肿瘤瞭望消化时讯

ASCO GI现场直击｜Josep M Llovet教授：EMERALD-1和RAISE研究有望改变现有肝癌治疗格局，值得期待

肿瘤瞭望消化时讯

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。肝癌领域全球顶级专家巴塞罗那大学（IDIBAPS, Hospital Clinic, University of Barcelona）Josep M Llovet教授作为讨论嘉宾，在当地时间19日的口头报告专场，对汇报的研究进行了热烈讨论。在《肿瘤瞭望》现场采访中，Josep M Llovet教授分享了现场讨论的EMERALD-1（LBA432）和RAISE研究（722）的主要内容，以及对肝癌领域的见解。现整理相关内容，以飨读者！

肿瘤瞭望：请您介绍一下自己（您的名字，职业和来自哪里）。您在本次大会上作为讨论嘉宾就口头摘要B场的两项研究进行了讨论，能否给我们分享一下这两项研究的主要背景，您认为它们入选的原因是什么？

Oncology Frontier: Please introduce yourself，including your name, profession and where are you from? As the discussion expert at this conference, you discussed the two studies in Oral Abstract Session B, can you share with us the main background of these two studies and why you think they were so important?

Dr. Llovet:大家好，我是Josep M Llovet。我是医学教授和纽约西奈山肝癌项目主任。我也是巴塞罗那大学医院的医学教授。EMERALD-1是一项双盲、安慰剂对照试验，评估度伐利尤单抗+贝伐珠单抗+ TACE对比TACE的疗效。该试验的主要终点无进展生存期为阳性。这是自2003年我们基于600个随机对照试验的荟萃分析，建立化疗栓塞作为标准治疗以来的第一个阳性试验。从那时起，已经报道了有超过15项试验，几乎所有的试验都是阴性的，主要终点是总生存期，有时是无进展生存期。所以我想说这是一个非常重要的试验。我们稍后会讨论结果的利弊，但我认为这对医生来说是一个好消息，尤其是对病人来说。第二项研究是RAISE。该研究是一项在中国5个医疗中心进行的随机II期研究，旨在寻找疗效信号。目的是探讨在切除后的辅助治疗，放疗对比最佳支持治疗是否可以预防复发或提高这些患者的无进展生存期。

Dr. Llovet:Hi, I am Josep M Llovet. I am Professor of Medicine and Director of the Liver Cancer Program at Mount Sinai in New York. I am also Professor of Medicine at the University of Barcelona Hospital.

Well, EMERALD-1 is a double-blind, placebo-controlled trial assessing durvalumab plus bevacizumab plus TACE versus TACE. The trial was positive for the primary endpoint of progression-free survival. This is the first positive trial in twenty years since we established chemoembolization as a standard-of-care in 2003, based on a meta-analysis of 600 randomized controlled trials. Since then, they have been more than 15 trials reported, almost all of them mostly negative with the primary endpoint of overall survival and sometimes progression-free survival. So I would say that this is a very important trial. We will later discuss the pros and cons of the results, but i think this is positive news for physicians, and particularly for patients.

The second study is RAISE. This study is a randomized phase II, seeking a signal of efficacy, and run in five centers in China. It is meant to explore, in the adjuvant setting after resection, whether radiation therapy versus best supportive care could prevent recurrence or improve progression-free survival in these patients.


肿瘤瞭望：能否请您分享一下这两项研究的主要结果以及重要的临床意义？

Oncology Frontier: Could you please share the main findings of these two studies and their important clinical implications?

Dr. Llovet:EMERALD-1试验取得了阳性结果。度伐利尤单抗+贝伐珠单抗+TACE组的中位无进展生存期为15个月，而TACE+安慰剂组的中位无进展生存期为8个月。这些结果表明该试验主要终点为阳性。RECIST的客观缓解率在三联疗法患者中约为50%，而单独使用TACE的患者中为30%，这一点也很重要。不良事件是可管控的。24%的患者出现3/4级治疗相关不良事件。因不良事件而停药的比例约为10%。总的来说，我认为这是疾病管理手段的进步。当然，看到总体生存数据是很好的，但我们正在等待，因为他们已经声明，他们将报告这项研究的最终总体生存趋势。但有了这些数据，我们有理由考虑这种联合治疗中期HCC。RAISE研究也是阳性的。这是使用放疗的Ⅱ期试验。我对这项研究的担忧是，他们纳入了切除边缘小于1cm的患者——这在西方作为纳入标准是很不寻常的。他们发现，与最佳支持治疗组相比，放疗组在无复发生存（RFS）方面明显更好。尽管如此，如果他们想要进入III期（因为如果他们想要在全球范围内研究这种疗法，他们需要这样做），他们需要将患者随机分配到接受阿替利珠单抗和贝伐珠单抗的辅助治疗，这是切除后辅助治疗的标准方案。Dr.Llovet:For EMERALD-1, the trial is positive. Median progression-free survival for durvalumab plus bevacizumab plus TACE was 15 months, compared to 8 months for TACE plus placebo. These results make for a positive trial for this primary endpoint. The objective response rate by RECIST was around 50% for patients with the triplet treatment, compared to 30% for patients with TACE alone, which is also important to highlight.Adverse events were manageable. Twenty-four percent of patients had grade 3/4 treatment-related adverse events. Discontinuation as a result of adverse events was around 10%. Overall, I think this is an advancement in the manage meant of the disease. Of course, it would be nice to see overall survival data, but we are waiting for that, because they have stated that they will be reporting the final overall survival trends for this study. But with this data, we have a rationale to consider this combination in intermediate HCC.The RAISE study is also positive. It is a phase II using radiotherapy. My concern with this study is that they included patients with a margin of resection of less than 1cm - this is quite unusual as an inclusion criteria in the West. They identified that radiotherapy was significantly better in terms of recurrence-free survival (RFS) compared to best supportive care. Nonetheless, if they want to move to phase III (because they need to do that if they want to study this therapy globally), they need to randomize patients to atezolizumab/bevacizumab, which is the standard-of-care for adjuvant therapy after resection.


肿瘤瞭望：大会现场专家们围绕这两项研究进行了哪些有意思的讨论？带给我们的临床启发有哪些？

Oncology Frontier: What interesting discussions did the experts have about these two studies, what do you think of the clinical inspirations for us?

Dr. Llovet:与传统的总生存期终点相比，EMERALD-1的主要讨论是无进展生存期是否足够强大以改变临床实践。这很难确定，因为没有足够的试验来确定无进展生存期作为生存期的替代终点。这就是为什么我们建议等待总体生存数据，以了解无进展生存和客观缓解率之间差异的强度。大家进行了激烈地辩论。同时，在安全方面，我认为它的安全性也很好。考虑到贝伐珠单抗与胃肠道出血相关，他们发现贝伐珠单抗组仅3%的患者出现胃肠道出血，这是可以接受的。我必须声明，在试验开始前6个月内，所有患者都应接受上消化道内窥镜检查，以排除静脉曲张。75%的患者没有静脉曲张，但25%的患者有静脉曲张。因此，这是需要考虑的。关于另一项试验的讨论主要是关于＜1cm切缘纳入标准的适用性。当作者解释纳入标准的流程图时，他们已经声明只有25%的患者被纳入该试验。约有200例患者被排除在外，因为他们的切缘＞1cm。我认为这是一个局限。另一个原因是我们知道，阿替利珠单抗/贝伐珠单抗是肝癌术后较好的辅助治疗选项，所以与安慰剂比较不再是一个选择。Dr. Llovet:The main discussion for EMERALD-1 is whether progression-free survival can be strong enough to change practice, compared to the conventional overall survival endpoint. This is very difficult to ascertain, because there are not enough trials to establish progression-free survival as a surrogate of survival. That is why we recommend waiting for the overall survival data to understand the strength of the difference between progression-free survival and objective response rate. that was one debate.Also, in terms of safety, I think the safety profile was quite good. Considering bevacizumab is associated with GI bleeding, they identified only 3% of patients with GI bleeding in the arm with bevacizumab, which is very acceptable. I have to state that within six months before starting in the trial, all patients should undergo upper GI endoscopy to discard varices. Seventy-five percent of the patients did not have varices, but 25% did have varices. Therefore, this is something to take into account.The discussion about the other trial was mostly about applicability of the inclusion criteria of the <1cm margin. When the authors explained the flowchart of the inclusion criteria, they already stated that only 25% of the patients evaluated for this trial were able to be included. Around 200 patients were excluded, because they had margins > 1cm. I think this is a limitation. The other is that we have this signal, but there is a huge competitor in atezolizumab/bevacizumab, so comparing to placebo is no longer an option.



肿瘤瞭望：您认为对于肝癌，临床还存在哪些治疗挑战？

Oncology Frontier: What do you think are the clinical challenges for hepatocellular carcinoma?

Dr. Llovet:我认为这个领域正朝着新辅助和辅助治疗的方向发展。我们还没有确定的新辅助治疗方案，在辅助治疗方面，我们只有阿替利珠单抗/贝伐珠单抗。该领域正越来越多地朝着疾病的早期治疗发展。通过这项试验，EMERALD-1和其他正在进行的试验，我确信我们将能够改善中期肝癌患者的预后。对于晚期疾病，我们现在使用阿替利珠单抗/贝伐珠单抗的中位OS上限约为20个月，因此新的组合需要挑战这一基准，但可能需要一段时间才能获得更好的联合治疗方案。当你联合使用太多的药物时，就会出现瓶颈，产生不良事件。所以我想说，目前的主要挑战是建立新辅助疗法和辅助疗法，包括目前的标准治疗。不用多说，另一个终点和未满足的需求是早期检测。在全球范围内，HCC监测项目的早期检出率非常低。在欧洲，早期肝癌检出率约为50%。在美国，这一比例约为30%。但在亚洲，比如中国，早期肝癌检出率非常低。为了延长寿命，我们需要更早地发现肿瘤。Dr. Llovet:Well, I think the field is moving towards neoadjuvant and adjuvant therapy. We dont yet have an established neoadjuvant therapy, and in the adjuvant setting, we just have atezolizumab/bevacizumab. More and more, the field is moving towards the early stages of disease. With this trial, EMERALD-1, and others that are ongoing, I am positive that we will be able to improve intermediate disease outcomes.With advanced disease, we now have a ceiling of around 20 months with atezolizumab/bevacizumab, so new combinations need to challenge this benchmark, but it will probably take a while to get better combinations. The bottleneck that occurs when you are combining too many drugs is creating adverse events. So I would say the main challenge at this point is to establish neoadjuvant and adjuvant therapies that include the current standard-of-care.Needless to say, another endpoint and an unmet need is early detection. Globally, early detection is very low for HCC using surveillance programs. In Europe, the pick-up rate is around 50%. In the US, it is around 30%. But in Asia, for instance in China, it is very low pick-up with surveillance programs. We need to detect tumors earlier to gain extra longevity.


EMERALD-1和RAISE研究简介

EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization

EMERALD-1：一项3期、随机、安慰剂对照的经动脉化疗栓塞和度伐利尤单抗（durvalumab）联合或不联合贝伐珠单抗（bevacizumab）治疗适合栓塞治疗的不可切除肝细胞癌患者

Abstract:LBA432

▋背景

在超过20年的时间里，TACE一直是符合栓塞条件的uHCC的标准治疗方案；然而，大多数接受TACE治疗的原发性肝癌患者在1年内病情进展。栓塞产生促炎性肿瘤微环境，增加VEGF信号；临床研究已经确立了免疫检查点抑制剂（ICIs；如D）和VEGF抑制剂（如B）。

▋方法

在EMERALD-1 （NCT03778957；双盲、全球、3期研究），符合栓塞条件的uHCC、Child-Pugh A至B7肝功能、ECOG PS 0-1分且无肝外转移证据的患者（pts）按1:1:1随机分为D+B+TACE组、D+TACE组或TACE组。TACE为cTACE或DEB-TACE（研究者选择）。患者接受D（1500mg）或安慰剂治疗D(Q4W)+TACE。在最后一次TACE完成后，患者接受D（1120 mg）或D+B安慰剂（15 mg/kg）或B安慰剂（Q3W）。主要终点是D+B+TACE vs TACE的无进展生存期（PFS）。次要终点包括D+TACE vs TACE的PFS、总生存期（OS）、客观缓解率（ORR）、进展时间（TTP）和D+B+TACE或D+TACE vs TACE的安全性。PFS、ORR和TTP采用盲法独立中心评价（RECIST v1.1）。

▋结果

共有616例BCLC A期(25.8%)、B期(57.3%)和C期(16.1%)患者被随机分为D+B+TACE组(n=204)、D+TACE组(n=207)或TACE组(n=205)。人口统计特征和基线特征在各组间总体平衡。在最终的PFS分析中，主要目标得到满足：D+B+TACE对比TACE的PFS显著改善(中位PFS，15.0 vs. 8.2个月；HR 0.77;95%CI：0.61-0.98；P=0.032[阈值0.0434])。结果在大多数预先指定的亚组中一致。D+TACE组对比TACE组的次要终点PFS无统计学意义(mPFS，10.0 vs. 8.2个月；HR 0.94；95%CI：0.75-1.19；P=0.638)。D+B+TACE、D+TACE和TACE组的ORR分别为43.6%、41.0%和29.6%，mTTP分别为22.0、11.5和10.0个月。没有发现新的安全信号。在D+B+TACE组(n=154)、D+TACE组(n=232)和TACE组(n=200)安全性分析集中，分别有32.5%、15.1%和13.5%的患者出现最大3/4级治疗相关不良事件(TRAEs);8.4%、4.3%和3.5%因TRAEs停药；0%、1.3%和2.0%死于TRAE。持续随访患者，等待OS数据。

▋结论

D+B+TACE是全球3期试验中第一个基于ICI的方案，与TACE相比，在符合栓塞条件的uHCC患者的PFS中显示出统计学和临床意义的显著改善。安全性是可控的，与D、B和TACE在uHCC中的安全性一致。D+B+TACE有可能为uHCC制定新的治疗标准。临床试验信息：NCT03778957。


Adjuvant radiotherapy after curative resection of hepatocellular carcinoma with narrow margin (≤1 cm): A phase 2, multicenter, randomized controlled trial.

窄切缘（≤1cm）肝癌根治性切除术后辅助放疗：一项2期、多中心、随机对照试验

摘要号：722

▋背景

RAISE是一项多中心、随机、开放标签、平行组的2期临床试验，旨在评估调强放疗（IMRT）与主动监测相比在治愈性切除后窄切限（≤1cm）肝细胞癌（HCC）患者中的疗效和安全性。

▋方法

将肝切除术后窄切缘的HCC患者按1:1的比例随机分为两组，一组接受IMRT（手术-IMRT组），另一组接受主动监测（手术组）。随机分层因素包括肿瘤大小（≤5 vs. > 5 cm）和微血管侵袭（存在 vs. 不存在）。在手术-IMRT组，患者在手术切除后1-3个月内接受IMRT。处方剂量计划在5～6周内按50-60GY/25-30F。主要终点为无复发生存期（RFS）。次要终点是安全性和总生存期（OS）。计划样本量为148例患者，以获得2年RFS率从45%提高到65%，风险比（HR）为0.54，单侧α为5%，power为80%。

▋结果

在2019年1月15日至2023年9月15日期间，来自中国6家医院的148例患者被随机分组：74例患者被分配到手术-IMRT组，74例患者被分配到手术组。中位随访时间为27.4个月（95%CI：23.2—29.2个月）。手术-IMRT组的2年RFS为78.37% (95%CI：64.35%-87.40%)，手术组的2年RFS为57.43% (95%CI：43.25%-69.28%) (P=0.028)。两组的中位OS均未达到。放疗相关的3-4级不良事件为血小板减少3例，中性粒细胞减少3例，血红蛋白降低1例。

▋结论

本试验表明，根治性切除后的辅助IMRT可为窄切缘HCC患者带来RFS上的获益。临床试验信息：NCT03732105。


摘要原文

（一）

EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization

Abstract:LBA432

Background:For >20 years, TACE has been a standard of care for embolization-eligible uHCC; however, most people with uHCC treated with TACE progress within 1 year. Embolization creates a proinflammatory tumor microenvironment and increases VEGF signals; clinical studies have established the role of immune checkpoint inhibitors (ICIs; e.g. D) and VEGF inhibitors (e.g. B) in advanced HCC.

Methods:In EMERALD-1 (NCT03778957; double-blind, global, Phase 3 study), participants (pts) with embolization-eligible uHCC, Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease were randomized 1:1:1 to the D+B+TACE, D+TACE, or TACE arms. TACE was cTACE or DEB-TACE (investigator choice). Pts received D (1500 mg) or placebo for D (Q4W) plus TACE. After completion of last TACE, pts received D (1120 mg) or placebo for D plus B (15 mg/kg) or placebo for B (Q3W). Primary endpoint was progression-free survival (PFS) for D+B+TACE vs TACE. Secondary endpoints included PFS for D+TACE vs TACE, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety for D+B+TACE or D+TACE vs TACE. PFS, ORR, and TTP were assessed by blinded independent central review (RECIST v1.1).

Results:In total, 616 pts with BCLC Stage A (25.8%), Stage B (57.3%), and Stage C (16.1%) were randomized to D+B+TACE (n=204), D+TACE (n=207), or TACE (n=205). Demographic and baseline characteristics were generally balanced across arms. At final PFS analysis, the primary objective was met: PFS significantly improved for D+B+TACE vs TACE (median [m]PFS 15.0 vs 8.2 months [mo]; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61–0.98; p=0.032 [threshold 0.0434]). Results were consistent across most prespecified subgroups. The secondary endpoint of PFS for D+TACE vs TACE was not statistically significant (mPFS 10.0 vs 8.2 mo; HR, 0.94; 95% CI, 0.75–1.19; p=0.638). ORR was 43.6%, 41.0%, and 29.6%, and mTTP was 22.0, 11.5, and 10.0 mo for D+B+TACE, D+TACE, and TACE, respectively. No new safety signals were identified. In the D+B+TACE (n=154), D+TACE (n=232), and TACE (n=200) safety analysis sets, respectively, 32.5%, 15.1%, and 13.5% of pts had maximum Grade 3/4 treatment-related adverse events (TRAEs); 8.4%, 4.3%, and 3.5% discontinued due to TRAEs; and 0%, 1.3%, and 2.0% died due to TRAEs. Pts continue to be followed for OS.

Conclusions:D+B+TACE is the first ICI-based regimen in a global Phase 3 trial to show statistically significant and clinically meaningful improvement in PFS, vs TACE, in pts with embolization-eligible uHCC. Safety was manageable and consistent with the safety profiles of D, B, and TACE in uHCC. D+B+TACE has the potential to set a new standard of care in uHCC. Clinical trial information: NCT03778957.

（二）

Adjuvant radiotherapy after curative resection of hepatocellular carcinoma with narrow margin (≤1 cm): A phase 2, multicenter, randomized controlled trial

Abstract：722

Background:RAISE is a multicenter, randomized, open-label, parallel-group phase 2 trial, aiming to assess the efficacy and safety of intensity modulated radiation therapy (IMRT) compared with active surveillance in hepatocellular carcinoma (HCC) patients with narrow margin (≤ 1 cm) following curative resection.

Methods:HCC patients with narrow margin were randomly assigned in a 1:1 ratio to receive either IMRT (Surgery-IMRT group) or active surveillance (Surgery group) after hepatectomy. Randomized stratification factors include tumor size (≤ 5 vs. > 5 cm) and microvascular invasion (presence vs. absence). In the Surgery-IMRT group, patients received IMRT within 1-3 months after surgical resection. The prescription dose was planned at 50-60 gray in 25-30 fractions over 5-6 weeks. The primary endpoint was recurrence free survival (RFS). The secondary endpoints were safety and overall survival (OS). The planned sample size was 148 patients in total to obtain an improvement in the 2-year RFS rate from 45% to 65%, to detect a hazard ratio (HR) of 0.54, with a one-sided alpha of 5% and 80% power.

Results:Between January 15, 2019, and September 15, 2023, 148 patients from 6 hospitals in China were randomized: 74 patients were allocated to the Surgery-IMRT group and 74 to the Surgery group. The median follow-up duration was 27.4 months (95% confidence interval [CI] 23.2-29.2 months). The 2-year RFS was 78.37% (95% CI 64.35%–87.40%) for the Surgery-IMRT group and 57.43% (95% CI 43.25%–69.28%) for the Surgery group (P=0.028). The median OS was not reached for the two groups. The following radiotherapy-related grade 3–4 adverse events were 3 thrombocytopenia, 3 neutropenia, and 1 hemoglobin decreased.

Conclusions:In conclusion, this trial showed that the adjuvant IMRT following curative resection can bring survival benefits of RFS for HCC patients with narrow margin. Clinical trial information: NCT03732105.

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