconcile the issue of either co-administration or prioritization of administration of all of these agents.

 

Heather McArthur教授：ALEXANDRA/IMpassion030是一项在全球范围内进行的开放标签的Ⅲ期研究，招募了2300名Ⅱ、Ⅲ期TNBC（三阴性乳腺癌）患者。在首次手术治疗后被随机分配接受辅助化疗或辅助化疗联合阿替利珠单抗（atezolizumab）治疗。该研究的主要终点是无浸润性疾病生存（IDFS）。

 

 

我们在会上公布了最新分析结果，也是对该研究的最终分析。简而言之，在意向治疗队列（ITT）人群中，阿替利珠单抗联合化疗进行辅助治疗并没有给患者带来IDFS的改善，这是主要终点的结果。我们还分享了其他终点最终分析更新的结果，包括PD-L1阳性亚组患者的IDFS，以及进一步的安全性分析。在所有亚组分析中，都没有发现支持阿替利珠单抗带来获益的证据，安全性与既往阿替利珠单抗相关研究报告的结果一致。

 

 

Oncology Frontier：Please tell us about the final analysis data from the ALEXANDRA/IMpassion030 study.

 

Heather McArthur：The ALEXANDRA/IMpassion030 study was a study that was designed to enroll 2300 patients with stage 2 or 3 triple negative breast cancer，and they were randomized after up-front surgery to receive adjuvant chemotherapy with or without a PD-L1-directed agent，atezolizumab，in this open-label phase 3 global study.The primary endpoint for this study was invasive disease-free survival.We provided the updated analysis.This was the final analysis that was presented at this congress.And in short，we showed no improvement in invasive disease-free survival in the intention-to-treat cohort with the addition of atezolizumab to adjuvant chemotherapy.That was the primary endpoint.And then we shared updates in the final analysis from some other endpoints，including invasive disease-free survival in the PD-L1 positive subset，and further safety analyses.There was no improvement in favor of atezolizumab with any subset interrogated，and the safety profile was consistent with prior reports and reports from other studies interrogating atezolizumab in a very intense setting across multiple tumor types.

Heather McArthur教授：考虑到在辅助治疗阶段使用了免疫检查点抑制剂，我认为这项研究结果是阴性的。我坚信，在疾病的早期阶段应用免疫调节是非常重要，就像其他多项研究所证实的、KEYNOTE-522研究所展示的那样，免疫治疗已经成为早期TNBC患者新辅助标准治疗的一部分。KEYNOTE-522研究中，在新辅助阶段应用化疗与帕博利珠单抗联合使用。因此，我认为联合使用的时机至关重要。

 

Oncology Frontier：What do you think is the reason for that results for this study?And what can we learn from this study for the treatment of TNBC patients?

 

Heather McArthur：I suspect that this was a negative study because of the adjuvant administration at the checkpoint inhibitor.I think that it is critically important that immune modulation be applied early on in the course of disease，as has been demonstrated with multiple other studies，and as has become a standard of care as a function of the KEYNOTE-522 study，where preoperative chemotherapy was co-administered with another checkpoint inhibitor，the PD-1-directed antibody，pembrolizumab.So I think the timing of the co-administration is critically important.

 

Heather McArthur教授：目前，在TNBC乳腺癌患者的治疗中，帕博利珠单抗是唯一一种获得医药监管部门批准用于治疗高危早期乳腺癌的免疫检查点抑制剂。帕博利珠单抗在术前与化疗联合使用，之后辅助治疗阶段继续使用九个周期，以完成总计一年的治疗。这是目前唯一一种在这种情况下获得批准的检查点抑制剂。

 

Oncology Frontier：How should we choose the right immunotherapy drug and regimen for TNBC breast cancer patients?

 

Heather McArthur：Well，currently，in the curative intent setting，pembrolizumab is the only checkpoint inhibitor that’s approved by health authorities for treatment of high-risk early-stage breast cancer with curative intent，and pembrolizumab is co-administered with chemotherapy in the preoperative setting and then continued as adjuvant therapy for an additional nine cycles to complete a total one-year course of pembrolizumab.So that’s currently the only checkpoint inhibitor that is approved in this setting.

 

Heather McArthur

美国德克萨斯大学西南医学中心西蒙斯癌症综合中心内科副教授和乳腺癌项目临床主任