Tryptophan

点上方蓝字“肿瘤瞭望消化时讯”关注我们， 然后点右上角“…”菜单，选择“设为星标” ASCO GI 2025微专辑 扫描二维码 可查看更多内容 编者按 在2025年1月23日召开的美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2025）上，HER2+胃癌的两项研究进展广受瞩目（摘要号：332和摘要号：393）。《肿瘤瞭望消化时讯》特将该两项研究进行了整理。现将内容整理如下，以飨读者。 研究简介 01 ASPEN-06研究 Evorpacept（ALX148，Evevo）是一种高亲和力的CD47阻断剂，具有一个惰性Fc区域，旨在安全地增强抗癌抗体依赖的细胞吞噬作用。Evorpacept正在评估与抗HER2疗法和检查点抑制剂在癌症患者中的联合应用。 ASPEN-06随机Ⅱ期试验评估了Evorpacept联合标准治疗（TRP）即曲妥珠单抗、雷莫芦单抗和紫杉醇用于治疗HER2+胃癌患者的疗效。本研究纳入了第2或3线治疗的HER2+晚期或转移性胃癌患者，这些患者在先前的抗HER2治疗后出现疾病进展，或对曲妥珠单抗联合紫杉烷类化疗无响应。HER2状态通过最近的GC组织样本确定。主要研究目标是比较Evorpacept-TRP的确认客观缓解率（ORR）与假设的TRP ORR=30%，采用单侧α误差为0.025，并确定Evorpacept对TRP在ORR上的临床有意义贡献（delta>10%）。 在整个随机人群中（N=127），ORR分别为40.3%（Evorpacept-TRP）和26.6%（TRP）。与历史对照的RP相比，Evorpacept-TRP的ORR差异没有统计学意义（P=0.095），但与TRP的ORR相比，Evorpacept-TRP的ORR显示出有意义的13.7% delta（探索性分析中P=0.028）。Evorpacept-TRP和TRP的中位无疾病进展生存期分别为15.7个月和7.6个月。在预先指定的人群中，即先前接受过抗HER2治疗后新鲜肿瘤组织中HER2+疾病的患者（N=48），与历史对照的RP相比，Evorpacept-TRP的ORR（54.8%）有显著优势（P=0.030），与TRP的ORR 23.1%相比，delta为31.7%（探索性分析中P=0.004）。Evorpacept-TRP具有良好的耐受性，安全性概况与先前的经验一致。 Evorpacept联合TRP在HER2+ GC中显示出有希望的抗肿瘤活性。使用新鲜活检组织确定的HER2+肿瘤的反应幅度最大，强调了抗HER2治疗后活检的重要性。与Evorpacept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抗HER2胃癌治疗辅助手段的持续研究。 02 Trigger研究 既往已经报道，在比较全身化疗与或不与曲妥珠单抗联合，随后进行手术治疗HER2阳性伴广泛淋巴结转移的晚期胃癌或食管胃交界处腺癌的随机Ⅱ期试验中，添加曲妥珠单抗到术前化疗中获得了更好的客观和病理反应。这里，我们报告了3年的随访数据。 符合条件的伴有广泛淋巴结转移的HER2阳性胃癌患者被随机分配到A组接受S-1/顺铂（SP：S-1 80–120 mg/body，第1~14天；顺铂60 mg/m²，第1天；q21天，3-4个疗程）或B组接受SP加上曲妥珠单抗（第一疗程8 mg/kg，之后每个疗程6 mg/kg，第1天）。胃切除术后，两组均添加了为期1年的S-1辅助化疗。主要终点是总生存期（OS），计划总样本量为130例患者，预期3年OS增加10%（70% vs 80%），单侧α为0.2，功效为0.75。 由于患者招募缓慢，该研究于2021年3月终止。总共有46例患者被随机分配到A组（22例患者）或B组（24例患者）。两组间患者特征平衡良好。A组有20例患者（90.9%）完成了计划的术前化疗，B组有23例患者（95.8%）完成。B组的客观缓解率倾向于高于A组（66.7% [16/24] vs 36.4% [8/22]，P=0.08），A组和B组分别实现了90.9%和91.7%的R0切除。A组和B组分别有54.6%（12/22）和54.2%（13/24）完成了辅助化疗。在中位观察期为4.1年的情况下，A组和B组的3年OS分别为68.2%和78.9%，风险比为0.698（95%置信区间[CI]：0.221~2.209）。A组和B组的3年无进展生存率分别为39.3%和62.3%，风险比为0.562（95% CI：0.229~1.377）。 研究发现，术前化疗使用SP加曲妥珠单抗是可行的，并且倾向于提高客观缓解率、OS和无进展生存率。我们正在计划与其他临床试验进行综合分析，以评估围手术期曲妥珠单抗的效果。 滑动查看摘要原文 332 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 3rd line 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. 393 A randomized phase II trial of systemic chemotherapy with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: 3-year follow-up data of the Japan Clinical Oncology Group study JCOG1301C (Trigger study). Background:We previously reported better objective and pathological response with the addition of trastuzumab to preoperative chemotherapy in the randomized phase II trial comparing the efficacy of systemic chemotherapy with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis. Here, we report 3-year follow-up data. Methods:Eligible patients with HER2-positive gastric cancer having extensive lymph node metastasis were randomized to receive preoperative chemotherapy with S-1/cisplatin (SP: S-1 80–120 mg/body on days 1–14, and cisplatin 60 mg/m2 on day 1, q21 days, 3-4 courses) in arm A or SP plus trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1 on each course) in arm B. After gastrectomy, adjuvant chemotherapy with S-1 was added for 1 year in both arms. The primary endpoint was overall survival (OS), and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year OS (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results:The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either arm A (22 patients) or arm B (24 patients). Patient characteristics were well balanced between the arms. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in arm A and in 23 patients (95.8%) in arm B. Objective response rate tended to be higher in arm B (66.7% [16/24]) than in arm A (36.4% [8/22], p=0.08), and R0 resection was achieved in 20 patients (90.9%) in arm A and 22 patients (91.7%) in arm B. The adjuvant chemotherapy was completed in 54.6% (12/22) in arm A and in 54.2% (13/24) in arm B. With the median observation period of 4.1 years, the 3-year OS was 68.2% in arm A and was 78.9% in arm B with a hazard ratio of 0.698 (95% confidence interval (CI), 0.221-2.209). The 3-year progression-free survival of arm A and arm B was 39.3% and 62.3%, respectively, with a hazard ration of 0.562 (95% CI, 0.229-1.377). Conclusions:Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to improve the objective response rate, OS and progression-free survival. An integrated analysis with other clinical trials evaluating perioperative trastuzumab is being planned. （来源：肿瘤瞭望消化时讯） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

点上方蓝字“肿瘤瞭望消化时讯”关注我们， 然后点右上角“…”菜单，选择“设为星标” ASCO GI 2025微专辑 扫描二维码 可查看更多内容 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。 滑动查看英文原文 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。 滑动查看英文原文 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 01 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。 02 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%）。 03 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。 04 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。 滑动查看摘要原文 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. （来源：肿瘤瞭望消化时讯） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。