编者按：在2024年SABCS大会上，美国匹兹堡大学Charles Geyer教授报告了NSABP B-59/GBG-96-GeparDouze研究的最新进展。该研究探索了阿替利珠单抗联合新辅助化疗是否能提高三阴性乳腺癌（TNBC）患者的无事件生存期（EFS）。尽管该研究未能达到主要终点，即未显示EFS的显著统计学改善，但亚组分析显示，一些患者似乎能从治疗中获益。Charles Geyer教授在SABCS现场接受了肿瘤瞭望的采访。在采访中他表示，尽管该研究结果为阴性，但其为三阴性乳腺癌患者的治疗提供了宝贵数据。

 

Charles Geyer教授：非常荣幸能在SABCS大会上向大家展示关于早期三阴性乳腺癌的III期研究的结果。NSABP B-59/GBG-96-GeparDouze这项研究是由我和美国国家乳腺和肠道外科辅助治疗研究组（NSABP）以及德国乳腺癌协作组（GBG）的同事们共同合作完成的，我们已经为此共同努力了大约八年时间。

 

该研究是一项双盲的III期临床试验，研究对象是确诊为II期或III期三阴性乳腺癌的女性患者，并且这些患者接受根治性辅助化疗。在美国，我们通常使用的标准治疗方案是紫杉类药物联合卡铂，然后再用蒽环类药物联合环磷酰胺。现在，在美国以及世界上许多其他国家，基于KEYNOTE-522研究的结果，治疗标准已经升级为在新辅助治疗和辅助治疗期间联合使用免疫检查点抑制剂帕博利珠单抗。

 

 

NSABP B-59/GBG-96-GeparDouze研究实际上是在KEYNOTE-522研究启动后大约八个月启动的，两项研究关注的核心问题是相同的：加入免疫检查点抑制剂是否能够在化疗的基础上提高患者的病理完全缓解率（pCR）、改善总体生存率（OS），并最终提升患者的生存状况。

 

帕博利珠单抗的研究（KEYNOTE-522研究）是一项规模宏大的全球性试验。NSABP B-59/GBG-96-GeparDouze研究规模则相对较小，主要集中在欧洲和美国，特别是德国和西班牙，实际上大部分工作是在欧洲完成的。因此，我们的患者招募时间比KEYNOTE-522研究长了将近一倍，这也是为什么我们的研究比KEYNOTE-522研究晚了几年才公布研究结果的原因。最初，我们的研究和KEYNOTE-522是同期开展的，但我们直到最近才累积足够的数据来报告主要终点——无事件生存期。我们研究的核心问题是：与PD-1抑制剂帕博利珠单抗不同，使用PD-L1抑制剂治疗三阴性乳腺癌会带来什么样的效果。

 

我们的研究和KEYNOTE-522研究之间还有一些显著的区别，我相信这些差异会引起大家的关注。例如，KEYNOTE-522研究采用2∶1的比例随机分组，招募了约1000例患者；而我们的研究采用1:1的比例随机分组，纳入了1550例患者，所以我们的研究规模更大。

 

 

我们的研究和KEYNOTE-522研究在入组标准上大致相似，主要针对T2或T3 N0（无淋巴结转移）或少量N+（淋巴结阳性）的患者。然而，两项研究在患者群体上也存在一些差异。KEYNOTE-522是一项全球性的研究，患者群体更具多样性，例如，研究中有相当大比例的亚洲患者。而我们的研究主要集中在德国和西班牙，因此患者大多是白人，这与当地的人口构成相符。这也导致两项研究在患者分布上有所不同，比如KEYNOTE-522研究中约一半患者是淋巴结阳性的，而我们的研究中只有40%。在治疗方案上，我们允许使用剂量密集型化疗方案，而KEYNOTE-522研究则要求每三周给药一次。我认为剂量密集型化疗是更符合标准的治疗方式，因此，应选择让医生和患者自行决定使用哪种方案。此外，由于CREATE-X研究的影响，在招募患者期间，我们调整了方案，允许未达到病理完全缓解（pCR）的患者接受卡培他滨治疗。这些是我们的研究和KEYNOTE-522的主要区别。

 

因此，我们研究中有一半未达到pCR的患者接受了卡培他滨治疗。这反映出我们与其他研究在患者群体和治疗方案上存在一些差异，我相信这些差异在进行交叉试验比较时会引起关注。最终的研究结果是，我们的研究未能达到主要终点，数据未能证明标准化疗中加入阿替利珠单抗可以使EFS有显著的统计学改善。因此，从验证明确疗效的角度来看，我们的研究结果是阴性的。不过，在亚组分析中我们发现，淋巴结阳性的患者似乎从中有所获益。尽管未达到主要终点，但这一发现可能为未来的研究提供重要的线索。

 

 

我们的研究发现，肿瘤较大的患者似乎能够获益，高TIL（肿瘤浸润淋巴细胞）水平的患者也表现出一定的获益。换句话说，阿替利珠单抗治疗在我们的试验中确实显示了活性，但整体来看，这种活性不足以让我们得出试验是阳性的结论。不过，我们为未来的研究积累了非常有价值的数据和样本。我们收集了所有患者的基线样本，还在治疗过程中对500名患者进行了活检。此外，我们也收集了未达到pCR的患者样本，这为我们提供了一个难得的机会，可以开展深入的转化研究，探索是否能够找到预测哪些患者更可能从治疗中获益的标志物。在三阴性乳腺癌治疗中，这是目前非常迫切的临床需求。目前，我们不得不为所有患者提供相同的治疗，因为我们尚未找到能够明确显示哪些患者会显著获益、哪些患者可能无明显获益的生物标志物。希望通过我们的这项研究，能够为解决这个关键问题做出贡献，从而推动精准治疗在三阴性乳腺癌中的应用。

 

 

Oncology Frontier:Please share the key findings of the NSABP B-59/GBG-96-GeparDouze study.In particular，what are the highlights regarding the efficacy and safety of atezolizumab when added to neoadjuvant chemotherapy and then used as adjuvant therapy in patients with stage II/III triple-negative breast cancer(TNBC)?

 

Prof.Charles Geyer:I had privilege today to present results of a phase III study in early triple negative breast cancer that my colleagues in the NSABP and German Breast Group had been working on together for quite a few years now，probably about eight years.The study was a double blind phase III trial for women who had stage II and III triple negative breast cancer at presentation and were candidates for curative neoadjuvant chemotherapy with our standard programs that we use here in the US of taxane carboplatin followed by anthrocycline cyclophosphamide.In our country now and many countries around the world，of course，the standard has become to co-administer the checkpoint inhibitor pembrolizumab（Pembro）during neoadjuvant therapy as well as adjuvant therapy based on KEYNOTE-522.

 

Our study actually started about eight months after KEYNOTE-522 started，and both studies were interested in the same question.Could a checkpoint inhibitor added to chemotherapy improve path CR，improve overall survival，and hopefully improve survival.

 

The Pembrolizumab study was an ambitious global study that was sponsored by the company，had multiple sites，patients around the world.Our study was a smaller study limited to Europe and U.S.，largely Germany and Spain，and actually in Europe.So it took us twice as long to accrue our study.And that’s why we learned the results of the KEYNOTE-522 several years before we were able to report our study.So our study actually started as a contemporary trial，but we just now had sufficient events to report our primary endpoint of event-free survival.And so，you know，it was just a question:could an inhibitor of PD-L1 as opposed to an inhibitor of PD-1，which is what Pembro inhibits，what kind of effect could it have in triple negative breast cancer.

 

Our study had some differences that I think people will be interested in.The KEYNOTE-522 study had a 2:1 randomization with about a thousand patients.We had 1:1 randomization with 1550 patients，so our trial was larger.

 

We both had similar criteria for being eligible for the study in terms of basically T2，T3，N0 or no positive patients.So we did recruit different population cohorts though because the KEYNOTE-522 study was a global study，had a broad representation.For instance，a substantial percentage of Asian patients were in KEYNOTE-522.In our study，we had relatively few Asian patients.Our studies were largely white patients just because that’s the makeup of Germany and Spain by and large.So our study differed in terms of the patient population.Half of their patients were no positive，only 40%of our patients were no positive.We also decided to allow dose-dense chemotherapy to be given.The KEYNOTE-522 study had specified every three weeks.We felt like，well，the standard is dose-dense，at least we should let doctors and patients decide.So these are some of the differences between the studies.We also，because of the impact of the CREATE-X study while we were recruiting our patients，had to ultimately allow patients who did not have a pCR to get Capecitabine.

 

And so half of our non-pCR patients got Capecitabine.So there are differences in the patient populations that came into the study.There’s also differences in the therapy that I think will be of interest，you know，doing the cross trial comparisons.Bottom line to our study was that we did not meet our primary endpoint.We did not show that adding atezolizumab to standard chemotherapy resulted in a statistically significant improvement in event-free survival.So we have to consider our study negative for the goal of showing clear superiority.However，when we look at our subsets，we did see our node-positive patients seem to benefit.

 

Patients with larger tumors seem to benefit.Patients who had high-TIL seem to benefit.So we have activity in our trial.It just wasn’t enough across the whole patient population for us to conclude the trial was positive.That said，we have collected specimens from all the patients at baseline.We had on-therapy biopsies in 500.We have the non-pCR patients so we have a real great opportunity to do what we hope will be very informative translational research to try to understand can we maybe identify some predictors of patients more likely to benefit because that’s still a need in triple negative breast cancer.We treat everybody.We haven’t been able to find biomarkers that tell us who really benefits a lot and who doesn’t benefit at all.We just have to treat everybody because we don’t have biomarkers.We’re hopeful that our study will be able to contribute to that critical question of biomarkers.

 

Charles Geyer教授：关于本研究的入组标准，要求患者必须接受中央实验室的诊断性检测，以确认患者为三阴性乳腺癌。肿瘤大小的要求是：如果患者没有淋巴结转移，肿瘤需达到≥2 cm；如果有淋巴结转移，肿瘤大小可以缩减至1厘米。没有纳入T4的患者，因此，研究针对的主要是中等风险人群。此外，患者需要具备正常的心脏、肾脏和肝功能，同时ECOG评分需在0～1范围内，表示身体状况良好或仅有轻微受限。排除标准主要是使用检查点抑制剂存在禁忌症的情况，以确保试验的安全性和数据可靠性。

 

我们的研究入组标准相对宽泛。患者的中位年龄为49岁，整体上是较为年轻且身体状况良好的群体。在研究中，我们设置了多个分层因素。由于招募工作分别在北美（美国和加拿大）以及欧洲（德国和西班牙）进行，我们将患者所在的地区（北美或欧洲）作为一个分层因素。同时，临床淋巴结状态（阳性或阴性）也是重要的分层变量。对于肿瘤大小，我们选择将其分为3厘米以下和3厘米以上，以便让分组更均衡，而不是采用传统的0-2厘米、2-5厘米、5厘米以上的划分方式。此外，我们还将PD-L1表达作为分层变量，使用SP142检测方法评估染色结果。最后一个分层变量是化疗方案的给药频率，即蒽环类（AC或EC）药物的给药间隔是每两周一次还是每三周一次。这些分层因素为我们更精准地分析不同亚组的治疗效果提供了重要基础。

 

 

Oncology Frontier:What were the key inclusion and exclusion criteria during patient enrollment?In addition，could you explain in detail how patients were stratified according to region，tumor size，chemotherapy regimen(AC/EC)，and lymph node status?

 

Prof.Charles Geyer:As far as eligibility went for the study，we did require central testing of a diagnostic core biopsy so we could confirm the patient had triple negative breast cancer.Tumors had to be≥2cm if a patient was no negative.If they were no positive，they could be down to one centimeter of any size.We did not include T4 tumors，so it was that intermediate risk group.Patients basically had to have normal cardiac，renal，hepatic function to be on a trial.ECOG status of zero to one.The exclusion criteria were largely things that are contraindications to using checkpoint inhibitors.

 

So it was a pretty broad eligibility criteria.The median age of our patients was 49，so it was a younger patient population，but a pretty healthy population.In terms of our stratification variables that we chose for our study，since we were doing recruitment here in the U.S.and Canada.The Germans were going to be doing recruitment in Spain and Germany.So we made continent，so to speak，Europe or U.S.，one of our stratification factors.We made clinical nodal status，a stratification factor，positive versus negative.We also made tumor size.We decided to split our three centimeters.The typical T and M is zero to two，two to five，five or greater.But we knew that if we kind of wanted to have roughly equal groups，so we said up to three and above three，that was a stratification variable.We included PD-L1 as a stratification，PD-L1 staining using the SP142 assay as one of our stratification variables.And then the final stratification variable was the regimen，the rate that they gave the AC or EC，dose down，was it every two weeks?Every three weeks.That was the other stratification variable that we used.

 

Charles Geyer教授：虽然我们的研究未能明确显示出疗效，但仍能带来一些有价值的发现。目前，三阴性乳腺癌治疗领域一个很大的需求是，如何识别出哪些患者能够真正从免疫检查点抑制剂治疗中获益，这将对治疗策略有很大的帮助。回想过去，我们曾为所有淋巴结阴性的女性提供化疗，即使明知对许多人可能并没有帮助，但因为有一部分患者确实能从中获益，所以我们必须这样做。当时我们缺乏分辨哪些患者需要治疗的工具，而现在，随着技术的进步，我们有了像Oncotype DX复发评分和Mammaprint这样的辅助工具，能够帮助判断哪些ER阳性的患者需要化疗，这是一个巨大的进步。我们也希望在检查点抑制剂的应用上，能实现类似的突破。

 

在三阴性乳腺癌患者治疗中我们可能面临类似的情况。我们知道这些患者需要化疗，而加入免疫检查点抑制剂后，整体疗效确实有所改善。然而到目前为止，除了肿瘤非常小的患者外，还没有明确的标志物能够告诉我们谁会真正受益。如果能找到一种预测性生物标志物，这将有助于我们精准判断哪些患者真正需要这种治疗。另一个可能推动治疗进展的方向是抗体药物偶联物（ADC）的应用，比如Dato-DXd和其他类似药物。目前有许多新型ADC正在探索中。如果它们对未达到pCR的患者的效果比卡培他滨更有效，我们可能会把这些药物进一步引入到新辅助治疗中。充分发挥ADC的潜力，这可能是下一步的关键。此外，还有进一步增强免疫反应的探索。但我认为，这或许是接下来的发展方向，而不是当前的首要任务。

 

Oncology Frontier:Based on the results of the NSABP B-59/GBG-96-GeparDouze trial，what do you think are the future research directions worth exploring in the treatment of TNBC?What are your expectations and suggestions for further improving the treatment effect and quality of life of TNBC patients?

 

Prof.Charles Geyer:Yeah，I mean，I think for us what we’re hopeful we can get out of our study，since we didn’t get there with an efficacy indication.A big need that many of us still feel is that it would be really helpful to be able to identify the subset of patients who benefit from receiving the checkpoint inhibitor.We used to give chemotherapy to all women with negative lymph nodes，knowing that we probably were not helping many women，but we’re helping some，a few，a lot.And we just didn’t have，we couldn’t do the tools.So now we have genomic markers like the Oncotype DX Recurrence Score，Mammaprint，other things that help us know which ER-positive patients need chemotherapy.That was a huge advance.

 

We probably have the same thing here in triple negative breast cancer.We know they need chemotherapy.When we added a checkpoint inhibitor，we do better overall.So far，there’s not been anything identified to tell us who does and doesn’t benefit other than having really small tumors.So if we can find some kind of a predictive biomarker，I think that would be very，very helpful to tell us who really needs it and doesn’t need it.Another thing that I think will move it forward is seeing how the ADCs come in，Dato-DXd，others，there’s a lot of them.If they can be even more effective than Capecitabine for the non-pCR，we’re also pulling them forward into the neoadjuvant setting.The potential to fully realize the ADCs is probably the next step，but there’s also then trying to further augment the immune response，but I think that’ll kind of be the，not the next thing，it’ll be the following thing in my view.

 

Charles Geyer

美国匹兹堡大学/UPMC希尔曼癌症中心

美国匹兹堡大学恶性血液学和肿瘤内科教授及临时部门主任

NSABP基金会首席科学官及乳腺癌委员会主席