编者按：2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2024）于当地时间1月18～20日在旧金山召开。本次会议汇聚了世界各地的顶尖专家，共襄消化肿瘤盛举，共享学术研究盛宴。在当地时间18日的口头报告专场，美国纪念斯隆-凯特琳癌症中心（Memorial Sloan Kettering Cancer Center）Yelena Y. Janjigian教授汇报了MATTERHORN研究中FLOT联合或不联合度伐利尤单抗治疗GC/GEJC（胃/胃食管结合部癌）的亚组pCR分析最新结果（LBA246）。在《肿瘤瞭望》现场采访中，Yelena Y. Janjigian教授分享了MATTERHORN研究的主要内容和自己印象深刻的研究。现整理相关内容，以飨读者！

肿瘤瞭望：您在本次大会上报告了?MATTERHORN研究的最新结果，能否给我们分享一下这项研究的主要背景、主要结果以及重要的临床意义？为什么这项研究如此引人瞩目？

Oncology Frontier:We know that you have presented the latest results of the MATTERHORN study at this conference, can you share with us the background, the main findings of this study and its important clinical implications,and why you think they were so important?

Dr. Janjigian:非常感谢您给我这个机会向您介绍我们在这次会议上的最新情况。我们汇报了III期MATTERHORN研究中按地理位置的亚组分析结果。如你所知，在美国和欧洲部分地区，FLOT（术前三药化疗）已成为公认的标准，但它不是一种全球性的治疗方案。亚洲、部分南美地区和美国在MATTERHORN研究之前，没有一项研究探讨了FLOT在围手术期的应用。MATTERHORN研究探索PD-L1抑制剂度伐利尤单抗联合FLOT对比安慰剂联合FLOT的疗效和安全性。之前，我们汇报了次要终点病理完全缓解（pCR），在这次会议上，我们汇报了地区和国家细分的亚组分析结果。术前使用免疫疗法的基本原理是为了治疗微转移灶，并让T细胞在手术后产生免疫反应。我们能够证明的是，MATTERHORN中确实有一些地理分布上的差异。例如，在亚洲，ECOG PS 0分的患者比例更高，胃癌的比例也高于胃食管结合部癌，T4和淋巴结阳性肿瘤的比例也高于世界其他地区。有趣的是，尽管在患者基线特征上有这些差异，但在完全缓解改善方面是相同的。强调在全球范围内应用这一方案是可行的。19%的患者来自亚洲，而大多数患者来自欧洲，在欧洲FLOT是公认的治疗方案。MATTERHORN的重要性不仅在于研究FLOT在围手术期的应用，还在于证明如果你用类似的治疗方法进行全球III期研究，全世界现在在胃和胃食管结合部腺癌的治疗方法上是能够一致的。无论地理位置如何，与安慰剂相比，结果更倾向于添加度伐利尤单抗。令人欣慰的是，超过90%的患者能够在手术前完成FLOT治疗，65%的患者能够完成术后FLOT辅助治疗，总共四个周期。这甚至比之前其他关于FLOT 的研究报告的结果还要好。展望未来，我们希望继续监测研究结果－这项研究的患者仍在密切随访。最终，主要终点是无事件生存期，我们需要等待数据成熟。Dr. Janjigian:Thank you very much for the opportunity to update you on our presentation at this meeting. We presented the subgroup analysis by geographic location from the phase III MATTERHORN study. As you know, in the United States and parts of Europe, FLOT (three-drug chemotherapy before surgery) has been an accepted standard, but it is not a global regimen. Before MATTERHORN, there had not been a study that explored the use of FLOT in the perioperative setting in Asia and parts of South America and the United States. MATTERHORN looked at the combination of the anti-PD-L1 therapy durvalumab with FLOT compared to placebo and FLOT.We presented the secondary endpoint of pathological complete response (pCR), and at this meeting, we are presenting the subgroup analysis of geographic and country breakdown. The rationale of using immunotherapy before surgery is to help treat micro metastases, and educate the T-cells to mount an immune response even after the surgery. What we were able to demonstrate is that we do have some geographic distribution differences in MATTERHORN. For example, in Asia we had a higher percentage of patients with ECOG 0 status and a higher percentage of gastric cancers compared to gastro-esophageal junction cancers, and a higher percentage of T4 and lymph node positive tumors compared to the rest of the world. What is interesting is that despite having these differences in the baseline patient characteristics, the difference in complete response improvement was the same. highlighting how this regimen can be applied globally. It is very feasible.Nineteen percent of patients were enrolled in Asia, while the majority of patients were from Europe where FLOT is the accepted regimen of choice. The importance of MATTERHORN is not only to study the use of FLOT in the perioperative setting, but also to demonstrate that if you do a global phase III study with a similar treatment, the world is now united in that approach to treatment for gastric and gastroesophageal adenocarcinoma.Regardless of geographic location, the results favored the addition of durvalumab compared to placebo. What is great to see is that over 90% of patients were able to complete their FLOT therapy before surgery, and 65% of patients were able to complete adjuvant FLOT, so all four cycles. That was even better than what was reported previously from the other FLOT studies. Moving forward, we want to continue to monitor the study outcomes - patients are still being followed closely in this study. Ultimately, the primary endpoint is event-free survival, and we need to wait for that data to mature.

肿瘤瞭望：大会现场专家们围绕这项研究进行了哪些有意思的讨论？您下一步的研究计划是？

Oncology Frontier: What are the interesting discussions that the experts have conducted about this research at the conference, or what are your next research directions?

Dr. Janjigian:最大的讨论是MATTERHORN的研究如何与KEYNOTE-585研究的数据相吻合。KEYNOTE-585研究使用了两种化疗药物（卡培他滨/氟尿嘧啶和顺铂）联合免疫药物帕博利珠单抗，我们已经在肿瘤学年鉴上看到了卡培他滨和顺铂联合帕博利珠单抗对比（卡培他滨和顺铂联合）安慰剂的数据。在这次会议上，我们看到了同一研究的FLOT亚组分析。实际上，KEYNOTE-585研究显示了无事件生存率的提高，但总体生存率的差异并不显著，这表明可能存在样本量问题。该研究的有趣之处在于，它是在MATTERHORN之前进行的，来自亚洲的患者很少（＜10%）。我们希望这些数据与我们在MATTERHORN看到的类似，并且它可以改变临床实践。MATTERHORN的研究设计更简单，只有一种方案，因此我们希望正在进行的分析将证明是一项阳性研究。Dr Janjigian:The biggest discussion has been how does the MATTERHORN study fit in with the KEYNOTE-585 data. KEYNOTE-585 used a two-drug combination in combination with pembrolizumab, also an immunotherapy, and we have seen the data published in Annals of Oncology for capecitabine and cisplatin with pembrolizumab versus placebo. At this conference, we have seen the FLOT subgroup analysis from the same study.That actually showed improved event-free survival, but the difference in overall survival is not significant, suggesting there might be sample size issues. What is interesting from that study because it came before MATTERHORN, is that there were very few patients enrolled from Asia (＜10%). We are hopeful that the data is similar to what we are seeing in MATTERHORN, and that it could change practice. MATTERHORN has a simpler study design with one regimen, so we are hoping that ongoing analysis will lead to a positive study.

肿瘤瞭望：您认为胃癌领域还面临哪些挑战？

Oncology Frontier: What challenges do you think the field of gastric cancer still faces?

Dr. Janjigian:胃癌的一大问题是在亚洲部分地区它是一种罕见的疾病，所以MATTERHORN的重要性在于手术治疗考虑的肿瘤分期和手术方法可以根据你接受治疗的地区而有很大的差异。在MATTERHORN，我们没有强制要求内镜超声或荧光镜检查，R0切除率并没有随着免疫治疗的加入而提高，R0切除率也只有85%左右。对我而言，这个数字低得令人失望，尤其是对我的医疗中心和中国卓越的医疗中心来说。我认为它强调了世界上其他地方可能是分期不足的患者，在一些肿瘤进展更晚期或淋巴结阳性的患者中，这种疾病被遗漏了。因此，需要将患者纳入多学科管理团队讨论，并应考虑所有治疗方案。Dr Janjigian:The big issue with gastric cancer is in parts of Asia it is rare disease, so the importance of MATTERHORN is that the staging and approach to surgical considerations can be very different according to the area you are being treated in. In MATTERHORN, we did not mandate endoscopic ultrasound or fluoroscopy, and what we saw was that the R0 resection rate was not improved with the addition of immunotherapy, and also the R0 resection rate was only around 85%.I think, first of all, I would say that was disappointingly low, especially for my center and the Centers of Excellence in China. I think it highlights that the rest of the world may be under-staging patients, and in some patients who have more advanced tumor extension or node-positive disease, that disease is missed. So patients needed to be included in a multidisciplinary management team discussion and all the treatment options should be considered.

肿瘤瞭望：请您介绍一下，此次会议上，还有哪些您印象深刻的研究？

Oncology Frontier: Could you please tell us what other studies that impressed you at this conference?

Dr. Janjigian:我的中国同事对不同类型的白蛋白紫杉醇联合免疫疗法治疗晚期鳞状细胞癌的研究给我留下了特别深刻的印象。这是一项设计非常好的研究，它证明了也许我们用于治疗的化疗药物的类型很重要，我们需要对此给予足够的关注。这让我思考如何设计我自己的研究，因为我们很容易给患者服用紫杉醇。白蛋白紫杉醇在美国还没有被批准使用，但我对这项研究很感兴趣。此外，我们看到SKYSCRAPER-08研究中，将PD-L1单抗与TIGIT单抗联合使用。这很有趣。很难从中得出太多结论，因为没有真正的比较组，但这是有趣的数据。Dr. Janjigian:I was particularly impressed by the study from my Chinese colleagues looking at different types of nab-paclitaxel in combination with immunotherapy in squamous cell cancer with advanced disease. It was a very well-designed study, and demonstrated that perhaps the type of background chemotherapy we use for therapy is important and that we need to pay adequate attention to that. It made me think about how I design my own investigatory studies, because we give paclitaxel so readily to patients. Nab-paclitaxel is not approved for use in the United States, but I was really intrigued by this study.Also, we saw the combination of anti-PD-L1 therapies with anti-TIGIT in the SKYSCRAPER-08 study. That was interesting. Hard to conclude too much from it because there wasn’t a true comparator arm, but it is interesting data.

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