摘要：免疫治疗是近年来在结直肠癌领域研究的热点之一。错配修复基因缺陷（dMMR）或微卫星高度不稳定（MSI-H）的结直肠癌患者是免疫治疗的主要获益人群。我们特邀美国Vanderbilt-Ingram癌症中心（VICC）的知名学者Cathy Eng教授为我们分享202
编者按：免疫治疗是近年来在结直肠癌领域研究的热点之一。错配修复基因缺陷（dMMR）或微卫星高度不稳定（MSI-H）的结直肠癌患者是免疫治疗的主要获益人群。我们特邀美国Vanderbilt-Ingram癌症中心（VICC）的知名学者Cathy Eng教授为我们分享2024年转移性结直肠癌的变革性治疗方法。
《肿瘤瞭望消化时讯》目前晚期结直肠癌新辅助治疗的主要进展是什么？您能否介绍一下这方面的一些重要研究？
Eng教授：人们对结肠癌新辅助治疗仍然很感兴趣。有一些非常有趣的数据表明，免疫检查点抑制或免疫疗法可能在早期结肠癌中显示出一些有前景的抗肿瘤活性。NEST-1和-2是一项针对早期结肠癌新辅助BOT（botensilimab）和BAL（balstilimab）治疗的小型试点研究，结果表明这两种药物不仅在他们观察的少数MSI-H高患者中显示疗效，而且在MSS人群中也存在一定的作用，这真的很值得关注。Myriam Chalabi有一些关于多年前发表的NICHE研究的早期数据，指出给予纳武利尤单抗和伊匹木单抗对早期结肠癌有抗肿瘤活性，我认为这就是真正推动这一思考过程向前发展的原因。
对于早期MSS型直肠癌患者，有一项非常好的单机构试点研究TARZAN，共入组38例患者，评估了贝伐珠单抗和另一种免疫检查点抑制剂阿替利珠单抗的作用。该联合治疗方案在早期直肠癌中表现出潜在的价值，包括非手术管理等。我认为未来我们需要完成更大规模的研究来验证这些发现。美国和国际上正在开展针对这一患者群体的研究，不仅包括MSS型患者，还包括MSI-H型患者。
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Dr Eng: Interest in neoadjuvant therapy for colon cancer is still up and coming. There are some very intriguing data to suggest that immune checkpoint inhibition or immunotherapy may have a role in early-stage colon cancer. There is some promising activity in early-stage colon cancer as well as early-stage rectal cancer. NEST-1 and -2, were very small studies looking at the role of neoadjuvantl BOT (botensilimab) and BAL (balstilimab). This is a small pilot study looking at early-stage colon cancer that suggests there is activity not just in the small number of patients they looked at who were MSI-high, but also in the MSI-stable population which is really intriguing. There was some early data from Myriam Chalabi regarding the NICHE study published many years ago, noticing that giving nivolumab and ipilimumab has activity in early-stage colon cancer. I think that is what really drove this thought process forward. It is very intriguing.
In rectal cancer, for early-stage disease, MSI-stable patients, there was a very nice single institution pilot study of 38 patients called TARZAN that also looked at the role of bevacizumab and atezolizumab, so another immune checkpoint inhibitor, in early stage rectal cancer, suggesting potential activity including non-operative management. So I think moving forward, we obviously need to validate these findings, and we need larger studies to be completed. There are ongoing studies being developed in the United States and internationally looking at this patient population, not just MSI-stable, but also MSI-high patients.
《肿瘤瞭望消化时讯》您如何看待全疗程新辅助治疗（TNT）在直肠癌中的价值？
Eng教授：我不确定亚洲的治疗情况，但在美国TNT现在已成为标准治疗。所谓全程辅助治疗是指同步放化疗后继续化疗，然后考虑保留括约肌和直肠癌的非手术方法。目前并非所有患者都必须接受手术，虽然手术以及术后辅助治疗曾经是所有接受放化疗患者的标准治疗。然而并非所有患者在手术后都完成了化疗，这引发了人们的思考：我们能否改变顺序？最重要的是，有没有可能保留括约肌并考虑非手术方法？我认为在全球范围内，非手术管理方面得到了广泛采用。在美国，我们目前有一项名为JANUS试验的大型Ⅱ/Ⅲ期研究基本上验证了推进全程新辅助治疗方法的考量。显然，我们的欧洲同事在不同的研究中做了同样的尝试。
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Dr Eng: I am not sure about care in Asia, but in the United States, it has become standard-of-care now regarding total neoadjuvant therapy. When we mention total neoadjuvant therapy, we mean concurrent chemoradiation therapy followed by chemotherapy, and then consideration of sphincter preservation and a non-operative approach for rectal cancer. So now, not all patients have to go to surgery, which used to be standard-of-care for all patients who had chemoradiation therapy, then they went to surgery, then they got additional chemotherapy after surgery. But not all patients were not completing their chemotherapy after surgery, so the thought process become, can we change the sequence and on top of that, potentially save the sphincter and consider a non-operative approach I think globally, this is being well-adopted in regard to non-operative management. In the United States, we currently have a large phase II/III study called the JANUS trial, which is basically validating that consideration for moving forward with a total neoadjuvant therapy approach. Obviously, our European colleagues are doing the same in a different study but with the same consideration.
《肿瘤瞭望消化时讯》您如何看待免疫疗法在结直肠癌中的作用，免疫疗法的发展为晚期结直肠癌的新辅助治疗带来了哪些积极影响？
Eng教授：免疫疗法在MSS或错配修复熟练（pMMR）型晚期结直肠癌中的作用尚未真正得到充分开发。目前有正在进行的临床试验正在考虑这一因素。至少根据以前的研究，发生肝转移患者的免疫治疗似乎疗效不佳，许多临床试验实际上使这些患者没有资格参与临床试验。对于MSI-H高或dMRR型患者，免疫疗法是标准治疗。然而MSI-H患者群体仅占所有患者的5%，远非大多数患者。来自CHECKMATE-8HW研究的非常有趣的数据表明，与KEYNOTE 177中报告的单药帕博利珠单抗的缓解率相比，纳武利尤单抗加ipilimumab的缓解率更高。CHECKMATE-8HW尚未报道比较纳武利尤单抗/伊匹木单抗与纳武利尤单抗的临床试验设计的其他组成部分，尽管非常期盼，但我们还没有任何这方面的数据。目前，与标准化疗相比，纳武利尤单抗联合ipilimumab具有非常令人瞩目的无进展生存期和缓解率，我们期待着最终数据的公布。
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Dr Eng: The role of immunotherapy in advanced colorectal cancer for MSI-stable or mismatch-repair proficient (pMMR) patients has not really been developed well yet. There are currently clinical trials ongoing that are looking at that consideration. We know, at least based on prior studies, that immunotherapy in patients with liver metastases don’t appear to fair as well, so now many of the clinical trials are actually making those patients ineligible for clinical trial participation. For MSI-high or deficient MRR patients, immunotherapy is a standard-of-care in that setting, but obviously, the MSI-high patient population is only 5% of all of our patients and far from the majority of our patients. There are very interesting data from CHECKMATE-8HW, which is nivolumab plus ipilimumab, suggesting that response rates are higher versus what was reported in KEYNOTE 177 with single agent pembrolizumab. This is comparing immune checkpoint inhibition versus standard chemotherapy. CHECKMATE-8HW has not yet reported the other component of the clinical trial design comparing nivolumab/ipilimumab versus nivolumab. We don’t have any of that data yet, and we all want that data. But currently, just based on comparison to standard chemotherapy, nivolumab plus ipilimumab had a very impressive progression-free survival, as well as impressive response rates. We look forward to the final data.
来源：肿瘤瞭望消化时讯
