2025年1月25日，美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2025）已于当地时间圆满落幕。LAPIS试验（摘要号675）评估了帕姆雷单抗联合化疗在不可切除的LAPC中的疗效和安全性，入选大会的口头摘要。《肿瘤瞭望消化时讯》的记者有幸针对该研究对美国弗吉尼亚梅森医院和医疗中心的Vincent J. Picozzi教授进行了独家专访， 详细解析了LAPIS研究的背景、结果和临床启示。

《肿瘤瞭望消化时讯》：您能简要介绍一下研究的背景和初衷吗？

Vincent J. Picozzi教授：帕姆雷单抗是一种单克隆抗体，可以结合一种叫做结缔组织生长因子（CTGF）的分子，这种分子在胰腺癌细胞与周围基质的相互作用中起着非常核心的作用。人们认为通过使用帕姆雷单抗可以抑制或破坏癌症与基质之间的协同作用，从而抑制其生长。这一点得到了很多支持，无论是在临床前转化研究方面，还是在I期和Ib期的早期临床试验中都表明它实际上可以增强化疗的效果，并有可能增加手术切除癌症的可能性。

Dr Picozzi: Pamrevlumab is a monoclonal antibody that binds to a molecule called connective tissue growth factor (CTGF). This molecule is very central to the interaction of pancreatic cancer tumor cells and the surrounding stroma. It was thought that by using pamrevlumab one could inhibit or disrupt the synergy between the cancer and the stroma, thereby inhibiting its growth. There was a lot of support for this, both in terms of preclinical translational research, as well as early clinical trials in phase I and phase Ib,? suggested that it could in fact enhance the effect of chemotherapy and potentially increase the potential for the cancer to be removed surgically.

《肿瘤瞭望消化时讯》：到目前为止，您试验的主要发现是什么？

Vincent J. Picozzi教授：我们的研究发现，尽管在使用帕姆雷单抗时没有产生额外的副作用，但当将其添加到化疗（本研究中为吉西他滨和白蛋白紫杉醇）中时，并未显示出对所有患者的整体生存获益，也未提高手术率。目前对患者亚组尚未进行分析，因此有可能在那里能看到一些获益，但就目前而言，对于所有患者来说，并没有明确的生存获益。

Dr Picozzi: The main findings have been that although using pamrevlumab does not produce additional side effects when added to chemotherapy (in this case, gemcitabine and nab-paclitaxel, unfortunately, it hasn’t been shown an overall survival benefit in all patients, or increase the rate of surgery. Now, patient subsets have yet to be analyzed, so it is possible that there may be benefits seen there, but at this point, for all patients, there is no definite benefit to survival.

《肿瘤瞭望消化时讯》：与其他药物相比，帕姆雷单抗-化疗联合方案的优势是什么？

Vincent J. Picozzi教授：首先，帕姆雷单抗-化疗联合方案没有明显副作用，这对于已经接受化疗且年龄稍大的患者来说是一大优势。另一个潜在优势是血液中的CTGF水平是成功的生物标志物。如果患者的CTGF水平较低，药物更有可能起作用。帕姆雷单抗作为一种非化疗的药物，没有明显的副作用并且有成功的生物标志物，所有这些因素使得对其进行研究变得很有趣。

Dr Picozzi: First of all, the absence of side effects, which is always good in patients who already receiving chemotherapy and somewhat older. Another potential advantage is that the level of CTGF in the blood is a biomarker for success. If those levels are low, it is more likely that the drug will work. It is a drug that is not chemotherapy, has no appreciable side effects, and has a biomarker for success. All of those things made it interesting to test.

《肿瘤瞭望消化时讯》：您认为这项试验的结果对现有的治疗策略有何影响？

Vincent J. Picozzi教授：不幸的是，该药物本身并未被证明在主动治疗中发挥作用，但我们将从一些转化数据和临床数据中学到很多东西，例如如何评估这些癌症的反应，药物是否发挥作用的方式，是否存在可能受益的不同患者亚组，以及对进行局部晚期和转移性胰腺癌临床试验方法的见解等，这些对未来其他药物可能更有用。我还要指出的是，实际上中国进行了一项与LAPIS试验平行的试验。尽管中国的结果在总体生存方面略有改善，但再次添加帕姆雷单抗到吉西他滨和白蛋白紫杉醇中并未显示出总体生存的益处。

Dr Picozzi: Well unfortunately, the drug itself has not been shown to have a role in active therapy, but we are going to learn quite a lot from some translational data and clinical data about how to assess response in these cancers, how the drug may or may not work, if there are different patient subsets that might benefit, and insights into the methodology of doing clinical trials for both locally advanced and metastatic pancreas cancer that may be more helpful for other drugs in the future. Something I will also point out, that there was a parallel trial to the LAPIS trial actually done in China. Although the Chinese results were somewhat better in terms of overall survival, once again there was no benefit in overall survival seen by adding pamrevlumab to gemcitabine and Abraxane (nab-paclitaxel).

LAPIS: Randomized phase 3 trial of chemotherapy (CTX) with and without pamrevlumab (PAM) for locally advanced pancreatic cancer (LAPC)

背景

在Ⅰ/Ⅱ期局部晚期胰腺癌（LAPC）试验中（NCT01181245；NCT02210559），当PAM与CTX联合使用时，改善了患者的缓解率、可手术资格和手术切除率。LAPIS试验（NCT03941093）评估了PAM + CTX在不可切除的LAPC中的疗效和安全性。

方法

LAPIS是一项全球性、双盲、安慰剂对照的Ⅲ期试验，研究对象为治疗初治的、经确认不可切除的LAPC成年患者。患者随机接受（1:1）PAM（35 mg/kg 每两周一次）或安慰剂（PBO）加上标准方案的CTX（吉西他滨+白蛋白紫杉醇[GnP]或FOLFIRINOX [FFX]）治疗，最多六个28天周期。基于FDG-PET的变化、可切除性和最终手术决定（由外科医生做出）。主要终点：总生存期（OS）；次要终点：无事件生存期（EFS）、无进展生存期（PFS）和客观缓解率（ORR）。对接受治疗的患者进行了安全性评估，包括治疗期间出现的不良事件（TEAEs）。

结果

共有143例和141例患者（中位数年龄，65.0 [31~90]岁；53.2%为男性）被随机分配到PAM组和PBO组。142例和141例患者接受了治疗：GnP，114例（79.7%）和112例（79.4%）；FFX，28例（19.6%）和29例（20.6%）。PAM组有64.8%的患者完成了6个治疗周期，而PBO组有68.1%的患者完成了6个治疗周期。PAM组和PBO组的生存情况相似，并且没有因治疗方案的不同而有所不同。对于PAM + FFX与PBO + FFX相比，呼吸系统、胸廓和纵隔疾病（39.3% vs. 27.6%）以及皮肤和皮下组织疾病（53.6% vs. 37.9%）的发生率在PAM组中高出10%以上；而PAM + GnP与PBO + GnP的TEAE频率相似。PAM组发生了一例治疗相关的死亡。

结论

LAPIS包含了重要的LAPC试验创新，包括治疗前后的FDG-PET成像、手术干预的客观标准、外部手术审查小组以及复合EFS测量。将PAM添加到CTX中并未增加额外的毒性，但并未改善不可切除的LAPC的生存结果。