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ASCO GI现场丨CD47阻断联合疗法在经治HER2阳性胃癌中显示抗肿瘤潜力

肿瘤瞭望消化时讯发表时间：2025-02-13 13:51:41

编者按：2025年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1月25日圆满落幕。本次会议上多项重磅研究数据公布，ASPEN-06研究（摘要号：332）是一项全球性的随机Ⅱ/Ⅲ期研究，旨在探讨evorpact（Evo）与曲妥珠单抗、雷莫芦单抗和紫杉醇联合疗法（TRP）在先前接受过抗HER2治疗且疾病进展的HER2阳性胃癌和食管癌患者中的疗效。在大会现场，《肿瘤瞭望消化时讯》的记者有幸针对该研究对日本国立癌症中心医院的Kohei Shitara教授进行了独家专访，现将内容整理如下，以飨读者。

《肿瘤瞭望消化时讯》：祝贺您的摘要被选为今年ASCO GI会议上的口头报告。能否请您简要介绍一下ASPEN-06研究的背景和初衷？

Kohei Shitara教授

ASPEN-06研究是一项全球性的随机Ⅱ/Ⅲ期研究，旨在探讨evorpact（Evo）与曲妥珠单抗、雷莫芦单抗和紫杉醇联合疗法（TRP）在先前接受过抗HER2治疗且疾病进展的HER2阳性胃癌和食管癌患者中的疗效。Evorpacept是一种CD47阻断剂，可以通过增强曲妥珠单抗等单克隆抗体的抗体依赖性吞噬作用。之前使用Evo已经减轻了血细胞减少或血液学毒性。在这项试验中，我们将患者随机分配到Evo-TRP组或单独TRP组。主要终点是客观反应率。在随机分配的127例患者中，约有40%的患者进行了组织活检以确认HER2状态，而65%的患者通过ctDNA确认了HER2阳性。Evo-TRP组的反应率为40.3%，而单独TRP组为26.6%。虽然Evo-TRP在与历史对照（帕博西尼和雷莫芦单抗的30%）比较时未达到统计学意义，但它显示出了Evo的疗效。与单独TRP相比，Evo-TRP的反应率提高了10%以上。此外，反应持续时间和无进展生存期（PFS）也有改善的趋势。非常重要的是，对于通过组织活检或ctDNA确认的HER2阳性患者，Evo的效果最佳。就安全性而言，没有出现显著的毒性增加。我们观察到中性粒细胞减少和贫血的发生率略高，但差异非常小。且没有增加中性粒细胞减少性发热。总体来说，这项试验表明Evo-TRP方案在HER2阳性胃癌/胃食管癌治疗中展现出了良好的抗肿瘤活性。

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Dr Shitara: The ASPEN-06 study is a global randomized phase II/III study investigating evorpacept (Evo) in combination with the trastuzumab, ramucirumab and paclitaxel combination (TRP) in patients with HER2-positive gastric and gastroesophageal cancer after progressing on previous lines of anti-HER2 therapy. Evorpacept is a CD47-blocking agent that enhances antibody dependent phagocytosis by monoclonal antibodies like trastuzumab. Previous use of Evo has attenuated a decrease in cytopenia or hematological toxicity. In this trial, we randomized patients to Evo-TRP or TRP alone. The primary endpoint was objective response rate. From a total of 127 patients who were randomized, around 40% were enrolled with fresh biopsies to confirm HER2, and 65% of patients had HER2-positivity confirmed by ctDNA. The primary endpoint of response rate was 40.3% with Evo-TRP and 26.6% with TRP alone. Evo-TRP did not meet statistical significance in terms of a comparison to historical control (30% with paclitaxel and ramucirumab), but it showed the clear combinatorial contribution of Evo because there is a >10% improvement in the response rate with Evo-TRP compared with TRP alone. There is a trend of improvement in the duration of response as well as PFS. And very importantly, the efficacy of Evo is best in patients with HER2-positivity from fresh biopsy or ctDNA. Regarding toxicity, there is no increase in significant toxicity. A little higher incidence of neutropenia and anemia was observed, but the difference was very small. There was no increase in febrile neutropenia. So, as a summary, this trial showed the promising activity of Evo-TRP for HER2-positive gastric/gastroesophageal cancer.

《肿瘤瞭望消化时讯》：您能否分享一下未来的研究计划？

Kohei Shitara教授

ASPEN-06研究是一项Ⅱ/Ⅲ期研究，所以下一步将进行III期研究，目前正在讨论几种研究方案的可能性。我相信当我们进入III期研究时，招募通过组织活检确认HER2阳性的患者将是合理的，但我们还需要与研究团队和监管机构进行额外的讨论。此外，这项研究还表明了CD47阻断在实体瘤中的可能性，这可能是第一个展示这种可能性的试验，不仅针对HER2，也针对其他可以用单克隆抗体靶向的靶点。Evo也可以与利妥昔单抗或其他药物结合使用。因此，Evo还有其他的研究机会和潜力。

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Dr Shitara: This is a phase II/III study, so the next step would be phase III, and several research scenario possibilities are under discussion. I believe when we move to phase III, enrolling patients with HER2-positivity from fresh biopsy would be reasonable, but we need additional discussions with the study team and regulatory authorities. Also, this study suggested the possibility of CD47 blockade in solid tumors, and this could be the first trial to show such a possibility, not only for HER2, but also for other tumors that can be targeted with a monoclonal antibody. Evo could be combined with rituximab or others. So there are other opportunities and potential.

研究简介

ASPEN-06 研究随机 2 期部分的最终分析：CD47 检查点抑制剂 evorpacept （ALX148）在 HER2 过表达胃癌/胃食管癌（GC）患者中的 Ⅱ/Ⅲ期研究

背景

Evorpacept（Evo）是一种高亲和力的CD47阻断剂，具有非活性的Fc区域，旨在安全地增强抗癌抗体依赖性细胞吞噬作用。Evorpacept正被评估与抗肿瘤抗体和检查点抑制剂联合使用用于多种癌症。

方法

ASPEN-06随机II期试验评估了Evo与标准曲妥珠单抗（T）、雷莫芦单抗（R）和紫杉醇（P）联合用于治疗HER2阳性胃癌（GC）患者。在先前接受过抗HER2治疗或之后病情进展的第二或三线HER2阳性晚期或转移性GC患者被随机分配到Evo（30 mg/kg 每2周一次）加TRP组或TRP组。HER2状态是在最近的GC组织样本中确定的。主要研究目标是比较Evo-TRP的确认客观反应率（ORR）与假设的RP ORR（=30%），采用单侧alpha误差为0.025，并确定Evo对TRP在ORR中的临床意义（delta>10%）。

结果

在整个随机人群中（N=127），ORR分别为40.3%（Evo-TRP）和26.6%（TRP）。与历史对照RP的ORR相比，Evo-TRP的ORR差异在统计学上不显著（P=0.095），但Evo-TRP的ORR相比TRP的ORR显示出了有意义的13.7%的delta（探索性分析中P=0.028）。Evo-TRP和TRP的中位持续反应时间（DOR）分别为15.7和7.6个月。在预先指定的经过先前抗HER2治疗后新鲜肿瘤组织中HER2阳性的人群（N=48）中，Evo-TRP的ORR（54.8%）与历史对照RP的ORR相比有显著优势（P=0.030），相比TRP的ORR 23.1%，delta为31.7%（探索性分析中P=0.004）。Evo-TRP耐受性良好，安全性特征与先前的研究一致。包括无进展生存期（PFS）在内的更新结果将在会议上展示。

结论

将Evo添加到TRP中在HER2阳性GC中显示出了有希望的活性。在使用组织活检确定的HER2阳性肿瘤中，反应程度最大，强调了抗HER2治疗后活检的重要性。与Evo的增强抗体依赖性吞噬作用的机制一致，这些数据支持其作为胃癌抗HER2治疗的辅助手段的持续研究。

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Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC).Background:Evorpacept (Evo) is a high affinity, CD47-blocker with an inactive Fc region designed to safely magnify anticancer antibody dependent cellular phagocytosis. Evorpacept is being evaluated across cancers, in combination with anticancer antibodies and checkpoint inhibitors.Methods:The ASPEN-06 randomized phase 2 trial evaluates Evo in combination with standard trastuzumab (T), ramucirumab (R) and paclitaxel (P) for the treatment of patients with HER2+ GC. Patients with 2nd or 3rdline HER2+ advanced or metastatic GC that has progressed on or after prior anti-HER2 therapy were randomized to Evo (30 mg/kg Q2W) plus TRP or TRP. HER2 status was determined in the most recent GC tissue sample. Primary study objectives were to compare confirmed ORR of Evo-TRP to an assumed ORR of RP (=30%) with one-sided alpha error of 0.025 and to identify a clinically meaningful contribution of Evo to TRP in ORR (delta>10%).Results:Among the entire randomized population (N=127) the ORR was 40.3% (Evo-TRP) and 26.6% (TRP), respectively. The difference between Evo-TRP's ORR compared to historical RP's ORR was not statistically significant (p=0.095), but Evo-TRP's ORR demonstrated a meaningful delta of 13.7% over TRP's ORR (p=0.028 in an exploratory analysis). Median DOR for Evo-TRP and TRP was 15.7 and 7.6 months, respectively. In a prespecified population with HER2+ disease in fresh tumor tissues after prior anti-HER2 treatment (N=48), Evo-TRP's ORR (54.8%) compared favorably to historical RP's ORR (p=0.030) with a delta of 31.7% over TRP's ORR of 23.1% (p=0.004 in an exploratory analysis). Evo-TRP was well tolerated with a safety profile consistent with prior experience. Updated results including PFS will be presented at the meeting.Conclusions:The addition of Evo to TRP showed promising activities in HER2+ GC. The magnitude of response was greatest in tumors identified as HER2+ using fresh biopsies emphasizing the importance of biopsies post anti HER2 therapy. Consistent with Evo’s mechanism of enhancing antibody dependent phagocytosis, these data support its ongoing investigation as an adjunct to anti-HER2 gastric cancer therapy.