Phase 2 Study Evaluating the Efficacy of the Combination of DKN-01 (DKK1 Inhibitor, Leap Therapeutics) and Pembrolizumab in the Treatment of Advanced or Recurrent Endometrial Cancer

To learn if the combination of DKN-01 and pembrolizumab can help to control advanced or recurrent endometrial cancer.

开始日期2023-08-29

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+3]

NCT05480306

/ Active, not recruiting临床2期

Randomized Phase 2 Study of DKN-01 Plus FOLFIRI/FOLFOX and Bevacizumab Versus FOLFIRI/FOLFOX and Bevacizumab as Second-line Treatment of Advanced Colorectal Cancer (DeFianCe)

This is a Phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced CRC patients.

开始日期2022-08-30

申办/合作机构

Leap Therapeutics, Inc.

NCT04363801

/ Active, not recruiting临床2期

A Phase 2, Multicenter, Open-Label Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients With Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (DisTinGuish)

A Phase 2, Multicenter, Open-Label Study of DKN-01 in Combination with Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients with Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

开始日期2020-07-29

申办/合作机构

Leap Therapeutics, Inc.

[+1]

100 项与 Sirexatamab 相关的临床结果

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100 项与 Sirexatamab 相关的转化医学

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100 项与 Sirexatamab 相关的专利（医药）

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项与 Sirexatamab 相关的文献（医药）

2025-02-01·APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY

DKN-01 Suppresses Gastric Cancer Progression Through Activating cGAS-STING Pathway to Block Macrophage M2 Polarization

Article

作者: Qi, Yingying ; Wang, Sisi ; Yang, Xiaohuan

Dickkopf-1 (DKK1) is a secretory antagonist that can bind with the Wnt coreceptor to desensitize cells to canonical Wnt ligands. DKN-01 is a specific antibody targeting secreted DKK1, which has been investigated as a monotherapy or combination therapy for various malignant tumors, including gastric cancer (GC). Tumor-associated macrophages (TAMs) with high plasticity usually present M2 phenotype, which can promote tumor progression. The aim of this study was to investigate the effect of DKN-01 on macrophage polarization in GC and the underlying molecular mechanism. To ascertain the effect of DKN-01 on GC tumor growth, we established a tumor-bearing mouse model and found that DKN-01 treatment suppressed tumor growth efficiently. Through RNA-seq and pathway enrichment analysis, we identified that the differentially expressed genes after DKN-01 treatment are associated with tumor immune-related pathways. Macrophage polarization was assessed using immunohistochemistry and quantitative real-time polymerase chain reaction. DKN-01 and knockdown of DKK1 promoted M1 polarization and inhibited M2 polarization of macrophages, while DKK1 overexpression got the opposite results. Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization.

2025-01-20·JOURNAL OF CLINICAL ONCOLOGY

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish

Article

作者: Stilian, Melissa C. ; Thoma, Mathis ; Ajani, Jaffer A. ; Scott, Aaron James ; Chung, Vincent ; Chiu, Vi K. ; Kagey, Michael H. ; Uronis, Hope Elizabeth ; Tejani, Mohamedtaki Abdulaziz ; Baum, Jason ; Sirard, Cynthia A. ; Sonbol, Mohamad Bassam ; Iqbal, Syma ; Wainberg, Zev A. ; Altura, Rachel A. ; Zhang, Ying ; Klempner, Samuel J.

PURPOSE:

The outcomes of anti–PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study.

PATIENTS AND METHODS:

Patients had untreated human epidermal growth factor receptor 2–negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m 2 once every 3 weeks, and capecitabine 1,000 mg/m 2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS).

RESULTS:

Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%.

CONCLUSION:

DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801 ).

2024-06-01·Hematology/oncology clinics of North America

Targeted Agents in Esophagogastric Cancer Beyond Human Epidermal Growth Factor Receptor-2

Review

作者: Mehlhaff, Eric ; Miller, Devon ; Ebben, Johnathan D ; Uboha, Nataliya V ; Dobrzhanskyi, Oleksii

Gastroesophageal cancers are highly diverse tumors in terms of their anatomic and molecular characteristics, making drug development challenging. Recent advancements in understanding the molecular profiles of these cancers have led to the identification of several new biomarkers. Ongoing clinical trials are investigating new targeted agents with promising results. CLDN18.2 has emerged as a biomarker with established activity of associated targeted therapies. Other targeted agents, such as bemarituzumab and DKN-01, are under active investigation. As new agents are incorporated into the treatment continuum, the questions of biomarker overlap, tumor heterogeneity, and toxicity management will need to be addressed.

项与 Sirexatamab 相关的新闻（医药）

2025-01-28

·FierceBiotech

Leap crashes as midphase data mark end of gastric cancer program

Leap decided to focus on colorectal cancer and drop plans to run a gastric cancer phase 3.\n Leap Therapeutics has come crashing down to earth. The biotech axed plans to advance into phase 3 in gastric cancer on the basis of midstage data, sending its stock down 60% to below $1, but it is forging ahead in another indication.Massachusetts-based Leap made the decisions after seeing data from two parts of a phase 2b trial of its anti-DKK1 antibody sirexatamab. The biotech reported a 35% response rate in colorectal cancer patients who received sirexatamab, bevacizumab and chemotherapy, compared to 23% in the active control arm.After an average of six months of follow-up, Leap saw signs of improved progression-free survival (PFS) in some subgroups. The signs are yet to translate into a statistically significant improvement in PFS and the number of PFS events is evenly balanced between the experimental and control arms, with 37 and 38, respectively. More people, 46, are still on the study drug than the control, 36.Leap said the “strong signal” supports taking the drug combination into a registrational phase 3 trial in second-line patients. The biotech saw higher response rates in some subgroups and will decide on the optimal population for the phase 3 as the data mature. That is as good as it got for Leap. The other part of the study assessed the effect of adding sirexatamab to tislelizumab, BeiGene\'s anti-PD-1 antibody, and chemotherapy in first-line advanced gastroesophageal junction and gastric cancer patients.The combination improved confirmed response rates in the intent-to-treat population and subgroups of PD-L1 negative patients by blinded independent central review (BICR). However, “there was a high level of discordance between investigator assessment and BICR,” Cynthia Sirard, M.D., chief medical officer at Leap, said in a statement. The trial will be negative on the PFS endpoints when it completes, Leap said.Based on the results, Leap decided to focus on colorectal cancer and drop plans to run a gastric cancer phase 3. Sirard said Leap will “explore strategic partnership opportunities to advance sirexatamab plus anti-PD-1 antibodies in gastric cancer and other indications where there is high DKK1 expression.” Leap CEO Douglas Onsi compared the colorectal and gastric opportunities at a Piper Sandler event last month, where he said “every single pharmaceutical company know[s] it is a very substantial U. S. and European market, and stands on its own.” “Gastric cancer is important to some companies and not to others,” Onsi added at the December event. “I think people look at the gastric opportunity as a PD-1 combination opportunity and the opportunity to take it beyond gastric to other PD-1 combinations.”

临床3期临床结果临床2期

2025-01-28

·Endpoints

Leap Therapeutics treks toward pivotal study in colorectal cancer, drops gastric cancer

Leap Therapeutics reported mixed results on Tuesday for an experimental treatment in gastric and colorectal cancer, announcing it is only moving forward with the latter indication. The biotech’s shares $LPTX fell nearly 70% on Tuesday morning to about 66 cents per share. The gastric cancer combo was Leap’s most advanced program. The gastric cancer portion of Leap’s Phase 2 DisTinGuish study enrolled 170 patients with first-line, advanced HER2-negative cancer. The patients received either Leap’s targeted drug sirexatamab on top of BeiGene’s checkpoint inhibitor Tevimbra and chemotherapy, or Tevimbra and chemotherapy alone. Sirexatamab is an antibody that targets DKK1, a protein that’s involved in a key cell pathway called the Wnt signaling pathway. The experimental group had a response rate of 52% when evaluated by blinded independent review, compared to 42% in the control group. Meanwhile, by investigator review, the groups had response rates of 52% and 56%, respectively. “While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer,” Leap said in a press release. In the same release, Leap chief medical officer Cynthia Sirard noted the “high level of discordance” between investigator and blinded review, saying “gastric cancer is a difficult tumor to assess radiologically.” The biotech is preparing another sirexatamab combo for a Phase 3 study in colorectal cancer after reporting initial Phase 2 data in that indication on Tuesday. The colorectal cancer portion of Leap’s Phase 2 study focuses on patients with microsatellite stable disease who previously tried one treatment for advanced cancer. As of the Jan. 3 data cutoff, the study included 188 patients who were split into two groups; the experimental group received sirexatamab plus bevacizumab and chemotherapy, and the control group received bevacizumab and chemotherapy alone. The experimental arm had a response rate of 35%, while the control arm had a response rate of 23%. Leap also broke down results by various subgroups, and it is weighing which populations to include in the Phase 3 study in colorectal cancer. The company said potential Phase 3 populations for the trial could include “DKK1 biomarker-selected, anti-VEGF naïve, anti-EGFR experienced, or RAS-wt patients.”

临床2期临床结果临床3期临床失败

2025-01-13

·ioncology

年度盘点丨锁爱莉教授：2024胃癌靶向治疗的进展与思考

点击蓝字关注我们年度盘点微专辑扫描二维码可查看更多内容编者按近年来，随着研究的深入，胃癌分子机制的探究逐渐由组织学分型过渡到分子分型，不同生物标志物对晚期胃癌的一线及后续治疗格局产生深远的影响。值此岁末之际，《肿瘤瞭望消化时讯》荣幸地邀请了西安交通大学第一附属医院的锁爱莉教授对2024年度晚期胃癌靶向治疗领域的热点与最新进展进行回顾与总结，回顾往昔，放眼未来，为晚期胃癌治疗的发展建言献策。锁爱莉教授西安交通大学第一附属医院肿瘤内科副主任主任医师，教授，博士生导师美国Emory大学访问学者中国抗癌协会食管肿瘤整合康复专委会常委中国抗癌协会肿瘤胃病学专委会常委中国抗癌协会整合肿瘤肾脏病专委会委员陕西省抗癌协会化疗专委会青委主任委员陕西省抗癌协会老年肿瘤外科专委会副主任委员陕西省抗癌协会安宁疗护专委会副主任委员主持国科金面上项目2项，一作/通讯作者SCI论文20余篇，IF>10的10余篇，授权国家发明专利3项晚期胃癌一线治疗随着研究的深入，胃癌分子机制的探究逐渐由组织学分型 (Lauren分型和WHO分型)过渡到分子分型 (TCGA和ACRG分型) 。癌症基因组图谱(TCGA)基于分子差异，提出将GC分为4组亚型：EB病毒阳性(EBV)、微卫星不稳定(MSI)、基因组稳定(GS)和染色体不稳定(CIN)。CIN亚型的分子特征包括TP53突变、RTK突变（EGFR、ERBB2、ERBB3、FGFR、JAK2、MET）、KRAS/NRAS、VEGFA等。胃癌分子特征为靶向治疗提供潜在靶点，目前HER2靶点已建立标准治疗，新型药物正在探索；而针对CLDN18.2、FGFR等的靶向治疗正在探索进军HER2阴性领域。 HER2——首个用于指导mG/GEJ患者临床决策的生物标志物不同研究中胃癌患者HER2过表达/扩增率存在差异，处于13%～22%不等的水平，既往两项大型多中心研究数据显示，中国胃癌患者的HER2阳性率为12%~13%。ToGA研究中，曲妥珠单抗+化疗开启了胃癌一线抗HER2治疗时代。随后，HER2靶向治疗开始了崎岖的探索之路，经历了拉帕替尼+化疗的3期TRIO-013/LOGIC 研究、帕妥珠单抗+曲妥珠单抗+化疗的3期 JACOB 等一系列失败研究。随着免疫治疗时代的到来，KEYNOTE-811 研究中的帕博利珠单抗+曲妥珠单抗+化疗重塑了晚期胃癌HER2阳性一线治疗。KEYNOTE-811 最终分析表明：ITT （OS：20 vs.16.8个月）和 PD-L1 CPS≥1 人群显著获益（OS：20.1 vs.15.7个月），结果支持该方案作为不可切除/转移性 HER2+ G/GEJ 合并 PD-L1 CPS≥1 患者的一线标准治疗。 Zanidatamab (ZW25) 是一种人源化、双特异性抗体，正在开发用于治疗 HER2-表达的癌症，包括HER2阳性GC/GEJC。ZW25+替雷利珠单抗+CAPOX 一线治疗的Ⅰb/Ⅱ期研究初步结果表明其良好的疗效和安全性。截至2022年11月22日，中位研究随访期18.2个月(范围：2.1～30.9)后，共有13例患者(39.4%)仍在接受治疗，DOR为22.8个月，中位PFS 16.7个月。 DESTINY-Gastric03 (DG-03)是一项Ⅰb/2期研究，意在探索T-Dxd单药或连用化疗/免疫治疗HER2+晚期/转移性食管、胃或胃食管交界处腺癌患者的安全性、耐受性、药代动力学、免疫原性以及初步抗肿瘤活性。DESTINY-Gastric03 研究第 2 部分（剂量扩展）评估了 T-DXd 单药或与氟嘧啶和/或帕博利珠单抗联合用于 HER2+（IHC 3+ 或 IHC 2+/ISH+）GC/GEJA 的一线治疗。DG-03研究结果表明，一线 T-DXd与氟尿嘧啶和/或帕博利珠单抗联合治疗疗效良好。 CLDN18.2——已被确证的胃癌新兴靶点 Claudin是一个由27种不同蛋白质组成的家族，是紧密连接的主要结构组分，可存在于全身各部位。Claudin18.2 (CLDN18.2）是Claudin18的一种亚型，在各种类型癌症中广泛表达，包括胃癌、食管癌、胰腺癌、肺癌和卵巢癌。2023~2024 ASCO GI/ASCO/ESMO公布了多种CLDN18.2靶向疗法的初步结果。2024年，日本、英国、欧盟、韩国、美国FDA 先后批准VYLOY (zolbetuximab) 与化疗联用一线治疗HER2阴性、CLDN18.2阳性的局部晚期不可切除或转移性G/GEJ腺癌。 2018年，安斯泰来开展zolbetuximab两项Ⅲ期临床研究——SPOTLIGHT和 GLOW，两项研究中，4507 例患者有有效的 CLDN18.2 IHC 结果1730 (38.4%) 显示 CLDN18.2 高表达；在 3705 例 HER2 阴性且具有有效 CLDN18.2 IHC 结果的患者中，1568 例 (42.3%) 显示 CLDN18.2 高表达。研究表明，Zolbetuximab联合化疗可显著降低疾病进展和死亡风险，恶心和呕吐是Zolbetuximab组最常见的TEAEs，最常见于第1个周期，且在随后的治疗周期中减少。基于这两项结果，Zolbetuximab成为全球首个且目前唯一获批的CLDN18.2靶向药物。最新ESMO胃癌在线指南也新增 CLDN18.2 作为HER2阴性患者一线治疗分层，推荐 zolbetuximab 联合化疗。此外，Zolbetuximab联合mFOLFOX6和纳武利尤单抗治疗CLDN18.2+、HER2- mG/GEJ患者的Ⅱ期试验正在开展，其他CLDN18.2靶向药在晚期GC/GEJC 一线治疗中的探索目前主要为单抗类（图1）。图1.CLDN18.2 靶向治疗在研药物 FGFR2b——一种新兴生物标志物以识别mG/GEJ亚组人群 FGFR2是跨膜酪氨酸激酶受体的成纤维细胞生长因子受体(FGFR)家族的成员，调节细胞存活、分化和增殖；FGFR2的基因组畸变包括扩增、点突变和致癌融合，已在各种类型的癌症(包括胃癌)中被发现。大型队列研究纳入493例GC患者，发现FGFR2过表达率为21.9%～32.1%。 Bemarituzumab是一种人源化IgG1单克隆抗体，可选择性与 FGFR2b 结合，抑制FGFR2b信号通路并介导ADCC。全球、随机、双盲、安慰剂对照Ⅱ期试验FIGHT研究评估了Bemarituzumab + mFOLFOX6 一线治疗 FGFR2b+G/GEJ腺癌的疗效和安全性。ITT人群显示：Bemarituzumab组mOS延长了5.7个月（19.2个月 vs. 13.5个月，HR 0.77）；FGFR2b+（IHC 2+/3+, ≥10%）的患者显示出更好的生存获益：mPFS HR 0.43；mOS HR 0.52。FGFR2b ≥ 10% 人群ORR达56.5%，且安全性可控。角膜 TEAEs 是 bemarituzumab-mFOLFOX6 组停止治疗的主要原因。≥2 级角膜事件的中位发病时间比任何级别的角膜事件的发病时间长（23.7 周 vs. 16.9 周），这表明在未来的研究中可能有机会通过预防措施及早识别和积极管理 AEs。中山大学肿瘤防治中心徐瑞华教授牵头开展的一项随机、多中心、双盲、安慰剂对照的 3 期FORTITUDE-101研究旨在评估比较 bemarituzumab 联合化疗与安慰剂联合化疗在≥10%的肿瘤细胞FGFR2b 表达阳性的晚期胃或 GEJ腺癌且既往未接受过针对不可切除或转移性疾病治疗的受试者中的有效性和安全性。期待相关数据的公布，为晚期胃癌一线治疗提供新的治疗武器。 DKK1——具备治疗潜力的Wnt/β-catenin双向调控靶点 DKK1在多种肿瘤中高度表达，它通过激活Akt信号通路，可以上调VEGFR2的表达，从而促进血管增生，为肿瘤的生存和增殖提供养分。另一方面，它通过调节Wnt信号通路，增强髓源性抑制细胞(MDSC)的免疫抑制能力。在胃癌/胃食管结合部癌中，DKK1的表达与不良预后、免疫抑制性免疫微环境、以及化疗抵抗相关。 Ⅱ期DisTinGuish研究评估DKN-01+替雷利珠单抗+化疗一线治疗晚期HER2- G/GEJ的疗效和安全性。研究发现，DKN-01+TIS+CAPOX 治疗组耐受性良好，毒性可控，大多数(76%)与DKN-01相关不良事件都是低等级。在2年随访中，与CheckMate-649的历史对照相比，无论是在全人群和PD-L1低表达亚组中，DKN-01+TIS+CAPOX治疗晚期GEA的中位PFS和中位OS均有获益。DKN-01 + tislelizumab + CAPOX在 mlTT人群 (73%) 和PD-L1低表达组(86%)中显示出积极的ORR。TIS联合CAPOX/mFOLFOX6在一线GEA的Ⅱ期随机对照研究 (Part C) 正在进行中 (NCT04363801)。二线治疗 HER2 DESTINY-Gastric01是一项在日本及韩国开展的随机、II期、多中心、开放标签研究(NCT03329690)，旨在评估德曲妥珠单抗(T-DXd；DS-8201)对比化疗用于至少经两种治疗进展的HER2阳性晚期胃癌患者的疗效和安全性。研究发现，T-DXd 治疗≥3线HER2阳性胃癌，疗效显著优于化疗（OS：12.5 vs 8.9个月；HR 0.60）。2021年1月FDA批准德曲妥珠单抗用于既往经曲妥珠单抗治疗的局部晚期或转移性HER2阳性G/GE腺癌患者。另外，基于DESTINY-Gastric06 (中国桥接单臂) 研究，德曲妥珠单抗已在中国获批用于胃癌三线及以上治疗的适应证。一项在西方(比利时，英国，意大利，西班牙，美国) HER2阳性G/GEJ癌患者中进行的开放标签、多中心、Ⅱ期研究DESTINY-Gastric02进一步确证 T-DXd 治疗2线HER2阳性胃癌，同样显示出良好疗效。德曲妥珠单抗二线治疗显示了有临床意义的持久缓解，中位OS达12.1个月；安全性特征与德曲妥珠单抗既往报道的安全性基本一致。 ARX788单药治疗HER2阳性晚期胃癌的多中心、剂量扩展Ⅰ期研究发现，患者的ORR为37.9%。ARX788单药 vs. 伊立替康/多西他赛二线治疗的Ⅱ/Ⅲ期ACE-Gastric-02研究正在进行当中。总之，HER2-ADC已改写后线HER2阳性晚期胃癌的治疗格局，并不断向前线推进，且与其他新型药物进行联合应用。 CLDN18.2 CMG901是一种靶向CLDN18.2的ADC，CMG901治疗经治晚期G/GEJC患者的Ⅰ期试验表明，CMG901（AZD0901）在接受过治疗的CLDN18.2高表达 G/GEJ 癌症患者中表现出良好的临床疗效，2.2 mg/kg组确认的ORR为48%；mPFS为4.8个月；mOS为11.8个月。CMG901总体耐受性良好，且安全性可控。 IBI389是一种抗CLDN18.2/CD3双特异性抗体，通过连接T细胞受体复合物中的CD3分子和肿瘤细胞膜上的CLDN18.2抗原，诱导免疫突触的形成。一项Ⅰ 期剂量递增和扩展研究评估了IBI38在实体瘤和胃癌或胃食管肿瘤患者中的安全性和初步疗效结果，研究表明IBI389在晚期实体瘤患者中显示出可控的安全性，未出现DLT，即使为600 μg/kg时安全性也可管理。IBI389≥10 μg/kg对CLDN18.2表达的G/GEJC患者显示出有希望的疗效，在26例CLDN18.2 2+/3+ ≥10%的患者中，ORR为30.8%，DCR为73.1%，中位PFS为3.5个月，评估IBI389单药或联合治疗晚期实体瘤患者的研究正在进行中。 satri-cel（CT041）是一种针对CLDN18.2 的自体嵌合抗原受体（CAR） T 细胞，CT041-CG4006 (NCT03874897) 试验评估了satri-cel对CLDN18.2阳性晚期胃肠肿瘤患者的安全性和有效性。该试验中期结果已于2022年6月报告，此次报告其最终结果。在接受satri-cel单药治疗的GC/GEJ癌患者（n=59）中，51例具有靶病灶：ORR为54.9%（28/51），DCR为96.1%（49/51），mDOR为6.4个月，mPFS为5.8个月，mOS为9.0个月。长期随访表明，satri-cel对接受过治疗的CLDN18.2阳性晚期胃肠肿瘤（尤其是GC/GEJ癌）患者显示出非常有前景的疗效和可控的安全性，与传统的抗肿瘤方法相比，它可能极大地影响现有的治疗格局并推动更广泛的创新研究。不同的组合策略、一线和围手术期应用以及疗效分子生物标志物，值得未来探索。多种靶向CLDN18.2疗法，例如ADC、双抗、CAR-T在后线治疗中的疗效都在进行下一步探索。 VEGFR TKI FRUTIGA是首个评估小分子VEGFR TKI呋喹替尼联合化疗2线治疗G/GEJ腺癌患者的疗效和安全性的随机Ⅲ期研究。FRUTIGA研究的主要结果已在2024年2月的ASCO全体会议系列会议上公布。与PBO+PTX组相比，F+PTX组显著提高mPFS（5.6个月 vs. 2.7个月；HR 0.57；P<0.0001）、ORR（42.5% vs. 22.4%，P<0.0001）和DCR（77.2% vs. 56.3%，P<0.0001）。F+PTX显示出OS获益的趋势（mOS 9.6个月 vs. 8.4个月；HR 0.96，P=0.6064）；且F+PTX耐受性良好，安全性与预期一致。FRUTIGA研究的探索性分析发现，呋喹替尼对伴有淋巴结转移的非弥漫性G/GEJ腺癌患者表现出优异的疗效。小结 HER2、dMMR、PD-L1、CLDN18.2四个关键靶点的检测有助于帮助患者选择合适的靶免治疗药物，开启晚期胃癌靶向精准治疗的新格局。而DKK-1初现疗效，或成为未来的潜在候选靶点。 CLDN18.2是目前已被确证的新兴靶点，其较高的阳性率表明1/3以上的胃癌患者将有可能从zolbetuximab的治疗中获益；CLDN18.2靶向治疗的临床研究囊括了几乎所有主流技术路线，且显示出有前景的初步结果。尤其是中国研究者已成为Claudin18.2靶向治疗研发领域的“领跑者”。已确立靶点的新型药物、新的联合治疗方案，和FGFR2b等新兴靶点的药物临床试验也在积极开展中。如何科学进行选择靶向治疗，使疗效最大化或是未来研究的重要方向。（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。

临床3期

100 项与 Sirexatamab 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
大肠腺癌	临床2期	美国	Leap Therapeutics, Inc.	2022-08-30
大肠腺癌	临床2期	德国	Leap Therapeutics, Inc.	2022-08-30
大肠腺癌	临床2期	韩国	Leap Therapeutics, Inc.	2022-08-30
胃食管交界处腺癌	临床2期	美国	BeiGene Ltd.	2020-07-29
胃食管交界处腺癌	临床2期	美国	Leap Therapeutics, Inc.	2020-07-29
胃食管交界处腺癌	临床2期	德国	Leap Therapeutics, Inc.	2020-07-29
胃食管交界处腺癌	临床2期	德国	BeiGene Ltd.	2020-07-29
胃食管交界处腺癌	临床2期	韩国	BeiGene Ltd.	2020-07-29
胃食管交界处腺癌	临床2期	韩国	Leap Therapeutics, Inc.	2020-07-29
胃食管交界处癌	临床2期	美国	Leap Therapeutics, Inc.	2020-07-29

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05480306 (DeFianCe, PRNewswire) 人工标引	临床2期	微卫星稳定型结直肠癌二线 Microsatellite Stable (MSS)	188	Sirexatamab + bevacizumab + chemotherapy	鬱選窪齋衊簾憲鹽築廠(簾衊鏇襯襯構餘鏇鹽構) = 遞淵醖顧艱蓋築襯顧鬱鏇餘醖繭衊襯窪願範繭 (鬱夢鹽蓋鑰選淵窪選選 ) 更多	积极	2025-01-28
				bevacizumab + chemotherapy	鬱選窪齋衊簾憲鹽築廠(簾衊鏇襯襯構餘鏇鹽構) = 窪繭醖廠淵簾繭觸顧範鏇餘醖繭衊襯窪願範繭 (鬱夢鹽蓋鑰選淵窪選選 ) 更多
NCT04363801 (DisTinGuish, PRNewswire) 人工标引	临床2期	胃食管交界处癌 \| 晚期胃癌一线 HER2 Negative	170	Sirexatamab + tislelizumab + chemotherapy	鹹築簾齋醖選襯衊構衊(範蓋憲鹽築築簾齋鬱鑰) = 築鬱積獵網鑰築顧鹽壓鬱窪壓獵網築獵襯遞遞 (鏇鏇醖窪衊餘顧糧願鹹 ) 更多	积极	2025-01-28
				Tislelizumab + chemotherapy	鹹築簾齋醖選襯衊構衊(範蓋憲鹽築築簾齋鬱鑰) = 鹹襯製窪夢衊構製觸鏇鬱窪壓獵網築獵襯遞遞 (鏇鏇醖窪衊餘顧糧願鹹 ) 更多
NCT04363801 (DisTinGuish, Pubmed \| J Clin Oncol)	临床2期	晚期胃食管交界处腺癌一线 DKK1-high tumor \| DKK1-low tumor	25	DKN-01	憲壓鏇夢製鬱鬱範廠襯(餘齋夢獵夢鬱醖鹽餘觸) = 遞蓋獵窪餘襯窪觸鏇築積艱衊遞鏇積築壓範鹽 (簾膚醖鹹鹽繭壓蓋餘憲, 49.8 ~ 89.3) 更多	积极	2024-10-21
NCT05480306 (DeFianCe, NEWS) 人工标引	临床2期	微卫星稳定型结直肠癌	33	DKN-01	製獵獵鹽醖蓋壓餘鬱衊(築壓築餘壓淵繭襯鹹夢) = 網襯蓋襯蓋願衊鑰簾窪窪觸膚製鬱鬱齋壓築獵 (範範鑰構獵衊醖鬱膚鑰 ) 更多	积极	2024-06-03
				DKN-01 (左结肠肿瘤)	製獵獵鹽醖蓋壓餘鬱衊(築壓築餘壓淵繭襯鹹夢) = 願顧鹹簾鬱範窪糧願鬱窪觸膚製鬱鬱齋壓築獵 (範範鑰構獵衊醖鬱膚鑰 ) 更多
NCT04057365 (CTgov)	临床2期	晚期胆管癌	15	Nivolumab+DKN-01 (DKN 01 and Nivolumab Safety Run in)	糧廠鏇鹹夢襯鏇繭窪獵 = 糧範鬱觸糧鏇憲衊選獵鏇衊範鏇積鏇積醖觸淵 (蓋鑰鏇衊憲壓積範壓壓, 願糧製獵積構製願餘壓 ~ 廠範積選顧壓淵餘範構) 更多	-	2024-04-10
				Nivolumab+DKN-01 (DKN 01 and Nivolumab)	鬱顧襯製遞積淵築壓蓋(淵範繭選鏇願顧鑰餘齋) = 鏇鹽鏇憲築蓋鬱膚壓衊願齋襯襯憲構齋選願遞 (齋願範壓觸鑰鬱鹽壓鏇, 膚積衊鹽遞獵膚壓遞憲 ~ 艱襯顧襯鹽襯觸醖鬱襯) 更多
NCT05480306 (DeFianCe, ASCO_GI2024) 人工标引	临床2期	微卫星稳定型结直肠癌二线 Microsatellite Stable (MSS)	33	DKN-01 + FOLFIRI/FOLFOX + bevacizumab	蓋糧夢鑰餘夢築網醖鑰(鏇範遞蓋鏇齋窪構餘夢) = 窪遞願憲鬱鹹構繭壓網顧鑰鹽積膚餘淵醖窪艱 (獵鹹糧醖構壓齋繭構鬱 ) 更多	积极	2024-01-18
NCT03837353 (CTgov)	临床1/2期	晚期前列腺癌	18	DKN-01+Docetaxel (Cohort 1A.1 (DKN-01 300mg, Docetaxel 75 mg/m2))	繭壓廠艱糧憲構鏇選獵(蓋窪鏇網醖顧築鹹製鹽) = 鬱積窪窪窪蓋製鏇構餘鹹膚廠廠製衊廠憲夢餘 (構積淵餘選積淵顧蓋製, 0) 更多	-	2023-12-18
				DKN-01+Docetaxel (Cohort 1A.2 (DKN-01 600mg, Docetaxel 75 mg/m2))	繭壓廠艱糧憲構鏇選獵(蓋窪鏇網醖顧築鹹製鹽) = 鬱餘遞鹽窪糧餘遞襯糧鹹膚廠廠製衊廠憲夢餘 (構積淵餘選積淵顧蓋製, 0) 更多
NCT04363801 (DisTinGuish, ASCO 12023 \| ASCO 22023) 人工标引	临床2期	晚期胃食管交界处腺癌一线	22	CAPOX+Tislelizumab+DKN 01 (ITT population)	膚鑰築糧膚醖齋鬱艱觸(範獵夢鏇憲繭鬱簾窪構) = 齋簾窪齋壓簾鑰構鏇壓膚鹽糧膚膚顧淵廠蓋簾 (餘網鹹艱壓遞簾艱淵壓 ) 更多	积极	2023-05-26
				CAPOX+Tislelizumab+DKN 01 (low tumor PD-L1 expression)	膚鑰築糧膚醖齋鬱艱觸(範獵夢鏇憲繭鬱簾窪構) = 蓋築糧襯艱衊鹽醖餘醖膚鹽糧膚膚顧淵廠蓋簾 (餘網鹹艱壓遞簾艱淵壓 ) 更多
NCT03395080 (Pubmed)	临床2期	复发性子宫内膜癌	-	DKN-01 monotherapy	膚範憲鏇窪襯艱鹹顧網(鑰製鹽壓繭鏇廠蓋範廠) = 糧壓願鹹齋築衊積壓鑰鏇遞衊製積鏇壓夢築範 (觸鑰鹹壓願鹹觸醖窪膚 ) 更多	-	2023-03-29
				DKN-01 in combination with paclitaxel	膚範憲鏇窪襯艱鹹顧網(鑰製鹽壓繭鏇廠蓋範廠) = 獵範顧範鹹積淵壓衊製鏇遞衊製積鏇壓夢築範 (觸鑰鹹壓願鹹觸醖窪膚 ) 更多
SITC2022	N/A	结直肠癌	-	DKN-01	鹽積齋醖製鹹繭齋範鏇(齋遞顧構窪願鏇窪選醖) = 醖獵艱觸鏇衊衊膚襯築獵顧鑰顧淵鏇餘淵構鹽 (糧夢獵製積齋醖網簾淵 )	-	2022-11-07
				5FU	鹽積齋醖製鹹繭齋範鏇(齋遞顧構窪願鏇窪選醖) = 願糧衊觸膚壓觸衊鏇獵獵顧鑰顧淵鏇餘淵構鹽 (糧夢獵製積齋醖網簾淵 )