编者按： 2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2024）已于当地时间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。法国索邦大学（Sorbonne Université）Thierry Andre教授在当地时间20日的快速口头报告专场汇报了CheckMate 8HW研究（LBA768）的最新数据。在《肿瘤瞭望》采访中， Thierry Andre教授 分享了此项研究的主要内容，以及对结直肠癌领域的见解。现整理相关内容，以飨读者！
一
肿瘤瞭望：您在本次大会上报告了CheckMate 8HW研究的最新结果，能否给我们分享一下这项研究的背景和主要结果？
Oncology Frontier: We know that you have presented the latest results of“the CheckMate 8HW study”at this conference, can you share with us the background and key findings of this study?
Dr. Andre: 当然可以，很乐意。帕博利珠单抗被批准用于一线治疗微卫星高度不稳定/错配修复缺陷（MSI-H/dMMR）转移性结直肠癌。然而，接受帕博利珠单抗治疗的患者的2年和5年无进展生存（PFS）率分别为48%和34%，仍然存在未满足的需求。因此，测试和评估抗PD-1和抗CTLA4的联合治疗非常重要，CHECKMATE 8HW的首要目标是在一线比较纳武利尤单抗（NIVO）+依匹木单抗（IPI）与化疗+靶向治疗在MSI-H/dMMR转移性结直肠癌中的疗效。
在一线治疗中，303例患者随机分为NIVO + IPI组(n = 202)或化疗组(n = 101)；在这些患者中，NIVO + IPI组的171例患者和化疗组的84例患者通过免疫组织化学和/或基于聚合酶链反应的测试集中确认了MSI-H/dMMR结果。中位随访24.3个月，NIVO + IPI组与化疗组相比显示了有临床意义和统计学意义的PFS改善，疾病进展或死亡风险降低79% (HR 0.21，95%CI：0.14-0.32； P <0.0001)。没有发现新的安全信号。
Dr. Andre:
Yes sure, with pleasure. Pembrolizumab is approved for microsatellite instability-high/mismatch repair-deficient (MSI-high/dMMR) metastatic colorectal cancer in the first-line setting. However, an unmet need still exists in the two- and five-year progression-free survival (PFS) rates for pembrolizumab - 48% and 34% respectively. For this reason, it is important to test and to evaluate the combination of a PD-1 and CTLA4, and it is the goal of CHECKMATE 8HW, as the first primary objective, to compare in first-line, nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy plus targeted therapy in MSI-high/dMMR metastatic colorectal cancer.
In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32];?P< 0.0001). No new safety signals were identified.
二
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？下一步的研究方向是？
Oncology Frontier: What are the interesting discussions that the experts have conducted about this study at the conference, and what are your next research directions?
Dr. Andre: 试验结果是阳性的，风险比为0.21，两组之间的差异很大——NIVO + IPI组中72%的患者在24个月时无进展，而化疗组为14%。问题是确定NIVO + IPI联合治疗是否能成为一线新的标准治疗，或者我们是否需要在帕博利珠单抗单药治疗或NIVO + IPI联合治疗之间做出选择，但目前，我们没有预测因素来选择单药治疗还是联合治疗。很明显，从一开始就将曲线分离的联合治疗效果更好，24个月时疾病控制率达到了令人难以置信的72%。下一步是（收集）该试验的第二个主要目标（数据）。该试验是NIVO + IPI、NIVO单药治疗和化疗之间的2:2:1随机分组。第二个主要目标涉及大量患者，因为第二个问题纳入了>1800例患者，并且是NIVO和NIVO + IPI之间的比较，不仅在一线，而且在所有线，因为研究纳入了所有治疗线的患者。
Dr. Andre: The trial is positive, with an incredible hazard ratio of 0.21 and a huge difference between the two arms - 72% of patients are progression-free in the NIVO + IPI compared to 14% in the chemotherapy arm at 24 months. The question is to define if the combination of NIVO + IPI is a new standard-of-care in first-line, or if we need to decide between pembrolizumab monotherapy or a combination of NIVO + IPI, but at this time, we don’t have a predictive factor to choose between the monotherapy and the combination.
It is clear that the combination works better with the separation of the curves from the beginning and an incredible 72% control of disease at 24 months. The next step is the second primary objective of this trial. The trial is a randomization 2:2:1 between NIVO + IPI, NIVO monotherapy and chemotherapy. The second primary objective relates to a large number of patients, because >1800 patients were included for the second question, and is a comparison between NIVO and NIVO + IPI, not only in first-line, but across all lines, because patients were included in the study across all lines of treatment.
三
肿瘤瞭望：您认为对于MSI-H/dMMR转移性结直肠癌，临床还存在哪些治疗挑战？
Oncology Frontier: What do you think are the clinical challenges for MSI-H/dMMR metastatic colorectal cancer (mCRC)?
Dr. Andre: 临床挑战是治愈患者，这是第一次有可能通过使用抗PD-1和抗CTLA4的免疫疗法来治愈转移性疾病。现在KEYNOTE-177研究中，35例使用帕博利珠单抗的患者在5年的随访后没有出现疾病进展。很明显，我们的目标是治愈转移性疾病。这是第一次在肿瘤医学中实现。在这种情况下，这真的是一种神奇的治疗方法。
Dr. Andre: The clinical challenge is to cure the patient, and for the first time, it is possible to cure metastatic disease with a medical therapy using immunotherapy with an anti-PD-1 and anti-CTLA4. Now with the KEYNOTE-177 with pembrolizumab we have 35 patients without progression of the disease after five years of follow-up. Clearly, the goal is to hopefully cure metastatic disease. This is the first time it is possible in medical oncology. It is really an amazing therapy in this situation.
四
肿瘤瞭望：请您介绍一下，此次会议上，有哪些您印象深刻的研究？
Oncology Frontier: Could you please tell us what studies that impressed you at this conference?
Dr. Andre: 这项研究是这次会议的独家新闻之一，因为它将用这种新的治疗方法改变实践。所有参加会议的人都对这个结果印象深刻。在肿瘤学中，很少有一个试验结果真正指向这样的结果。业界接受了此研究结果，看到这样的结果真的很高兴。现在提出的问题是用这种组合治疗患者的可能性。
Dr. Andre: This study was one of the scoops of the meeting, because it will change practice with this new possibility of therapy. All of the participants at the meeting were impressed by this result. In oncology, it is rare to have a trial result that really points to one outcome. The community accepted and was really happy to see this kind of result. The question raised now is the possibility to treat patients with this combination.
研究简介
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study
纳武利尤单抗（NIVO）+依匹木单抗（IPI） vs. 化疗（chemo）一线（1L）治疗微卫星高度不稳定/错配修复缺陷（MSI-H/dMMR）转移性结直肠癌（mCRC）：CheckMate 8HW研究的第一个结果
背景
MSI-H/dMMR mCRC患者（pts）采用标准化疗±靶向治疗的预后较差。基于2期CheckMate 142研究，NIVO±IPI已在许多国家被批准用于MSI-H/dMMR mCRC患者。CheckMate 8HW （NCT04008030）是一项随机3期研究，比较NIVO + IPI与NIVO或化疗治疗MSI-H/dMMR mCRC患者。我们报告了NIVO + IPI与化疗在1L环境下的盲法独立中心评价（BICR）的无进展生存期（PFS）。
方法
≥18年的复发性或不适合手术的mCRC患者和根据局部检测的MSI-H/dMMR状态被纳入不同的治疗线。先前未治疗的患者以2:2:1随机分配到NIVO (240 mg) + IPI (1 mg/kg) Q3W(4次剂量，然后NIVO 480 mg Q4W)， NIVO (240 mg) Q2W（6次剂量，然后NIVO 480 mg Q4W）或化疗±靶向治疗；治疗持续至疾病进展或不可接受的毒性（所有组），或最长2年（NIVO±IPI组）。对于有BICR记录的化疗进展的患者，允许选择换成NIVO + IPI治疗。双主要终点是NIVO + IPI vs化疗（1L）和NIVO + IPI vs NIVO（所有线）在中央确认的MSI-H/dMMR mCRC患者中的BICR（根据RECIST v1.1）的PFS。
结果
在一线治疗中，303例患者随机分为NIVO + IPI组(n = 202)或化疗组(n = 101)；在这些患者中，NIVO + IPI组的171例患者和化疗组的84例患者通过免疫组织化学和/或基于聚合酶链反应的测试集中确认了MSI-H/dMMR结果。中位随访24.3个月，NIVO + IPI组与化疗组相比显示了有临床意义和统计学意义的PFS改善，疾病进展或死亡风险降低79% (HR 0.21，95%CI：0.14-0.32； P <0.0001)。没有发现新的安全信号。
结论
NIVO + IPI在先前未治疗的MSI-H/dMMR mCRC患者中显示出优于化疗的PFS。与化疗相比，NIVO + IPI具有不同的安全性，更少的3-4级治疗相关不良事件（TRAEs）。这些结果支持NIVO + IPI作为MSI-H/dMMR mCRC患者的一线标准治疗选择。临床试验信息：NCT04008030。
摘要原文
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study
Background: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo ± targeted therapies. NIVO ± IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study. CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO + IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO + IPI vs chemo in the 1L setting.
Methods: Pts ≥ 18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC.
Results: In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32];P< 0.0001) (Table). No new safety signals were identified (Table).
Conclusions: NIVO + IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO + IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO + IPI as a standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information:NCT04008030.