编者按：近日，2025年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI）在美国加利福尼亚州旧金山举行。《肿瘤瞭望》特邀瑞士洛桑大学医院Anna Dorothea Wagner教授分享EORTC-1203 GITC临床研究的创新结果，评估了曲妥珠单抗和帕妥珠单抗联合化疗在HER2阳性胃癌围手术期治疗中的疗效。Anna Dorothea Wagner教授指出，尽管EORTC-1203 GITC试验存在一定局限性，但该研究结果揭示了抗HER2靶向治疗在改善HER2阳性胃癌患者生存结局方面的潜力，未来仍需要大规模研究予以验证。Anna Dorothea Wagner教授的研究及其观点为HER2阳性胃癌的精准治疗提供了新的思路和方向。

Anna Dorothea Wagner教授：目前，对于不可切除的晚期或转移性HER2阳性胃癌患者，化疗联合曲妥珠单抗或化疗联合曲妥珠单抗+帕博利珠单抗已成为标准治疗策略，并且抗HER2靶向治疗也展现出了显著疗效。

 

众所周知，在HER2阳性乳腺癌患者中，曲妥珠单抗新辅助治疗可将五年总生存率提高约10%。对于局部晚期或转移性胃癌，西方国家也会采用围手术期化疗作为标准治疗方案，手术联合围手术期化疗的五年OS率约为50%。在HER2阳性胃癌患者中，仅在转移阶段进行抗HER2治疗是不合理的，因此对于早期阶段患者，我们开展了EORTC-1203 GITC试验，在围术期治疗中引入靶向治疗手段，以期进一步提升生存率。我们的目标就是通过优化治疗策略，增加患者实现长期缓解的可能性。

 

Oncology Frontier:Could you please introduce the current status of HER2-targeted treatment for gastric cancer?

 

Dr.Anna Dorothea Wagner:It’s my pleasure to respond to this question.Currently，adding trastuzumab to chemotherapy—either alone or in combination with pembrolizumab—is the standard of care for patients with advanced or metastatic gastric cancers who cannot be cured.Targeting HER2 has also been highly effective in the treatment of both metastatic and localized breast cancer.

 

In breast cancer patients，neoadjuvant trastuzumab improves five-year overall survival by about 10%.For locally advanced or localized gastric cancer，perioperative chemotherapy is the standard of care in Western countries.The overall survival rate with surgery and perioperative chemotherapy is approximately 50%at five years.The idea behind our trial was to improve survival by incorporating targeted therapy for patients with HER2-positive tumors.It seemed inconsistent to offer HER2-targeted therapy only in the metastatic setting and not when patients have a chance of being cured.Our aim was to increase their likelihood of achieving long-term remission.

 

Anna Dorothea Wagner教授：本研究为一项开放标签、随机、对照的Ⅱ期临床试验，纳入了来自欧洲、韩国和新加坡37个中心的患者，按1:2:2随机分组，分别予以化疗、化疗+曲妥珠单抗、化疗+曲帕双靶。主要终点为主要病理缓解率（MPR），由两位资深病理学家独立评估，如有分歧，则由第三位专家进行复核。次要终点包括无进展生存期（PFS）和总生存期（OS）。

 

该试验旨在评估在标准围手术期化疗基础上，单独加用曲妥珠单抗或联合使用曲妥珠单抗和帕妥珠单抗，能否将MPR从25%提高到45%。试验方案规定，首先测试双抗体联合方案，如果结果阳性，再进一步考察单抗体方案。

 

图1.研究设计

 

Oncology Frontier:What is the design of the EORTC-1203 GITC"INNOVATION"clinical study?

 

Dr.Anna Dorothea Wagner:This was an open-label，randomized phase 2 trial with a 1:2:2 randomization.The study included patients from 37 centers across Europe，South Korea，and Singapore.The primary endpoint was the major pathologic response rate，which was independently assessed by two senior pathologists，with a third expert reviewing discrepancies.Secondary endpoints included progression-free survival and overall survival.

 

The trial was designed to evaluate an improvement in the major pathologic response rate from 25%to 45%by adding trastuzumab alone or a combination of trastuzumab and pertuzumab to standard perioperative chemotherapy.The protocol specified that the double-antibody combination would be tested first，and if positive，the single-antibody approach would be examined.

 

Anna Dorothea Wagner教授：在2015年研究启动时，标准的全身治疗方案为顺铂联合氟尿嘧啶；然而，在2019年FLOT-4试验结果公布后，化疗方案更新为FLOT方案。

 

本研究结果显示，仅在围手术期化疗中加入曲妥珠单抗，总体MPR率较单纯化疗提高了13.7%。具体来说，在接受以FLOT为基础的新辅助治疗患者中，MPR率从33.3%提升至53.3%，我们认为这是一个显著优势。然而，在接受曲帕双靶治疗的患者中，我们观察到的患者获益甚微，未能提高总生存率或总缓解率，这可能与化疗强度的相对降低有关；同时，双靶组的腹泻等不良反发生率显著上升。因此，本研究结果不支持使用曲帕双靶联合化疗的用药方案。

 

图2.EORTC-1203 GITC研究的MPR率

 

在本研究中，单独使用曲妥珠单抗在MPR和PFS方面较单纯化疗表现出了显著获益，3年PFS率的风险比为0.85。其中，在化疗方案修改前接受治疗的患者优势更为显著（HR：0.64）。在化疗方案修改后，这种优势变得不再明显（HR：1.04）。对于3年总生存率，风险比为0.89，其中方案修改前为0.77，修改后为0.99。

 

图3.化疗方案修改前后的PFS和OS

 

进一步分析发现，无复发生存期（RFS）与MPR呈强相关性。达到MPR的患者相较于未达到MPR患者，其RFS的风险比为0.26，OS的风险比为0.25，这一结果具有高度相关性。然而，由于样本量相对较小且研究提前终止，MPR的提高并未能转化为具有统计学意义的OS获益。

 

图4.MPR与否对RFS及OS的影响

 

本研究结果应与日本TRIGGER试验以及德国HER-FLOT试验的结果一并考虑。TRIGGER试验显示，对于HER2阳性且有限淋巴结转移的胃癌患者，加用曲妥珠单抗具有生存获益。HER-FLOT试验则显示，接受FLOT联合曲妥珠单抗新辅助治疗患者的3年生存率高达82%，这与本研究中76%的3年生存率结果几乎一致。

 

尽管由于样本量较小且生存结果尚未达到统计学显著性水平，目前尚不能推荐曲妥珠单抗联合化疗作为围手术期标准治疗方案，但该方案较高的缓解率表明，曲妥珠单抗可为肿瘤体积较大的HER2阳性胃癌患者的手术创造有利条件。因此，是否在当前围术期化疗的基础上加入曲妥珠单抗，应依据患者的具体情况，由医生和患者共同权衡利弊后作出决定。

 

Oncology Frontier:How do you evaluate the performance of trastuzumab and pertuzumab in this study?

 

Dr.Anna Dorothea Wagner:When we initiated the trial in 2015，the standard systemic treatment was a combination of cisplatin and fluoropyrimidine.However，after the publication of the FLOT-4 trial in 2019，the chemotherapy backbone was updated to FLOT.

 

Our findings indicate that adding trastuzumab alone to perioperative chemotherapy increased the major pathologic response rate by 13%overall.Specifically，in patients treated with neoadjuvant FLOT，the response rate improved from 33.3%to 53.3%，which we consider a significant advantage.However，in patients treated with both trastuzumab and pertuzumab，the benefit was marginal，likely due to reduced chemotherapy intensity.Moreover，the double-antibody regimen did not improve overall survival or response rates and was associated with increased toxicity，particularly diarrhea.Therefore，our study does not support the use of this combination.

 

Conversely，trastuzumab alone demonstrated clear benefits in major pathologic response rate and progression-free survival.In the overall patient population，the hazard ratio for progression-free survival was 0.85，with a notable advantage in patients who received the treatment before the amendment(HR:0.64).However，after the amendment，the benefit was not as pronounced(HR:1.04).For overall survival，the hazard ratio was 0.89—0.77 before the amendment and 0.99 after.

 

Relapse-free survival showed a strong correlation with major pathologic response.Patients who achieved a major pathologic response had a hazard ratio of 0.26 for relapse-free survival and 0.25 for overall survival，which is highly significant.However，due to the small sample size and premature closure of the study，the improvement in major pathologic response rate did not translate into a statistically significant overall survival benefit.

 

Our study should be viewed in the context of two other trials.The Japanese TRIGGER trial demonstrated a survival benefit of trastuzumab for patients with HER2-positive gastric cancer and limited lymph node metastases.Additionally，the HER-FLOT trial，led by Ralf Hofheinz，reported an impressive three-year survival rate of 82%in patients treated with neoadjuvant FLOT plus trastuzumab，which aligns with our findings of 76%survival at three years.

 

While trastuzumab cannot yet be recommended as a standard addition to perioperative chemotherapy due to the small sample size and lack of significant survival results，its higher response rate suggests that it could be beneficial for patients with large tumors where tumor shrinkage is crucial before surgery.Thus，the decision to add trastuzumab should be made on an individual basis，weighing the potential benefits and risks between doctor and patient.