Albumin-Bound Paclitaxel

点击上方蓝字 关注我们编者按：抗HER2治疗是HER2高表达（IHC 3+或IHC 2+且FISH+）晚期胃癌患者的治疗基石，近年来抗HER2联合免疫一线治疗进一步改善了患者预后，而新型HER2 ADC进一步增加了后线治疗的选择，但二线治疗仍存在抗HER2治疗空白。在2025年BOC/BOA大会的胃癌专场上，北京大学肿瘤医院彭智教授分享了近期ASCO大会的最新研究进展，并在接受《肿瘤瞭望》的采访中，进一步介绍了晚期胃癌的治疗现状，以及新型药物将如何填补治疗空白和改变临床治疗格局。01《肿瘤瞭望》：化疗、免疫、抗HER2治疗等为晚期胃癌患者构筑了一线治疗防线。但对于治疗失败的患者，二线及后线治疗仍存在哪些未被满足的临床治疗需求？彭智 教授北京大学肿瘤医院近年来，靶向治疗、免疫检查点抑制剂（ICIs）、抗体偶联药物（ADCs）等构筑了新的晚期胃癌治疗格局。新版CSCO胃癌指南按照HER2高、中、低/不表达进行分层治疗。在晚期一线治疗中，抗HER2＋免疫已成为HER2高表达的治疗标准，HER2中/低/不表达患者则选择化疗，或基于PD-L1、Claudin18.2表达选择免疫或靶向联合化疗；二线治疗中，无论HER2表达状态如何，以紫杉醇联合抗VEGFR靶向治疗或单独化疗为主，dMMR/MSI-H患者可选择免疫治疗；在三线治疗中，德曲妥珠单抗（T-DXd）、维迪西妥单抗（RC48）是HER2高表达患者的优选方案，HER2中表达患者选择RC48，而HER2低/不表达患者以单药抗VEGFR靶向治疗、免疫治疗为主[1]。由此可见，在当前的晚期胃癌治疗格局中，二线抗HER2治疗实际上仍然是空白的。表1. 2025版CSCO胃癌晚期治疗I级推荐[1]一线治疗HER2高表达HER2中/低/不表达·PD-L1 CPS≥1分：免疫＋曲妥＋化疗·PD-L1 CPS＜1分：曲妥＋化疗·根据PD-L1 CPS或TAP水平选择化疗联合免疫治疗；·Claudin18.2表达患者选择化疗联合佐妥昔单抗；·奥沙利铂/顺铂＋氟尿嘧啶类或氟尿嘧啶类＋紫杉类二线治疗HER2高表达HER2阴性dMMR/MSI-H，无论HER2状态·紫杉醇联合雷莫西尤单抗；·单药化疗·紫杉醇联合雷莫西尤单抗；·单药化疗恩沃利单抗等免疫治疗三线治疗HER2高表达HER2中表达HER2低/不表达·德曲妥珠单抗；·维迪西妥单抗·维迪西妥单抗·阿帕替尼；·纳武利尤单抗单药另一方面，在当前紫杉醇联合抗VEGFR二线治疗（不区分HER2状态）的大型III期临床试验中，尽管有一致的无进展生存期（PFS）改善，但总生存期（OS）获益有所差异；而针对HER2阳性患者，曲妥珠单抗跨线治疗的PFS和OS、客观缓解率（ORR）均无获益[2-5]。因此，亟需为晚期胃癌患者寻找新的二线治疗方案，满足患者更多的治疗需求，尤其需要进一步填补二线抗HER2治疗的空白。表2.已报道晚期胃癌二线治疗III期研究（非头对头比较，请谨慎解读）[2-5]_RAINBOW研究（N=665）Rainbow-Asia研究（N=440）FRUTIGA研究（N=703）T-ACT研究（N=91）治疗方案雷莫西尤单抗±紫杉醇（不区分HER2状态）呋喹替尼±紫杉醇（不区分HER2状态）曲妥珠单抗±紫杉醇（HER2+）中位OS（月）9.6 vs 7.4，HR 0.80，P=0.0178.71 vs 7.92，HR 0.963，P=0.74269.6 vs 8.4，HR 0.96，P=0.606410.2 vs 10.0，HR 1.23中位PFS（月）4.4 vs 2.9，HR 0.635 ，P＜0.00014.14 vs 3.15，HR 0.714 5.6 vs 2.7，HR 0.57，P＜0.00013.7 vs 3.2，HR 0.91；P=0.3ORR28% vs 16%，P=0.000126.5% vs 21.9%42.5% vs 22.4%，P＜0.000132% vs 33%，P=1.0002《肿瘤瞭望》：您在本次BOC/BOA大会上，介绍了近期ASCO大会报道的新型HER2 ADC二线治疗的DESTINY-Gastric-04（DG-04）研究。您如何评价该研究结果及其可能对临床实践产生的影响？彭智 教授北京大学肿瘤医院T-DXd是新一代靶向HER2的抗体偶联药物（ADC），具有高药物抗体比、旁观者效应、循环稳定等药物机制优势，使其显示出高效低毒的药物特征，在众多实体瘤领域取得了突破性进展。在晚期胃癌领域，既往报道的DG-01、06研究已改变临床实践，T-DXd成为HER2高表达晚期胃癌患者的≥3线治疗标准[1]；而在欧美国家开展的II期DG-02研究[6]显示T-DXd在HER2高表达晚期胃癌二线治疗中具有巨大的应用潜力，大家对T-DXd能否进一步改变二线治疗格局充满期待。DG-04是一项全球多中心、III期随机对照临床试验[7]，纳入了494例接受过曲妥珠单抗治疗进展的晚期HER2阳性（IHC 3+或IHC 2+/ISH+）胃及胃食管结合部腺癌患者，随机（1:1）接受T-DXd或雷莫西尤单抗＋紫杉醇（RAM＋PTX）治疗。中国研究者和患者也为该研究贡献了重要的数据，有将近20%的入组患者来自中国或其他地区（两组各49例）。此次ASCO大会报道的中期分析数据显示达到了主要终点，T-DXd组患者的中位OS达到了14.7个月，相较于RAM＋PTX组延长3.3个月（14.7 vs 11.4个月），死亡风险显著降低30%（HR 0.70，95%CI：0.55-0.90，P=0.0044）。值得注意的是，RAM＋PTX组有25.8%的患者后续接受了HER2 ADC治疗，其中21.0%的患者接受了T-DXd后续治疗。在删除后续治疗影响后，T-DXd组相较于RAM＋PTX组的死亡风险降低幅度扩大至36%（HR 0.64，95%CI：0.44-0.93）。图1. DG-04研究主要终点OS结果（上）及其亚组分析（下）在次要终点方面也显示了T-DXd的全面获益：T-DXd组患者的中位PFS显著延长，疾病进展或死亡风险显著降低26%（6.7 vs 5.6个月，HR 0.74，95%CI：0.59-0.92，P=0.0074）；ORR显著提高15.2%（44.3% vs 29.1%，P=0.0006）；疾病控制率（DCR）提高16%（91.9% vs 75.9%）中位持续缓解时间（DoR）延长2.1个月（7.4 vs 5.3个月）。此外，T-DXd的安全性良好，不良事件可管可控，其≥3级的治疗期间不良事件（TEAEs）（68.0% vs 73.8%）、严重TEAEs（41.0% vs 43.3%）发生率均低于RAM＋PTX组；且耐受良好，导致停药、剂量中断、减剂量的TEAEs发生率均低于RAM＋PTX组。T-DXd的不良事件谱与既往报道一致，主要表现为中性粒细胞减少、贫血、白细胞减少等血液毒性，总体上低于或相近于RAM＋PTX组（图2）。图2. DG-04研究安全性汇总（上）及不良事件谱（下）从上述研究结果可见，T-DXd用于晚期胃癌二线治疗，相较于当前标准方案具有显著的生存获益改善和疗效提升，且表现了出色的治疗安全性和耐受性。如前所述，当前胃癌晚期二线治疗并没有抗HER2治疗方案，而是使用抗VEGFR联合化疗。DG-04研究的成功，无疑将填补这一治疗空白。03《肿瘤瞭望》：展望未来，您认为新型HER2 ADC还有哪些重要的研究方向，有望如何进一步改变临床实践？彭智 教授北京大学肿瘤医院新型HER2 ADC正在改变晚期胃癌的治疗格局，未来有望进一步向前拓展。在晚期胃癌一线治疗领域，我们知道基于KEYNOTE-811研究[8]，“靶免化”（帕博利珠单抗＋曲妥珠单抗＋FP或CAPOX）联合方案已被临床广泛应用。基于HER2 ADC的联合治疗能否进一步革新晚期一线治疗标准？目前，T-DXd±帕博利珠单抗＋氟尿嘧啶或卡培他滨的DG-05研究[9]以及HER2双特异性抗体Zanidatamab±替雷利珠单抗＋化疗的HERIZON-GEA-01研究[10]等晚期胃癌一线治疗的III期临床试验正在开展中，国内外也有其他HER2 ADC向晚期一线治疗发起冲刺，期待未来能够进一步取得阳性结果并改变临床实践。△III期DG-05研究设计此外，ADC、靶向和免疫治疗药物的研发也在不断升级中，尤其双靶点的单克隆抗体显示了巨大的应用潜力。ARTEMIDE-Gastric01研究[11]将探索T-DXd联合氟尿嘧啶以及PD-1/TIGIT双特异性抗体Rilvegostomig方案，用于HER2高表达及PD-L1 CPS≥1的晚期胃癌一线治疗的疗效和安全性，有望提供新的胃癌精准治疗方案。除了HER2以外，胃癌治疗靶点变得越来越丰富，包括Claudin18.2、MET、EGFR或FGFR2等均有新的研究进展，例如FGFR2b抑制剂贝玛妥珠单抗联合mFOLFOX6用于晚期胃癌一线治疗的III期FORTITUDE-101研究已经于近期宣布达到主要研究终点[12]。随着可治疗靶点的增加，不同靶点共表达的患者应该如何选择精准治疗策略？也是未来值得进一步探索的问题。参考文献上下滑动查看更多内容[1]中国临床肿瘤学会（CSCO）指南工作委员会.CSCO胃癌诊疗指南.人民卫生出版社.2025年4月.[2]Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6[3]Xu RH, Zhang Y, Pan H, et al. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021;6(12):1015-1024. doi:10.1016/S2468-1253(21)00313-7Wang F, Shen L, Guo W, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024;30(8):2189-2198. doi:10.1038/s41591-024-02989-6[4]Wang F, Shen L, Guo W, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024;30(8):2189-2198. doi:10.1038/s41591-024-02989-6[5]Makiyama A, Sukawa Y, Kashiwada T, et al. Randomized, Phase II Study of Trastuzumab Beyond Progression in Patients With HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: WJOG7112G (T-ACT Study). J Clin Oncol. 2020;38(17):1919-1927. doi:10.1200/JCO.19.03077[6]Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023 Jun 14:S1470-2045(23)00215-2.[7]Shitara K, Gumus M, Pietrantonio F, et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study.2025 ASCO.LBA4002.[8]Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402(10418):2197-2208. doi:10.1016/S0140-6736(23)02033-0[9]Kohei Shitara, et al.An open-label, randomized, multicenter, phase 3 study of trastuzumab deruxtecan (T-DXd) + chemotherapy (chemo) ± pembrolizumab (pembro) versus chemo + trastuzumab ± pembro in first-line metastatic HER2+ gastric or gastroesophageal junction (GEJ) cancer: DESTINY-Gastric05.ASCO 2025;TPS4207[10]Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol. 2022 Sep;18(29):3255-3266.[11]ruihua Xu, et al.ARTEMIDE-Gastric01: A phase 3 randomized study of rilvegostomig with fluoropyrimidine and trastuzumab deruxtecan (T-DXd) as first-line (1L) treatment for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer (GC/GEJC).ASCO 2025;TPS4204[12]https://investors.amgen.com/news-releases/news-release-details/amgen-announces-positive-topline-phase-3-results-bemarituzumab彭智 教授博士，博士生导师北京大学肿瘤医院主任医师北京大学博雅青年学者国家级青年人才项目获得者中国抗癌协会胃癌专委会委员中国抗癌协会肿瘤转移专委会委员中国抗癌协会肿瘤精准治疗委员会委员CSCO胃癌专家委员会委员兼秘书CSCO肿瘤营养治疗专家委员会委员中国免疫学会临床免疫分会委员北京癌症防治学会消化道精准治疗专委会副主任委员北京癌症防治学会胃癌防治专委会秘书长《中华医学杂志》《肿瘤综合治疗电子杂志》编委获得中华医学会一等奖、中国抗癌协会青年科学家奖、中国抗癌协会一等奖等（来源：《肿瘤瞭望》编辑部）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。

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。