肿瘤瞭望消化时讯

ASCO GI现场直击｜Dr. Chantrill：白蛋白紫杉醇联合卡铂一线治疗胃肠道神经内分泌癌表现出初步疗效，未来可期

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（2024 ASCO Gastrointestinal Cancers Symposium，ASCO GI 2024）于美国当地时间2024年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19日的快速口头报告专场，澳大利亚卧龙岗医院（Wollongong Hospital）Lorraine A. Chantrill教授汇报了白蛋白紫杉醇联合卡铂一线治疗胃肠道神经内分泌癌（GI-NECs）的最新研究结果（Abstract 589）。在《肿瘤瞭望》现场采访中，Lorraine A. Chantrill教授介绍了此项研究和后续的研究计划。现整理相关内容，以飨读者！

现场之声

肿瘤瞭望：您在本次大会上报告了“白蛋白紫杉醇联合卡铂一线治疗胃肠道神经内分泌癌（GI-NECs）”的最新结果，能否给我们分享一下这项研究的主要背景？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 “a study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)” at this conference, can you share with us the background and why you think they were so important?
Dr. Chantrill：非常感谢。我的名字是Lorraine a . Chantrill，我汇报的研究是NABNEC，研究对象为一组罕见的患者，也就是患有高级别胃肠道神经内分泌癌（NEC）的患者。从胃肠道神经内分泌癌的治疗轨迹来看，我们还没有开展过很多研究，所以在这类患者群体中进行研究真的很重要。胃肠道神经内分泌癌的标准治疗一直是卡铂联合依托泊苷，但这是从小细胞肺癌中推测出来的。所以观察胃肠道神经内分泌癌和小细胞肺癌的生物学行为是否不同很重要，我们很想在这个患者群体中尝试使用白蛋白紫杉醇。

Dr. Chantrill：Thank you very much. My name is Lorraine A. Chantrill, and this is an NABNEC study, and it's in a rare group of patients, that is, patients with high grade GI Neuroendocrine carcinomas(NEC). From the GI Neuroendocrine carcinomas track, we don't have a lot of studies to go on yet, so really important to do a study in this patient group. The standard of care has always been carboplatin combinated with etoposide , but that was taken from small cell lung cancer. So it was really important to see whether GI-Neuroendocrine carcinomas behave differently to small cell lung cancer, we really wanted to try nab-paclitaxel in this patient group.


肿瘤瞭望：能否请您分享一下这项研究的主要结果以及重要的临床意义？

Oncology Frontier: Could you please share us the main findings of this study and its important clinical implications?

Dr. Chantrill：该研究达到了其主要终点客观缓解率，与对照组相比，客观缓解率有所改善。研究结果真的很棒。虽然这项研究并不能真正显示无进展生存期或总生存期的改善，但我们这项小样本研究的结果支持进一步进行更大样本的研究。

Dr. Chantrill：The study met its Primary endpoint, and the primary endpoint was objective response rate that would be improved by comparison to the control group. And that was really great. This study was not power to really show an improvement in progression free survival or overall survival. But we're hoping that the results from this small study was to do a larger study.


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 study at the conference, and what are your next research directions?

Dr. Chantrill：是的，所以我们真的很想推进这项研究，做一个更大样本量的研究，也许是一项Ⅲ期研究。正如你所知，现在很多癌症，我们都在尝试添加免疫疗法。也许这种癌症也能增加免疫疗法。但我们必须与国际伙伴合作。因此，澳大利亚胃肠试验小组希望与国际伙伴合作进行更大规模的研究。
Dr. Chantrill：Yeah, so we really like to progress this and do a larger study, maybe a phase Ⅲ study. And as you know, a lot of cancers now, we're trying to add immunotherapy. Maybe that's a role for adding immunotherapy for this cancer. But we would have to collaborate with international partners. So the Australian gastrointestinal Trials Group would like to collaborate with international partners on a larger study.

肿瘤瞭望：您认为胃肠道间质瘤领域还面临哪些挑战？

Oncology Frontier: What challenges do you think the field of gastrointestinal neuroendocrine carcinomas still faces?
Dr. Chantrill：还有很多挑战。高级别胃肠道NENs较罕见，而且，我们对其生物学的理解也很差，因为我们没有做足够多的研究，我们没有做足够多的组织分析、基因研究。我们正处在研究这种特殊癌症的初期。

Dr. Chantrill：There are a lot of challenges. The high grade gastrointestinal NENs are very Rare, but also, our understanding of the biology is very poor, because we haven't done enough studies, and we haven't done enough tissue analysis, genetic studies. We really are at the beginning of our discovery in this particular cancer.

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研究简介

NABNEC: A randomised phase II study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)NABNEC：一项随机II期研究，白蛋白紫杉醇联合卡铂作为胃肠道神经内分泌癌（GI-NECs）的一线治疗

背景

神经内分泌癌是一种罕见的侵袭性癌症。迄今为止还没有随机试验来建立晚期G3胃肠道（GI） NENs（神经内分泌肿瘤）的标准治疗方法。从小细胞肺癌的数据推断，标准做法是用依托泊苷和卡铂治疗G3 GI-NENs。紫杉醇在NECs中也有活性，但没有关于白蛋白紫杉醇作用的数据。NABNEC （ANZCTR # 12616000958482）旨在确定卡铂和白蛋白紫杉醇在晚期G3 GI-NENs中的活性、安全性和耐受性，并加深我们对此类NENs生物学和影像学特征的了解。

方法

NABNEC被设计为一项随机非对照II期研究，评估白蛋白紫杉醇在晚期和（或）转移性不可切除G3 GI-NENs患者中的活性。统计计划是，实验组的46例可评估患者将给予80%的权重和95%的置信区间来排除30%的RR，以支持6个月时更有趣的50%的RR。修改方案3.0版本，在12例患者后暂停随机分配到对照组。主要终点为RECIST 1.1标准的客观缓解率（RR）。次要终点为无进展生存期、总生存期、NCI-CTCAE V4.03不良事件和生活质量（EORTC QLQC30、QLQ-GINET21问卷）。转化研究终点包括血液和组织生物标志物，包括循环肿瘤细胞谱、突变谱（全外显子组测序）和与临床终点相关的DNA甲基化谱。18-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）与早期反应的相关性也被评估。

结果

2016年9月至2021年12月期间，纳入来自16个中心的60例患者，其中58例为可评估患者，12例（对照组），46例（实验组）。43例（75%）患者肿瘤Ki-67>55%；其余的Ki-67在20%到55%之间。约20%为胰腺原发；超过一半的患者有肝转移。NABNEC试验达到了主要终点。实验治疗组的RR为53%(38%—69%)，对照组为42%(16%—71%)。两种治疗的无进展生存率无差异。实验组的24个月总生存率为25%，对照组为17%。白蛋白紫杉醇组3级毒性更差（52% vs. 42%）。正在分析生活质量和第三阶段结果。

结论

卡铂联合白蛋白紫杉醇是治疗G3 GI-NENs的有效方案。需要在III期研究中进行进一步评估。

临床试验信息：ACTRN12616000958482。


摘要原文

NABNEC: A randomised phase II study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)

Background:

Neuroendocrine carcinomas (NEC) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced G3 gastrointestinal (GI) NENs（neuroendocrine neoplasms）. Extrapolating from small cell lung cancer data, standard practice is to treat G3 GI-NENs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of?nab-paclitaxel. NABNEC (ANZCTR # 12616000958482) aimed to determine the activity, safety and tolerability of carboplatin and?nab-paclitaxel in advanced G3 GI-NENs and to enhance our understanding of the biology and imaging characteristics of such NENs.

Methods:

NABNEC was designed as a randomised non-comparative phase II study, evaluating the activity of?nab-paclitaxel in patients with advanced and/or metastatic non-resectable G3 GI-NENs. The statistical plan was that 46 evaluable patients in the experimental arm would give 80% power and 95% confidence to rule out a 30% RR in favour of a more interesting RR of 50% at 6 months. Protocol version 3.0 was amended and randomisation to the control arm was suspended after 12 patients. Primary endpoint was objective response rate (RR) by RECIST 1.1. Secondary endpoints were progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational research endpoints include blood and tissue biomarkers including circulating tumour cells profiling, mutation profile (whole exome sequencing) and DNA methylation profile correlated with clinical endpoints. Correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response has also been evaluated.

Results:

60 patients were accrued between Sep 2016 and Dec 2021 from 16 centres, resulting in 58 evaluable patients, 12 (control arm), 46 (experimental arm). 43 patients (75%) had tumours with Ki-67>55%; the remainder had Ki-67 between 20 and 55%. About 20% had pancreatic primaries; more than half had liver metastases. The NABNEC trial met its primary endpoint. RR was 53% (38-69%) in the experimental treatment arm compared to 42% (16-71%) in the control group. Progression free survival was not different between the 2 treatments. 24m overall survival was 25% in the experimental group compared to 17% in the control. Grade 3 toxicity was worse in the nab-paclitaxel arms (52% v 42%). Quality of life and tertiary outcomes are being analysed.

Conclusions:

The combination of carboplatin and nab-paclitaxel is an active regimen for G3 GI-NENs. Further evaluation in a Phase III study is warranted. Clinical trial information: ACTRN12616000958482.

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