编者按：日前，第47届欧洲肿瘤内科学会（ESMO）年会在法国巴黎召开。会上，ELAINE 1研究结果公布。《肿瘤瞭望》记者邀请到该项研究PI——美国梅奥医学中心Matthew Goetz教授对ELAINE 1的研究设计及相关结果进行介绍。

 

△美国梅奥医学中心Matthew Goetz教授

 

肿瘤瞭望：首先，请您为我们简要介绍一下ELAINE 1研究。

 

First，please give us a brief introduction to the ELAINE 1 study.

 

Matthew P.Goetz教授：ELAINE 1研究是一项随机对照的Ⅱ期临床研究，该研究探索了选择性雌激素受体调节剂拉索昔芬（LAS）对比氟维司群（Fulv）在CDK4/6抑制剂治疗进展后ESR1突变的晚期乳腺癌患者中是否具有更好的抗肿瘤活性。

 

众所周知，在接受芳香化酶抑制剂治疗的人群中，大约有30%到40%的患者会发生基因突变。其中，ESR1基因是主要的突变基因，它引起的内分泌抵抗又与较差的预后相关。患者往往有较高的转移率，特别是能够引起内脏疾病的转移。我们对氟维司群这一药物很熟悉，既往临床前和临床研究已证明，与芳香化酶抑制剂相比，氟维司群（雌激素受体下调剂，SERD）对ESR1突变患者的治疗效果更佳，研究者也在努力开发应对ESR1突变的新药。

 

在既往的几年中，我们看到了很多关于口服选择性雌激素受体下调剂的数据，拉索昔芬是一种选择性的雌激素受体下调剂。早在20世纪90年代就被用于预防乳腺癌，并在Pearl研究中被证明可以降低乳腺癌的发病率，同时也是治疗骨质疏松症的有效药物。大量临床前数据表明，拉索昔芬与突变的雌激素受体紧密结合，具有抑制雌激素受体转录活性以及抑制肿瘤生长和转移的作用。这些研究都是拉索昔芬单药与CDK 4/6抑制剂的联合作用下进行的。

 

ELAINE 1研究试验设计非常简单，它纳入了绝经后局部晚期或远处转移的雌激素受体阳性HER2阴性（ER+/HER2-）乳腺癌患者，这些患者经CDK4/6抑制剂＋芳香化酶抑制剂治疗12个月后出现进展，循环肿瘤DNA检测≥1个ESR1突变。

 

该研究中共有201例患者接受了ESR1突变筛查，103例患者随机分配到拉索昔芬组（52例）或氟维司群组（51例）。随机接受每日口服拉索昔芬5 mg或肌肉注射（IM）Fulv 500 mg（第1、15和29天，然后每4周），直到患者出现疾病进展、死亡、不可耐受的毒性等，主要研究终点：无进展生存（PFS）；次要研究终点包括临床获益率（CBR）、客观缓解率（ORR）、不良事件。治疗期间每2个月或者按临床需要进行影像学肿瘤评估。

 

 

主要研究终点表明，氟维司群组的PFS为4.04（2.93～4.04）个月，而拉索昔芬组的PFS为6.04（2.82～8.04）个月，HR 0.669（95CI：0.445～1.125），P=0.138；但PFS数据结果没有统计学意义。12个月无进展生存率分别为30.7%vs 14.1%。

 

 

拉索昔芬组对比氟维司群组的ORR为13.2%vs 2.9%（P=0.12）；两组患者的CBR分别为36.5%vs 21.6（P=0.12）。但是，这些结果同样不具备统计学意义。

 

 

该研究最耐人寻味的一方面是：评估了ESR1变异的突变体等位基因片段。当观察基线和8周的疗效时，我们发现与氟维司群相比，拉索昔芬在降低血液中的ESR1变异方面效果更佳，具体而言就是Y537S的突变。基于此突变，我们对使用拉索昔芬的患者进行了分层，几乎所有患者的这种突变都出现了明显减少，而使用氟维司群的患者中Y537S基因的突变出现增加。这提示拉索昔芬对ESR1突变有治疗作用。

 

早在2022年6月的ASCO大会上，ELAINE 2研究就探索了拉索昔芬联合阿贝西利对ESR1突变乳腺癌患者的治疗疗效，入组的患者使用CDK4/6抑制剂后都出现了疾病进展。在该项研究中，患者的客观缓解率与临床获益率均较好。因此，我们未来的研究计划是探索拉索昔芬与其他靶向治疗的疗效，如CDK4/6抑制剂或mTOR抑制剂等。

 

The ELAINE 1 clinical trial was testing whether lasofoxifene，which is a selective estrogen receptor modulator，provided better anti-tumor activity than the drug fulvestrant in patients with ESR1 mutated breast cancer.Stepping back，we know that the estrogen receptor is mutated in approximately 30 to 40%of patients who are treated with an aromatase inhibitors.

 

These ESR1 mutations have been shown to be a major problem that they lead to not only endocrine resistance，but they are associated with a worse prognosis.Patients tend to have higher rates of metastasis，especially to visceral disease sites.

 

So，there has been great interest in developing new drugs that would target these ESR1 mutations.Of course，we are familiar with fulvestrant.Both pre-clinical and clinical studies have demonstrated that fulvestrant appears to be a superior drug to aromatase inhibitors for targeting these ESR1 mutations.

 

In the last few years，we have seen a lot of data with regard to the oral SERDs(selective estrogen receptor downregulators).At this meeting，we also heard some data with regard to the oral SERDs.Lasofoxifene is a SERM，a selective estrogen receptor modulator，and it is an older drug.It was tested back in the 1990s as a drug for the prevention of breast cancer，and was shown in the PEARL trial to reduce the incidence of breast cancer，as well as being an effective drug in treating osteoporosis.

 

There was substantial pre-clinical data demonstrating that lasofoxifene tightly bound the mutated estrogen receptor，and specifically had effects to inhibit estrogen receptor(ER)transcriptional activity，as well as to inhibit tumor growth and metastases.These studies were done both as a single agent and in combination with a CDK4/6 inhibitor.

 

The ELAINE 1 trial was a very simple design taking women who had a diagnosis of ER-positive，HER2-negative metastatic breast cancer，who had progressed on an aromatase and a CDK4/6 inhibitor，and they had circulating tumor DNA evidence for ESR1 mutation.Patients(approximately 200)were screened for these ESR1 mutations，and approximately 100 were randomized to either fulvestrant or lasofoxifene.The results of the trial demonstrated that lasofoxifene improved progression-free survival from 4 months with fulvestrant，up to 6 months with lasofoxifene.

 

However，these results were not statistically significant.Similarly，when we look at other markers of efficacy，such as response rates and clinical benefit rate，again，both of these were improved with lasofoxifene.For example，the response rate with lasofoxifene was 13%versus<3%with fulvestrant.Again，a trend towards statistical significance，but it didn’t meet the criteria.

 

One of the most intriguing aspects of this study was evaluating the mutant allele fraction for the ESR1 variants.When looking at the baseline in week 8 results，we found that lasofoxifene did a much better job of decreasing ESR1 variants in the blood stream compared with fulvestrant.More specifically，focusing on the Y537S alteration(which is a fairly nasty/difficult mutation and one that we stratified patients on)，lasofoxifene decreased this alteration in nearly all patients by a significant amount，where by in the fulvestrant arm，we saw an increase in the mutant allele fraction for the Y537S alteration.

 

This tells us that lasofoxifene is having an on-target effect，and really a proof-of-principle.So where do we go from here?Where we go from here is quite clear because based on the ELAINE 2 trial(a trial presented at the American Society of Clinical Oncology Meeting back in June)，that trial tested lasofoxifene plus abemaciclib in patients with ESR1-mutated breast cancer，and again，in highly refractory disease(these patients had progressed on CDK4/6 inhibitors，and most of them，chemotherapy).In that trial，a very impressive 50%response rate，and a clinical benefit rate of nearly 14 months was seen.Going forward，the plan is to test lasofoxifene in combination with other targeted therapies，such as abemaciclib or other targeted therapies.for example，mTOR inhibitors.

 

肿瘤瞭望：该研究结果的披露，对HR+/HER2-晚期乳腺癌患者的治疗有何重要意义？

 

What are the implications of the disclosure of this study for the treatment of patients with HR+/HER2-advanced breast cancer?

 

Matthew P.Goetz教授：ELAINE 1研究的意义在于为ESR1突变患者提供了更多治疗选择。当前，ELAINE 1研究数据显然还不足以获得监管部门对相关适应证的批准，还需要更大规模的研究进行探索。然而，该研究的意义在于，对于ESR1突变患者而言，拉索昔芬似乎是一种有效的治疗药物。这里说的有效是指其药效学效应和所提及到的积极疗效数据。我认为对患者来说，主要的收获是无论是SERD还是SERM，都需要与其他靶向疗法（如CDK4/6抑制剂）结合进行测试和研究。

 

I think the implications for patients based on the ELAINE 1 trial are that there will be more options down the road for treating patients with ESR1 mutations.Now，ELAINE 1 was not sufficient obviously for regulatory approval.That would require a much larger study.However，the implications are that lasofoxifene appears to be an effective drug in terms of its ability to target the ESR1 mutation.I say effective in terms of its pharmacodynamic effect and the positive efficacy signals we are seeing.I think the major take-home for patients is that，going forward，these drugs，whether a SERD or SERM，will need to be tested and studied in combination with other targeted therapies，such as the CDK4/6 inhibitors.

 

肿瘤瞭望：从人群特征看，研究入组的乳腺癌患者年龄偏大，分期也偏晚，接受lasofoxifene治疗的患者安全性如何？

 

In terms of population characteristics，the breast cancer patients enrolled in the study were older and staged later.How safe is Lasofoxifene treatment for patients？

 

Matthew P.Goetz教授：在安全性方面，拉索昔芬的耐受性表现极佳，我们没有看到明显的毒副作用。我们相当感兴趣的毒性反应是静脉血栓栓塞或血栓。一般来说，选择性雌激素受体调节剂与血栓形成的高风险有关，如他莫昔芬。这项比较拉索昔芬和氟维司群的试验尽管是一项小型试验，但重要的是我们在接受拉索昔芬治疗的患者中并没有观察到血栓。

 

 

With regard to the safety lasofoxifene was really，extremely well tolerated.There were no significant toxicities that were seen.One of the toxicities that we were quite interested in was the venous thromboembolism or blood clots.We know that Selective estrogen receptor modulator in general，are associated with a higher risk of the blood clots，such as tamoxifen.In this trial comparing lasofoxifene and fulvestrant(albeit a small trial)，the important thing was that there were no blood clots observed in patients treated with lasofoxifene.