编者按：2025年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2025）已于当地时间1月25日圆满落幕。在大会现场，EORTC-1203——INNOVATION试验（摘要号LBA331）的结果公布，引起了全球学者的目光。《肿瘤瞭望消化时讯》的记者有幸针对该研究对瑞士洛桑大学医院的医学肿瘤学家Anna Dorothea Wagner教授进行了独家专访，现将内容整理如下。

《肿瘤瞭望消化时讯》：您能否简要介绍一下您研究的主要背景？

我们在其他试验中发现，接受FLOT加曲妥珠单抗治疗的患者有很高的病理缓解率，在试验中实现主要病理缓解的患者与那些没有实现主要病理缓解的患者相比，实际上在无复发生存率和总生存率方面都有显著的生存益处。这一差异在统计学上是显著的，风险比为0.25。不幸的是，我们试验中的无进展生存期和总生存期的结果并没有显示出任何显著优势，这可能是由于几个不同的原因。这项研究没有针对总生存期进行足够的统计功效设计，并且由于缺乏进一步的资金而提前终止，因此结果是不成熟且统计功效不足的。但在我看来，基于这一显著更高的主要病理缓解率，将曲妥珠单抗添加到FLOT方案中应该被考虑，并且应该与患者进行讨论以权衡利弊，尤其是在需要高反应率以实现治愈性切除的情况下。

Dr Wagner: First of all, my name is Anna Dorothea Wagner. I am a medical oncologist from the University Hospital of Lausanne in Switzerland, and it is my pleasure to discuss the results of EORTC-1203, the INNOVATION trial, for Oncology Frontier from China. The background for the INNOVATION trial was that for HER2-positive gastric cancer, we know since the publication of the ToGA trial in 2010, that the addition of trastuzumab to palliative chemotherapy improves survival significantly. Since then, we have a drug that is cheap and well-tolerated, we have a target and we know that there was benefit, but we knew that when patients have metastatic disease that we can’t cure them. We know that, at least in Western countries, patients with resectable gastric cancer have a relatively poor prognosis, and we need perioperative chemotherapy to improve survival outcomes. At present, the standard-of-care for perioperative chemotherapy is FLOT, and with perioperative treatment with FLOT, we can achieve an overall survival at 5 years of 50%, and at 3 years of 56%. This is what we wanted to improve. Twenty percent of gastric cancer patients are HER2-positive, and this is why we conducted this trial in patients with stage Ib-III HER2-positive gastric cancer, who were randomized to three trial arms. One arm is chemotherapy alone. The second arm was chemotherapy plus trastuzumab. And the third arm was chemotherapy plus trastuzumab and pertuzumab. The chemotherapy backbone when we started was cisplatin and fluoropyrimidine, and after the publication of the FLOT4 trial, this was changed to the FLOT regimen as the chemotherapy backbone. The primary endpoint of our trial was major pathological response rate (mpRR), and what we observed is that the clear winner in major pathological response are the patients treated with FLOT as a chemotherapy backbone and trastuzumab alone. Patients with FLOT in our trial had a major pathological response rate of 33%. Those who were treated with FLOT plus trastuzumab had a major pathological response of 53%. Patients with the double antibody combination of trastuzumab and pertuzumab did not show an advantage in major pathological response due to a higher toxicity, especially diarrhea, it was not possible to give the full dose of FLOT in the necessary number of cycles. So, the double antibody combination is not a good choice. But what we saw is that not only is there this high response rate in the patients treated with FLOT plus trastuzumab, but we also saw that those patients in the trial who achieved a major pathological response had, in fact, a significant survival benefit, both relapse-freeand overall survival, compared to those patients who didn’t have a major pathological response. That was statistically significant with a hazard ratio of 0.25. Unfortunately, the results for progression-free and overall survival in our trial did not show any significant advantages, which was probably due to a couple of different reasons. This study was not powered for overall survival, and it was closed prematurely due to lack of further funding, so the results are immature and underpowered. But in my view, on the basis of this significantly higher major pathological response rate, the addition of trastuzumab to FLOT is something that should be considered and discussed individually with the patient balancing benefits against the risks, especially in the situation where a high response rate is needed for curative resection.

《肿瘤瞭望消化时讯》：与其他药物相比，曲妥珠单抗和帕妥珠单抗在胃癌围手术期治疗中的治疗价值如何？

《肿瘤瞭望消化时讯》：您认为这种治疗方案的引入对HER-2阳性胃癌患者的治疗将产生什么影响？

研究简介

EORTC-1203 GITC“INNOVATION”：将曲妥珠单抗 （T） 联合或不联合帕妥珠单抗 （P） 整合到 HER-2 阳性胃癌的围手术期化疗中的总生存结果

背景

10%～20%的胃癌（GC）为HER-2阳性。围手术期抗HER2靶向治疗的作用尚不明确。

方法

这项随机、开放标签的II期试验旨在探究围手术期化疗（CT）单独使用或与T或T和P联合使用对于HER-2阳性胃癌（GC）和食管胃交界处癌（EGJC）的益处。共纳入172例经中央确认为HER-2阳性且可切除的GC或EGJC患者（UICC TNM分期Ib-III）。患者按1:2:2的比例随机分为三组：A组（仅CT）（35例）；B组（CT+ T [8 mg/kg，随后每3周6 mg]）（67例）；C组（CT + T+ P [每3周840 mg]）（70例）。CT最初为顺铂（80 mg/m2，d1）和卡培他滨（2 x 1000 mg/m2/d，d1），术前术后各进行3个周期。在FLOT-4研究结果公布后（Al-Batran, Lancet 2019），方案进行了修订。CT改为四个周期的FLOT方案，对于不适合FLOT的患者，以FOLFOX或CAPOX作为替代方案。在B组和C组中，T和P在CT结束后继续以相同剂量进行，总共17个周期。在随机分配的172例患者中，有161例符合所有关键入选标准并开始接受分配的治疗（符合方案人群）。在修订方案后，中心确定的大体病理反应率（mpRR）在A、B、C组分别为33.3%、53.3%和37.9%，而在修订前分别为8.3%、16.7%和12.5%（ASCO 2024，摘要4057）。这里，我们报告了中位随访4.3年后的无进展生存期（PFS）和总生存期（OS）。

结果

在A、B、C组中，3年和5年的无进展生存率分别为63.6%、64.7%、50.4%和51.9%、61.0%、47.9%。与单独使用CT相比，CT+T的PFS风险比（HR）为0.88（90% CI:0.51~1.53），而CT+T+P的HR为1.40（90% CI：0.82~2.37）。A、B、C组3年和5年的生存率分别为75.6%、76.9%、65.2%和60.5%、67.5%和62.6%。与单独使用CT相比，CT+T和CT+T+P的总生存期（OS）风险比分别为0.89（95% CI：0.42~1.88）和1.29（95% CI：0.62~2.66）。

结论