编者按：当地时间5月31日~6月4日，2024年美国临床肿瘤学会（ASCO）年会在美国芝加哥召开，这是全球规模最大、级别最高、学界最权威的肿瘤学术会议之一。宾夕法尼亚大学的胃肠肿瘤学家Kim Reiss主持了上消化道肿瘤口头报告专场，会后，我们特邀Dr.Reiss点评今年ASCO大会上消化道肿瘤领域的“明星”研究。

《肿瘤瞭望消化时讯》：您能否就本次入选大会口头报告的几项重要研究进行一下点评？

Dr.Reiss：首先是ARMANI试验，该试验评估了HER2阴性晚期胃或胃食管交界处癌患者在一线FOLFOX治疗达到稳定后转换维持治疗的作用。患者被随机分配至紫杉醇加雷莫西尤单抗组或继续使用FOLFOX化疗组。该研究结果为阳性，表明与继续使用FOLFOX的患者相比，接受转换维持治疗的患者总生存期有统计学意义的改善。然而，值得注意的是，与继续接受FOLFOX治疗的患者相比，接受转换维持治疗的患者发生毒副事件的概率要高得多，生存获益约为两个月。这引发了一个问题：这是否应该被接受作为一种标准的治疗或者我们是否应该仍然考虑将其看做临床患者的一种治疗选择。

另一项非常重要的试验是CheckMate 9DW，该试验观察了未经治疗的晚期肝细胞癌患者使用伊匹木单抗和纳武利尤单抗与TKI治疗相比的疗效。这也是一项在肝癌一线治疗领域的阳性研究。我认为它很重要的原因是，对于一些因静脉曲张或其他出血风险高的问题而无法使用阿替利珠单抗/贝伐珠单抗的患者来说，双免治疗对该人群来说是一种完全合理的一线选择。

ABC-07研究也非常重要，尽管该试验结果是阴性的。该研究评估了已经取得疾病稳定的晚期胆管癌患者，继续接受化疗联合立体定向放疗（SBRT）与单独继续化疗相比的疗效，结果表明在这种情况下联合放疗没有获益，生存率没有变化。因此，我认为可以肯定的是，放化疗联合不会成为这类患者的新标准治疗。

最后一项研究PASS-01是一项针对初诊晚期胰腺癌患者的精彩研究，患者被随机分配至吉西他滨/白蛋白结合型紫杉醇组或FOLFIRINOX组。这项研究真正重要的部分是随之而来的大量转化研究，它们试图确定可能有助于预测能够从每种方案中受益的生物标志物。该试验传递给我们的一点信息是：针对普通人群中的一线治疗方案，吉西他滨/白蛋白结合型紫杉醇实际上略优于FOLFIRINOX，这与比较NALIRIFOX和吉西他滨/白蛋白结合型紫杉醇的NAPOLI3研究的结果直接相反。正如从他们提出的亚组分析中看到的那样，有一些证据表明，生物标志物如肿瘤的基础或经典分型可能会提示我们要选择哪种治疗。作为一名临床工作者，它带给我们的启示是我们需要以更强大的方式去开发和验证这些生物标志物和临床表征，以便将它们引入临床，并以此为依据筛选适合各种治疗方案的患者。

Dr Reiss: First is the ARMANI trial, which evaluated the role of switch maintenance in patients with HER2-negative advanced gastroesophageal and esophageal cancers who had achieved stability on FOLFOX. Patents were randomized to be switched to paclitaxel plus ramucirumab or remain on FOLFOX. The study was positive and demonstrated a statistically meaningful improvement in overall survival in patients who underwent switch maintenance compared to those who remained on FOLFOX. However, it was noted that patients who received the switch maintenance had a substantially higher number of toxicities compared to those who remained on FOLFOX, and the survival benefit was roughly two months. What that calls into question is whether this should be accepted as a standard-of-care or whether we should still be considering using this as a treatment for patients in the clinic. Another trial that was really important was the CHECKMATE 9DW, which looked at ipilimumab and nivolumab in patients with untreated advanced hepatocellular carcinoma compared to TKI therapy. This was also a positive study in the first-line setting. The reason I think this is important is that there are patients who are coming in who cannot get bevacizumab. In the situation where a patient cannot get atezolizumab/bevacizumab because of varices or other issues with high risk for bleeding, this is now a totally reasonable first-line option for that population. ABC-07 was also very important, albeit a negative trial. This was a patient population of patients with cholangiocarcinoma with advanced disease who had achieved stability on therapy, and who underwent stereotactic body radiotherapy (SBRT) in addition to continued chemotherapy versus continued chemotherapy alone, and this demonstrated no benefit with the addition of radiotherapy in this setting with no change in survival. So I think we can safely say that is not going to be a new standard-of-care there. The final study I would mention is PASS-01 - a huge effort and wonderful study in patients with new diagnoses of advanced pancreas cancer. Patients were randomized to gemcitabine/nab-paclitaxel or FOLFIRINOX. The really important piece of this study is the enormous amount of translational work that went along with it to try to identify biomarkers that might help us predict who would benefit from each regimen. What we learned in the trial and kind of the top-line is that we still have some equipoise about what is the best first-line regimen in the general population. Gemcitabine/nab-paclitaxel actually slightly outperformed FOLFIRINOX, which is in direct opposition to the NAPOLI 3 study with NALIRIFOX and gemcitabine/nab-paclitaxel. As you will see from the subgroup analyses that they presented, there are some demonstrations that biomarkers, such as being basal or classical type in the cancers, might tell you which treatment you want to do. What it really brings home I think for me as a clinical translation person is that we really need to develop those biomarkers and signatures in a more robust manner, validate them so they can be brought into the clinic, and use that as a way to identify the right patients for each regimen.

《肿瘤瞭望消化时讯》：目前临床上关于胃食管癌大家关注的问题还有哪些？将来进一步深入研究的方向是什么？

Dr.Reiss：有一些胃食管癌，特别是晚期疾病患者在临床上仍然难以治疗，存在很多未满足的临床需求和改进的空间。我认为这次ASCO会议的一大亮点是在全体会议上作为首个摘要的ESOPEC试验，它明确表明胃食管交界处癌或食管癌患者目前的围手术期标准治疗是FLOT方案，而不是之前的CROSS方案。目前尚不清楚的是，免疫疗法将如何在这些患者中发挥作用或者是否会发挥作用。基于CheckMate 577的结果纳武利尤单抗免疫疗法被推荐在CROSS后用于手术时有残留病灶的患者。当前围手术期FLOT已成为大多数患者的标准治疗，问题是如何将免疫治疗纳入其中呢？希望该试验关闭时将为我们提供问题的答案。

在转移性胃癌中，存在的未知问题之一是如何对局限转移性疾病患者进行局部治疗，或者是否应该进行局部治疗？RENAISSANCE试验评估手术联合标准化疗用于实际上已经在FLOT的诱导治疗中取得疾病稳定的局部转移性胃癌患者的疗效，结果表明在这种情况下进行手术没有任何获益，单独化疗也能取得同样的疗效。

当然，我们也在等待EA2183试验的结果，该试验由威斯康星大学的Uboha博士领导，该试验正在研究在化疗后获得疾病稳定的局限性转移性食管癌和胃癌患者进行放疗能否获益。我认为这仍然是一个悬而未决的问题。目前没有明显的前瞻性数据表明应该联合放疗。

欧洲也正在研究早期食管癌是否能够通过合理的诱导治疗以及密切的随访和监测以完全避免手术治疗。对于食管癌，尤其是老年患者，食管切除术是一种创伤性非常大的手术，会带来很多不良的影响。因此有人提出一个疑问：具有某些特征的亚组人群是否可以完全避免手术呢？我们也在等待该研究的结果。

最后，正如其他胃肠道疾病一样，上消化道肿瘤领域的生物标志物非常关键！我们已经有了HER2、Claudin18.2、PD-L1、MSI等靶点，但关于我们应该如何通过这些生物标志物来指导患者的治疗还存在很多悬而未决的问题。例如，如何正确识别患者？如何正确地安排治疗的顺序等等。显然，我们还有很多工作要做。Dr Reiss: There are some gastroesophageal cancers, especially patients with advanced disease, but also patients with local disease, that remain incredibly difficult to treat, and there are still a lot of unmet needs and room for improvement certainly as we treat this disease. Things that we are still wondering about and one of the big highlights from this ASCO Meeting I think was in the Plenary Session as the first abstract - the ESOPEC trial that definitively, in my opinion, demonstrated that perioperative FLOT in gastroesophageal and esophageal patients is now the standard-of-care, as opposed to the prior CROSS regimen. What still is unknown is how immunotherapy will play a role, or if it will play a role, in those patients. As you recall, nivolumab immunotherapy, based on CHECKMATE-577, was used after CROSS in patients with residual disease at time of surgery. Now that perioperative FLOT is going to become standard-of-care for most patients (at least those fit enough to receive perioperative FLOT), the question is how are we going to put immunotherapy in there. When the MATTERHORN trial wraps up, that will hopefully provide us with that answer. In the meantime, it doesn’t seem clear to me that there is an automatic role for immunotherapy if you are using perioperative FLOT in this patient population. In the metastatic setting, one of the remaining unknown questions is how we layer in, or should we layer in, localized treatment for patients with limited-metastatic disease. The RENAISSANCE trial, which added surgery to standard chemotherapy in this patient population with limited disease who had already achieved some stability on induction therapy with FLOT actually, demonstrated that there was no advantage to getting surgery in that setting, and that chemotherapy alone was just as good. We also await, of course, the outcome of the EA2183 trial, which is led by Dr Uboha from the University of Wisconsin, that is looking at the same sort of patient population in limited-metastatic disease, but seeing if radiation in the setting of patients who have received stability after chemotherapy might be beneficial. I think that is still an unanswered question. Right now, no obvious prospective data suggest this is something we should be doing for patients. Finally, in Europe, it is also being studied whether surgery in the early stage setting of esophageal cancer might be able to be avoided completely with really good induction treatment, and then with very close and careful monitoring. For patients, especially for elderly patients, having an esophagectomy is a very morbid procedure with a lot of downstream effect. There is a question of whether in a very small population and a population with certain characteristics, we could avoid surgery altogether. We await the outcomes there as well. Finally, in upper GI cancers, like in every GI disease, biomarker, biomarker, biomarker! We have HER2-positive, Claudin-18.2, PD-L1, MSI, but there are a lot of open questions still about how we should treat those patients by certain biomarkers. How do we identify them properly? How do we order the therapy correctly? Obviously, there is lots more to come.

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