ESMO GI 2025微专辑扫描二维码可查看更多内容编者按2025年欧洲肿瘤内科学会胃肠道肿瘤大会(ESMO GI)于当地时间7月2日盛大启幕!作为全球肿瘤学界瞩目的学术盛会,本届大会Proffered Pape session与Mini Oral session再度汇聚胃肠肿瘤领域重磅前沿成果。其中,Mini Oral session专场特设"胃肠肿瘤创新专场",从全球众多投稿中遴选出7项突破性研究,集中展现胃肠道肿瘤诊疗的创新进展。入选研究涵盖胰腺癌领域2项重磅成果(摘要号:259M0、260MO)、胃肠道肿瘤(GI)1项临床突破(摘要号:479MO)、结直肠癌领域1项创新实践(摘要号:6MO)、肝细胞癌领域2项前沿探索(摘要号:149MO、150MO)、胃食管肿瘤领域1项研究(摘要号:388MO)。为及时传递学术价值,本文已优先完成胰腺癌与GI领域3项研究的梳理,剩余4项成果将陆续发布。期待与全球同道共飨学术盛宴,携手推动胃肠肿瘤精准诊疗迈向新高度!259MO - BXCL701联合帕博利珠单抗二线治疗晚期胰腺导管腺癌背景胰腺导管腺癌(PDAC)对免疫检查点抑制剂耐药,部分原因在于肿瘤免疫微环境(TME)处于“冷”状态。BXCL701(’701)是一种二肽基肽酶4、8、9及成纤维细胞激活蛋白的小分子抑制剂。研究表明,’701与抗PD-1抗体联用在小鼠PDAC模型中具有抗肿瘤活性,其机制包括:1.激活炎症小体并表达CXCL9以募集和激活CXCR3+淋巴细胞;2.CD8+ T细胞及其他效应细胞浸润肿瘤;3.诱导适应性免疫;4.减少PDAC肿瘤微环境中的纤维化。方法在正在进行的Ⅱ期临床试验(EXPEL PANC NCT05558982)中,二线晚期PDAC患者接受’701治疗,剂量为第1周期(21天)第1~7天每日两次口服0.2 mg,第8~14天每日两次0.3 mg,后续周期每21天第1~14天每日两次0.3 mg,同时每21天静脉注射帕博利珠单抗200 mg(所有周期)。主要终点为二线治疗晚期PDAC患者的18周无进展生存率(PFS18weeks)。据历史数据,二线治疗PFS18weeks≤30%;采用Simon两阶段(最小化)设计,若真实缓解率为50%,在Ⅰ类错误率0.05、检验效能80%条件下,第一阶段需19例患者,第二阶段需20例(共39例可评估)。若第一阶段19例可评估患者中7例在18周时无进展,则进入第二阶段。结果研究已入组21例患者,其中3例仍在治疗中。16例可评估患者中4例在18周时无进展。18例可评估患者中,3例达到部分缓解(PR,17%),4例疾病稳定(SD,22%),疾病控制率(DCR)为39%。1例缓解者为MSI-H型PDAC,另2例为MSS型。PFS为2.3个月(95%CI:1.58~5.29),中位总生存期(OS)尚未达到(NR,95%CI:4.54~NR)。未发现新的安全性信号。将分析基线及治疗期间肿瘤活检标本,以探索疗效机制并比较缓解者与非缓解者的特征。结论本研究将确定’701联合帕博利珠单抗在晚期PDAC二线治疗中的疗效。初步结果显示,该方案在历史上对免疫治疗耐药的人群中具有疗效。临床试验注册号:NCT05558982。260MO - AGITG ASCEND研究:在未经治疗的mPDAC患者中,评估certepetide(CERT)或安慰剂(PLA)联合吉西他滨+白蛋白紫杉醇的随机、双盲Ⅱ期研究——队列B的PFS结果背景CERT(又名LSTA1或CEND-1)是一种新型环状多肽,可促进联合给药药物在肿瘤和基质中的渗透,可能增强抗肿瘤活性。ASCEND研究是一项随机Ⅱ期试验,旨在探索在吉西他滨(GEM)联合白蛋白紫杉醇(NPC)一线化疗基础上,添加单次静脉注射CERT(队列A,已报告)或两次间隔4小时静脉注射CERT/PLA(队列B)对mPDAC的疗效(NCT05042128)。CERT在人体内的半衰期约为1.5小时。方法队列B中,63例ECOG评分0~1分的mPDAC患者按2:1随机分配至GEM/NPC联合静脉注射CERT(3.2 mg/kg)或PLA,每28天周期的第1、8、15天分两次给药(间隔4小时),并按年龄(<65/≥65岁)、ECOG评分(0/1)、肝转移(是/否)和研究中心分层。队列B为探索性研究,未预设统计学假设。主要终点为通过Kaplan-Meier法计算的6个月(mo)PFS,次要终点包括中位PFS(mPFS)、OS、客观缓解率(ORR)和毒性。结果队列B共入组63例患者(CERT组42例,PLA组21例)。CERT组6个月PFS率为60.8%(95%CI:44.1%~73.9%),PLA组为25%(95%CI:9.1%~44.9%)。CERT组mPFS为7.5个月,PLA组为4.7个月(HR 0.60,95%:CI 0.34~1.07,P=0.08)。CERT组ORR为45.2%,PLA组为19%。CERT组DCR为85.9%,PLA组为61.9%。CERT组初步中位OS为10.3个月,PLA组为9.2个月。安全性方面,与GEM/NPC的历史数据一致,CERT组88%患者发生3、4、5级不良事件,PLA组为77%。CERT组与PLA组的3/4级血液学毒性:中性粒细胞减少(34.3% vs. 28.6%)、血小板减少(19% vs. 14.3%)。结论双剂量CERT联合GEM/NPC在mPDAC中显示出具有临床意义的PFS和ORR改善趋势,且安全性可控。6个月PFS率支持进一步探索CERT作为mPDAC新型治疗药物。临床试验注册号:ACTRN12621001290886(ANZ)。479MO - 创新型TCR-β链靶向双特异性抗体invikafusp alfa单药治疗抗PD(L)1耐药、抗原富集型胃肠道(GI)肿瘤的Ⅰ/Ⅱ期临床研究背景Invikafusp是一种选择性双T细胞激动剂,靶向Vβ6/Vβ10 T细胞,正在START-001研究中评估其作为单药治疗抗PD(L)1耐药、抗原富集型实体瘤(包括GI癌)的疗效。Ⅰ期结果显示,invikafusp在多种GI肿瘤中具有单药抗肿瘤活性。所有患者在invikafusp治疗前均对多线治疗(包括抗PD(L)1)耐药。基于初步临床结果,美国FDA授予invikafusp治疗TMB-H型结直肠癌的快速通道资格。方法抗原富集型(TMB-H、MSI-H或两者兼有,或HPV相关)GI肿瘤患者接受静脉注射invikafusp,每2周一次,剂量为最佳生物效应剂量(OBD)0.08 mg/kg(推荐Ⅱ期剂量,RP2D)或0.12 mg/kg。结果截至2025年3月31日,共入组22例患者,涵盖7种不同GI肿瘤,中位既往治疗线数为4线。22例患者中18例已完成至少1次肿瘤评估。其中12例(67%)达到疾病控制[部分缓解(PR)+疾病稳定(SD)]。根据RECIST标准,4例(22.2%)PR包括:3例转移性结直肠癌(mCRC)(2例MSS TMB-H型,其中1例缓解持续约12个月;1例MSI-H型,曾接受ICI治疗)和1例MSI-H型胃食管交界癌(曾接受ICI治疗)。另有2例(11.1%)(1例胰腺癌和1例MSS mCRC)肿瘤缩小,总体达SD。18例中6例(33.3%)达SD:5例MSS mCRC和1例食管癌。未发现新的安全性信号。最常见治疗相关不良事件(TEAE)主要为短暂性1~2级细胞因子释放综合征(CRS),与invikafusp的作用机制一致。未报告4级非实验室检查相关TEAE或治疗相关5级事件。与GI肿瘤外患者类似,GI肿瘤患者的invikafusp血药浓度(AUC和Cmax)也呈剂量依赖性升高。值得注意的是,外周血CD8+ Vβ6/Vβ10 T细胞峰值增加超过400%,观察到持续且选择性的Vβ6/Vβ10 T细胞扩增。结论创新型选择性双T细胞激动剂invikafusp作为单药治疗,在多种GI癌(尤其是结直肠癌)中显示出具有临床意义的抗肿瘤活性。Ⅱ期扩展研究正在抗原富集型GI肿瘤中进一步探索invikafusp的疗效。临床试验注册号:NCT05592626。摘要原文259MO - BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinomaBackgroundPancreatic ductal adenocarcinoma (PDAC) is resistant to immune checkpoint inhibitors, in part due to a cold tumor immune microenvironment (TME). BXCL701 (‘701) is a small molecule inhibitor of dipeptidyl peptidases 4, 8, 9 and fibroblast activation protein. We have shown that combinations of ‘701 and anti-PD1 antibodies have anti-tumor activity in murine PDAC models due to 1) activation of the inflammasome and expression of CXCL9 to attract and activate CXCR3+ lymphocytes, 2) tumor invasion of CD8+ T cells and other effector cells, 3) induction of adaptive immunity and 4) reduced fibrosis in the PDAC TME.MethodsIn an ongoing phase II clinical trial (EXPEL PANC NCT05558982), patients (pts) with second-line advanced PDAC receive ‘701 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in pts with advanced PDAC treated in the second-line setting. We estimate that historical 2nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% if the true response rate of 50%, we will need 19 pts in stage 1 and 20 in stage 2 (a total of 39 evaluable). Seven of 19 evaluable pts will need to be progression-free at 18 weeks to trigger stage 2.ResultsTwenty-one pts have enrolled on the study, including 3 still on treatment. Four out of 16 evaluable pts have been progression-free at 18 weeks. Of 18 evaluable pts, 3 had partial responses (17%), and 4 had stable disease (22%), for a disease control rate of 39%. One responder had MSI-H PDAC, the other 2 were MSS. Median PFS is 2.3 months (95% CI 1.58-5.29), and median overall survival is not reached (NR, 95% CI 4.54-NR). No new safety signals have been identified. Baseline and on-treatment tumor biopsies will be analyzed to understand the mechanisms underlying therapeutic benefit and examine the characteristics of responders vs. non-responders.ConclusionsThis study will determine the efficacy of ‘701 + pembrolizumab in second-line advanced PDAC. Preliminary findings suggest efficacy in a historically immunotherapy-resistant population.Clinical trial identificationNCT05558982. 260MO - AGITG ASCEND study: Randomised, double-blind phase II study of certepetide (CERT) or placebo (PLA) added to gemcitabine plus nab-paclitaxel in patients with untreated metastatic pancreatic ductal adenocarcinoma (mPDAC): Cohort B progression-free survival (PFS) resultsBackgroundCERT (aka LSTA1 or CEND-1) is a novel cyclic peptide that improves penetration of co-administered drugs into tumour and stroma, potentially leading to increased anti-neoplastic activity. ASCEND is a randomised phase 2 trial designed to investigate the impact of adding CERT either as a single IV dose (cohort A previously reported) or two IV doses of CERT/PLA separated by 4 hours (h) (cohort B) to gemcitabine (GEM) plus nab-paclitaxel (NPC) as first-line chemotherapy for mPDAC (NCT05042128). CERT’s half-life in humans is ∼1.5 h.MethodsIn cohort B 63 participants with mPDAC and ECOG 0-1 were randomised 2:1 to receive GEM/NPC plus IV CERT (3.2 mg/kg) or PLA, administered twice separated by 4 h, on days 1, 8, & 15 every 28-day cycle, with stratification was by age (< 65/≥65 years), ECOG (0/1), presence of liver metastases (Y/N), and trial site. Cohort B is exploratory and not powered to test a specific hypothesis. The primary outcome is 6-month (mo) PFS determined by the Kaplan-Meier method. Secondary outcomes were median PFS (mPFS), overall survival (OS), objective response rate (ORR), and toxicity.ResultsSixty-three patients (42 CERT, 21 PLA) were enrolled in cohort B. Six-mo PFS for CERT was 60.8% (95% CI 44.1%, 73.9%) and for PLA was 25% (95% CI 9.1%, 44.9%). mPFS was 7.5 mo for CERT & 4.7 mo for PLA (HR 0.60 95% CI 0.34, 1.07, p=0.08). ORR was 45.2% for CERT & 19% for PLA. Overall disease control rate was 85.9% for CERT & 61.9% for PLA. Preliminary median OS was 10.3 mo with CERT and 9.2 mo with PLA. Consistent with prior reports for GEM/NPC, grade 3/4/5 adverse events occurred in 88% of subjects in the CERT arm and 77% in the PLA arm. Grade 3/4 haematologic toxicity for CERT v PLA: Neutropenia 34.3% and 28.6%, thrombocytopenia 19% and 14.3%.ConclusionsDouble-dose CERT + GEM/NPC demonstrated trends for a clinically meaningful PFS and ORR improvements in mPDAC, with a manageable safety profile. The 6-mo PFS rate (60.8%) supports further investigation of CERT as a novel therapeutic agent in mPDAC.Clinical trial identificationACTRN12621001290886 (ANZ). 24 Sept 202 479MO - Phase I/II clinical investigation of invikafusp alfa, a first-in-class TCR-beta chain-targeted bispecific antibody, as monotherapy in patients with anti-PD(L)1-resistant, antigen-rich gastrointestinal (GI) cancersBackgroundInvikafusp, a selective, dual T cell agonist targeting Vβ6/Vβ10 T cells, is being evaluated in START-001: a multicenter Phase 1/2 monotherapy trial in patients with anti-PD(L)1-resistant, antigen-rich solid tumors including GI cancers. Phase 1 results showed monotherapy anti-tumor activity in multiple GI cancers. All these patients were resistant to multiple lines of therapies including anti-PD(L)1 prior to invikafusp treatment. Based on these initial clinical results, US FDA granted Fast Track Designation for invikafusp in TMB-H colorectal cancer.MethodsPatients with antigen-rich (TMB-H, MSI-H or both, or HPV-associated) GI tumors are treated with IV invikafusp, Q2W, at the OBD of either 0.08 mg/kg (RP2D) or 0.12 mg/kg.ResultsAs of 31 March 2025, 22 patients with a median of 4 prior lines of therapies across 7 different GI tumors were enrolled. Eighteen of 22 patients had ≥ 1 tumor assessment so far. Twelve (67%) of these 18 patients had disease control [partial response (PR) + stable disease (SD)]. Four (22.2%) PRs per RECIST included 3 mCRC (2 MSS TMB-H with one response lasting ∼12 months and 1 MSI-H post ICI) and 1 MSI-H GE junction cancer post ICI. Two additional patients (11.1%) (1 pancreatic cancer and 1 MSS mCRC) had tumor shrinkage with overall SD. Another 6 (33.3%) of 18 had SD: 5 MSS mCRC and 1 esophageal cancer. No new safety signals were seen. The most common TEAE was predominantly transient, grade 1-2 CRS, consistent with invikafusp’s MoA. No grade 4 non-lab TEAEs or treatment-related grade 5 were reported. Like in patients with non-GI tumors, a dose-dependent increase in invikafusp serum concentrations (AUC and Cmax) was also observed in patients with GI tumors. Notably, sustained and selective expansion of predominantly Vβ6/Vβ10 T cells was observed with >400% peak increase in peripheral CD8+ Vβ6/Vβ10 T cells.ConclusionsInvikasfusp, a first-in-class selective, dual T cell agonist, as monotherapy, led to clinically meaningful anti-tumor activity in various GI cancers, particularly in CRC. The Phase 2 expansion is ongoing in antigen-rich GI tumors to further investigate the efficacy of invikafusp in these cancers.Clinical trial identificationNCT05592626.(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。