Phase Ib Study of CBP-1019 in Combination With FOLFOX +/- Bevacizumab, Pembrolizumab, or Enzalutamide for Metastatic TRPV6-overexpressing Solid Tumors of Epithelial Origin

An open-label, Phase Ib dose escalation and dose expansion clinical trial evaluating the safety and efficacy of CBP-1019 combinations in patients with solid tumors of epithelial origin.

开始日期2024-12-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06628310 / Not yet recruiting临床2期

A Phase 2 Randomized Study to Evaluate the Safety, Efficacy, and Optimal Dose of ABBV-400 in Combination With Fluorouracil, Leucovorin, and Budigalimab as First-Line Treatment in Subjects With Locally Advanced Unresectable or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma (AndroMETa-GEA-977)

Cancer is a condition where cells in a specific part of body grow and reproduce uncontrollably. The purpose of this study is to assess adverse events and change in disease activity when ABBV-400 is given in combination with Fluorouracil, Leucovorin, and a programmed cell death receptor 1 (PD1) inhibitor (Budigalimab) (AFLB) to adult participants to treat locally advanced unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEA).
ABBV-400 and Budigalimab are investigational drugs being developed for the treatment of mGEA. Fluorouracil and Leucovorin are drugs approved for the treatment of mGEA. This study will be divided into two stages, with the first stage treating participants with increasing doses of ABBV-400 within the AFLB regimen until the dose reached is tolerable and expected to be efficacious. Participants will then be randomized into groups called treatment arms where one group will receive fluorouracil, leucovorin, and oxaliplatin (FOLFOX). A further two treatment groups will receive AFLB, but with two optimized doses of ABBV-400 to allow for the best dose to be studied in the future. Approximately 180 adult participants with mGEA will be enrolled in the study in 51 sites worldwide.
In the dose escalation stage participants will be treated with increasing intravenous (IV) doses of ABBV-400 within the AFLB regimen until the dose reached is tolerable and expected to be efficacious. In the dose optimization stage participants will be receive FOLFOX or receive AFLB, but with one of two optimized doses of ABBV-400The study will run for a duration of approximately 6 years.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.

开始日期2024-12-08

申办/合作机构

AbbVie, Inc.

NCT04516681 / Recruiting临床3期IIT

Vitamin C Intravenously With Chemotherapy and Adebrelimab in Metastatic Colorectal Cancer With High Expresison Level of GLUT3

Previous preclinical study has shown that high levels of ascorbic acid (AA) possesses the ability to kill human colorectal cancer cells and high expression of GLUT3 will augment the efficacy of AA. To date, no previous studies have investigated the combination of therapeutic role of AA and PD-L1 antibody in metastatic colorectal cancer with high expression of GLUT3. This protocol is a randomized controlled study of AA infusions combined with Adebrelimab and FOLFOX +/- bevacizumab versus treatment with FOLFOX +/- bevacizumab alone in metastatic colorectal cancer patients with high expression of GLUT3.

开始日期2024-12-01

申办/合作机构

复旦大学

100 项与奥沙利铂相关的临床结果

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100 项与奥沙利铂相关的转化医学

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100 项与奥沙利铂相关的专利（医药）

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14,148

项与奥沙利铂相关的文献（医药）

2025-01-01·JOURNAL OF ETHNOPHARMACOLOGY

Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer

Article

作者: Wang, Zhonglin ; Wang, Jiaying ; Ye, Lihua ; Zheng, Yihu ; Yu, Yun ; Xie, Chenjun ; Yu, Ying ; Zhuge, Weishan ; Kuang, Keke ; Cui, Ri ; Wu, Tao ; Tu, Xinyue

ETHNOPHARMACOLOGICAL RELEVANCE:

Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood.

AIM OF THE STUDY:

To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity.

MATERIALS AND METHODS:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin.

RESULTS:

The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone.

CONCLUSIONS:

Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

2025-01-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Bulk integrated single-cell-spatial transcriptomics reveals the impact of preoperative chemotherapy on cancer-associated fibroblasts and tumor cells in colorectal cancer, and construction of related predictive models using machine learning

Article

作者: Wang, Shukui ; Pan, Yuqin ; Chen, Yuhan ; Gao, Rui ; Ding, Muzi ; Lou, Jinwei ; Qin, Jian ; Xiao, QianNi ; Hu, Shangshang

BACKGROUND:

Preoperative chemotherapy (PC) is an important component of Colorectal cancer (CRC) treatment, but its effects on the biological functions of fibroblasts and epithelial cells in CRC are unclear.

METHODS:

This study utilized bulk, single-cell, and spatial transcriptomic sequencing data from 22 independent cohorts of CRC. Through bioinformatics analysis and in vitro experiments, the research investigated the impact of PC on fibroblast and epithelial cells in CRC. Subpopulations associated with PC and CRC prognosis were identified, and a predictive model was constructed using machine learning.

RESULTS:

PC significantly attenuated the pathways related to tumor progression in fibroblasts and epithelial cells. NOTCH3 + Fibroblast (NOTCH3 + Fib), TNNT1 + Epithelial (TNNT1 + Epi), and HSPA1A + Epithelial (HSPA1A + Epi) subpopulations were identified in the adjacent spatial region and were associated with poor prognosis in CRC. PC effectively diminished the presence of these subpopulations, concurrently inhibiting pathway activity and intercellular crosstalk. A risk signature model, named the Preoperative Chemotherapy Risk Signature Model (PCRSM), was constructed using machine learning. PCRSM emerged as an independent prognostic indicator for CRC, impacting both overall survival (OS) and recurrence-free survival (RFS), surpassing the performance of 89 previously published CRC risk signatures. Additionally, patients with a high PCRSM risk score showed sensitivity to fluorouracil-based adjuvant chemotherapy (FOLFOX) but resistance to single chemotherapy drugs (such as Bevacizumab and Oxaliplatin). Furthermore, this study predicted that patients with high PCRSM were resistant to anti-PD1therapy.

CONCLUSION:

In conclusion, this study identified three cell subpopulations (NOTCH3 + Fib, TNNT1 + Epi, and HSPA1A + Epi) associated with PC, which can be targeted to improve the prognosis of CRC patients. The PCRSM model shows promise in enhancing the survival and treatment of CRC patients.

2025-01-01·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

LC-MS-based serum metabolomics analysis and potential biomarkers for oxaliplatin induced neurotoxicity in colorectal cancer

Article

作者: Hua, Yujiao ; Ding, Yongjuan ; Zhang, Yan ; Chen, Jinghua ; Lv, Juan

Oxapliplatin-induced peripheral neuropathy (OIPN) is a significant adverse effect encountered in patients with colorectal cancer undergoing oxaliplatin therapy. However, the pathogenesis of OIPN remains unclear. This study aimed to identify potential diagnostic biomarkers for OIPN and discover the metabolic pathways associated with the disease. Serum samples were collected from 218 subjects, including patients with OIPN and control (CONT). The metabolite profiles were analyzed using nontargeted liquid chromatography-mass spectrometry (LC-MS) serum metabolomics method. Subsequently, differentially altered metabolites were identified and evaluated through multivariate statistical analyses. In this study, patients with OIPN and CONT were distinguished by ten significant metabolites. The levels of racemethionine, O-acetylcarnitine, stearolic acid, aminoadipic acid, iminoarginine, galactaric acid, and all-trans-retinoic acid were increased, whereas the levels of 3-methyl-L-tyrosine, 5-aminopentanoic acid, and erythritol compared were found to be diminished in patients with OIPN when compared to the CONT. Through receiver operating characteristic (ROC) curve analysis, racemethionine, stearolic acid, 5-aminopentanoic acid, erythritol, aminoadipic acid, and all-trans-retinoic acid were pinpointed as promising biomarkers for OIPN. Significantly altered pathways included amino acids (arginine biosynthesis, beta-alanine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, lysine degradation, and phenylalanine, tyrosine and tryptophan biosynthesis), lipid (linoleic acid metabolism and the biosynthesis of unsaturated fatty acids), and energy metabolism. This study, by identifying serum biomarkers and dissecting metabolic pathways, offers a groundbreaking perspective on the susceptibility mechanisms underlying OIPN. It stands as an invaluable resource for the adjunctive diagnosis of OIPN, with the potential to diminish the incidence of adverse reactions and to enhance the objectivity and reliability of clinical diagnoses of OIPN.

1,084

项与奥沙利铂相关的新闻（医药）

2024-11-04

·GlobeNewswire-Health Care

Tizona Therapeutics Announces Expansion of Phase 1b Clinical Trial to Evaluate TTX-080 in Combination with EGFR Inhibitor Cetuximab and Chemotherapy in Advanced Colorectal Cancer

Oct. 31, 2024 -- Tizona Therapeutics, Inc., a privately held, clinical-stage company developing cancer immunotherapies, today announced the initiation of two randomized arms within the ongoing Phase 1b clinical trial of TTX-080, a novel, first-in-class antibody targeting HLA-G. Patients with biomarker-defined metastatic colorectal cancer (mCRC) will be enrolled to receive either TTX-080 plus cetuximab and FOLFIRI or cetuximab and FOLFIRI alone in the second-line setting. “Although screening and increased awareness have helped clinicians identify colorectal cancer earlier, approximately one in four individuals will still be diagnosed with metastatic disease,” said Christine O’Brien, Chief Executive Officer of Tizona Therapeutics. “Based on clinical data presented earlier this year at ASCO, we believe TTX-080 has strong potential to improve clinical outcomes in patients with biomarker-defined, metastatic colorectal cancer, who urgently need new treatment options.” The recently added randomized arms within the ongoing Phase 1b, open-label clinical trial will evaluate either TTX-080 plus cetuximab and FOLFIRI or cetuximab and FOLFIRI alone in patients who have previously received 5-FU and oxaliplatin in the front-line or adjuvant setting (relapse within 6 months). Eligible patients are those with mCRC tumors that are MSS, WT RAS, WT BRAF, and HER2-negative. The primary endpoint of the trial is overall response rate with safety, duration of response, median progression-free survival and median overall survival as secondary endpoints. Additional information about the clinical trial can be found on clinicaltrials.gov (NCT04485013). Tizona is a privately held, clinical-stage immunotherapy company that develops first-in-class medicines to deliver transformational benefits for people with cancer. Tizona translates scientific breakthroughs into therapeutics that stimulate the immune system and counter immune suppression. Tizona is advancing its lead therapeutic candidate, TTX-080, which targets HLA-G, in a Phase 1b clinical study in advanced colorectal cancer. The content above comes from the network. if any infringement, please contact us to modify.

免疫疗法

2024-11-03

·ioncology

靖昌庆教授：胃癌围术期免疫治疗的若干思考

编者按临床应用免疫检查点抑制剂（ICI）为局部进展期胃癌或胃食管结合部腺癌提供了新的治疗手段，获得了更高的治愈率。最近的一些临床试验明确地表明，ICI与化疗或放化疗联合，或者ICI联合抗HER2或抗血管内皮生长因子受体与化疗具有多药协同与互补作用；与单纯化疗相比，联合治疗能明显提高病理完全缓解率、主要缓解率或ypT0N0比例等，并有望改善患者预后。在刚刚结束的2024 CACA·整合胃癌大会上，山东省立医院靖昌庆教授总结了近年来在胃癌围手术期联合应用ICI与其他治疗模式的一系列临床试验结果，深入讨论了ICI应用于胃癌新辅助和辅助治疗的现状，探讨了未来新的围手术期免疫联合治疗的可行性。胃癌围手术期以化疗为主的“三明治”模式初行成在2006年之前，胃癌还是以单纯手术治疗为主，患者5年生存率仅为23%[1]。为了进一步提高胃癌患者的总体生存，研究者们在围手术期治疗方面做了诸多探索（图1）。图1. 改变胃癌围手术期临床实践的主要试验的时间轴 2006年，英国的MAGIC研究［2］结果显示，ECF方案（表柔比星+顺铂+5-氟尿嘧啶）术前化疗较单纯手术可明显降低肿瘤大小和分期，提高患者的5年OS率（36%）和PFS率，为术前新辅助化疗在欧洲胃癌患者中广泛使用提供了强有力的证据。随后，2017年发布于ASCO年会的德国的FLOT4研究［3］证实术前FLOT方案（5-氟尿嘧啶+亚叶酸钙+奥沙利铂+多西他赛）方案优于ECF方案，5年OS率为45%，因此欧洲将围手术期化疗的推荐方案改为FLOT方案。术前新辅助治疗的研究随后也在亚洲开展，包括PRODIGY研究［4］、RESOVLE研究［5］和JCOG0501研究［6］。中国的RESOLVE研究结果表明，与手术+术后XELOX方案（卡培他滨+奥沙利铂）辅助治疗相比，术前SOX方案（S-1+奥沙利铂）+手术+术后SOX方案辅助治疗可显著地改善胃癌患者的生存，5年OS率达到了60%（图2）。图2. 患者OS 上述研究证明了胃癌围术期化疗的初步探索，取得成功，有效提高胃癌患者的5年生存率，并且在世界范围内被各大指南推荐。当前，以术前新辅助化疗+手术+术后辅助化疗为主的“三明治”模式也逐渐进入大家视野，获得了大家的认可。但此时的“三明治”疗法最主要的就是化疗，其疗效仍不够，局部晚期胃癌的预后仍然不够理想，所以研究者们并没有停止继续探索的步伐。胃癌围手术期免疫治疗喜忧参半近年来，免疫治疗迅速发展，在胃癌的“兄弟肿瘤”黑色素瘤中率先实现突破。SWOG S1801研究验证了新辅助-辅助帕博利珠单抗与辅助帕博利珠单抗单药相比对可切除黑色素瘤的疗效：“三明治”组2年EFS为72%，单纯辅助治疗组为49%，“三明治”模式胜出。那么在免疫治疗时代，“三明治”模式能否同样给围术期胃癌治疗带来更多获益？事实上，自免疫治疗加入胃癌围手术期治疗，我们看到了很多研究热点，很多临床研究开始尝试将免疫治疗与各种疗法相结合，如免疫+化疗、免疫+靶向、双免、免疫+靶向+化疗、免疫+放化疗等，由此滋生了大量的临床研究。除了上述研究热点外，还有很多非特异免疫也加入了“肿瘤大作战”，如红色诺卡氏菌细胞壁骨架、铜绿假单胞菌注射液、胸腺法新等，促进机体免疫，配合系统用药等等。但是，不管哪种联合，目的只有一个，即通过联合作战，提高胃癌的治疗有效率。 1.术前新辅助免疫治治疗免疫联合化疗 2023年全球MATTERHORN研究[7]的Ⅲ期期中分析结果表明，度伐利尤单抗+FLOT方案围手术期治疗可切除胃/胃食管结合部癌具有显著统计学意义的pCR的改善，对比安慰剂联合FLOT方案提升12% （19% vs. 7%；OR 3.08，P＜0.00001，图3），并且度伐利尤单抗组的分期降级率也高于安慰剂组（pT0：23% vs. 11%；pN0：52% vs. 37%），更多受试者达到T0和N0。此外，两组不良事件发生率也相似，安全性良好。总之，MATTERHORN研究使更多患者获得手术降期，但是pCR获益能否转化为生存获益，仍需继续观察。让我们继续期待未来早日看到MATTERHORN研究最终结果。图3. 中心评估和研究者评估的pCR率 2023年在第20届美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI）上，天津医科大学肿瘤医院梁寒教授、丁学伟教授开展的PERSIST研究[8]初步结果发布，同样为我们带来了好消息。该研究结果显示，信迪利单抗联合SOX方案（奥沙利铂+替吉奥）作为可切除局部晚期胃/胃食管交界部癌围手术期治疗的pCR率（27.9%）、MPR率（65.2%）和降期率（79.7%）令人鼓舞，且安全性可控。但事情并不能总如人意。2024年，KEYNOTE-585研究[9]同样探索了新辅助免疫联合化疗方案，其结果于2024年欧洲肿瘤内科学会（ESMO）年会上发布，令人感慨不已。该研究结果显示帕博利珠单抗联合化疗对比安慰剂联合化疗新辅助和辅助治疗胃癌，可以显著提升患者的pCR率（主队列：pCR率为14.2% vs. 2.8%; ITT人群：pCR率为13.4% vs. 2.0%，图4），但EFS（44.4 vs. 25.7个月）及OS（ 71.8 vs. 55.7个月）很遗憾未达到统计学差异，所以研究最终以失败而告终。图4. 主要研究数据图但即便如此，我们也很难将KEYNOTE-585研究彻底定义为失败的研究，因为他确实对后续研究有诸多启示，比如（1）新辅助免疫治疗联合化疗的pCR率提高，在乳腺癌、恶性黑色素瘤的诸多研究中，更长期的随访都提示pCR与长期生存获益相关，这表明可能随着随访时间延长能看到更多的生存获益。（2）从数值上看虽然MSI-H和Non-MSI-H均有pCR获益，但MSI-H似乎有更大的获益趋势，为后续筛选优势人群提供了启示。（3）EFS为44.4% vs. 25.3%，从数值上看获益比较明显，也许对统计假设进行调整，更大的样本量能看到不一样的结果；（4）本研究中不同CPS评分获益不同，这可能也会为未来研究的精准人群探讨提供更多线索。总之，KEYNOTE-585研究让我们看到了EFS极大的获益趋势，但未达统计学意义，这不禁让人怀疑，这到底是统计学的遗憾还是临床的遗憾？免疫联合抗血管生成药物和化疗发布于Journal of Clinical Oncology（JOC）的DRAGON IV Ⅲ期临床研究[10]首次期中分析结果显示，卡瑞利珠单抗联合化疗+阿帕替尼对比化疗围手术期治疗局晚期可切除胃/胃食管结合部腺癌，可显著提高主要研究终点pCR（全人群pCR率：18.3% vs. 5.0%, OR 4.5, P＜0.0001；进行手术人群的pCR率：21.3% vs. 5.8%，图5）。该研究是首个评估围手术期免疫联合抗血管生成和化疗治疗可切除胃或胃食管结合部腺癌的Ⅲ期临床试验，让PD-L1 CPS 评分、EBV状态、MMR等细分人群越来越受到更多关注。目前该研究仍在继续，EFS数据尚未成熟。但总体来看，在化疗的基础上联合免疫和低剂量抗血管药物，整体安全性可控，未影响手术进行。未来患者长期生存获益和患者耐受性是关注重点。总之，DRAGON IV研究使胃癌围手术期免疫治疗迈入了新的征程。图5. pCR率免疫联合放化疗发表于nature communications的一项研究[11]，尝试将信迪利单抗与同步放化疗进行联合，治疗局部晚期胃及胃食管交界处腺癌，结果显示其pCR率达到38.2%，MPR的患者占比更是高达79.4%（27/34），治疗患者的中位EFS和无病生存期（DFS）也分别达到21.1和17.0个月。该研究开启了胃癌围手术期治疗新模式。 2.术后辅助免疫治疗我们知道新辅助和辅助免疫治疗获益机制不同。新辅助治疗是在给予免疫治疗后，将原位肿瘤转变为“自体疫苗”从而激活抗肿瘤免疫反应，活化的肿瘤特异性CD8+ T细胞通过机体迁移寻找并消灭微病灶。目的是术前降低肿瘤负荷，激活CD8+T细胞寻找肿瘤细胞，消除微转移，延长患者生存。而辅助免疫治疗机制是在原发肿瘤切除后，剩余循环肿瘤特异性CD8+ T细胞和转移灶部位的T细胞增加，清除残留的肿瘤组织。其目的是针对微小转移病灶，减少复发，降低远处转移的风险，延长生存。所以，除了上述探索外，也有研究者对单独术后辅助免疫治疗进行了探索。 CheckMate 577研究[12]是一项评估纳武利尤单抗辅助治疗可切除的食管癌或胃食管交界部癌的全球性、Ⅲ期、随机、双盲、安慰剂对照研究，其结果显示纳武利尤单抗表现出更好的DFS结果（图6），复发或死亡风险降低31%，中位DFS是安慰剂的两倍。不同组织学亚型的DFS进行事后分析，均可观察到DFS获益。由此，纳武利尤单抗成为首个在新辅助放化疗EC/GEJC切除术后，DFS较安慰剂显示出统计学显著且具有临床意义改善的辅助治疗。图6. DFS 但2023年美国临床肿瘤学会年会公布的Attraction-5研究[13]结果显示：pⅢ期胃癌、胃食管结合部腺癌患者术后辅助治疗在化疗基础上增加纳武利尤单抗，并不能带来无复发生存期的明显延长，最终也是以失败告终。由此可见，当前“三明治”模式或是胃癌免疫围手术期治疗的优选。胃癌围手术期精准治疗的展望虽然当前胃癌围术期免疫联合化疗仍在艰难前行，大规模Ⅲ期研究结果暂无标准答案，但随着当前精准医学理念不断深化，精准医学体系逐步形成，胃癌围手术期治疗必然会逐渐趋于精准。当前我们可以通过基因组分析，如PD-L1表达水平、TMB和MSI、EGIC分型、综合多学组分析、特定基因改变等等以及肿瘤微环境、液体活检、机器学习等，帮助我们更深入地了解患者状态，在治疗前做到精准筛选优势人群，为患者“量身定制”治疗方案。此外，在治疗中，我们也可以通过联合新型疗法，通过精准调节肿瘤微环境、提供协同共刺激、调节肠道菌群，克服免疫治疗耐药这一难题。综上所述，胃癌围术期治疗为胃癌患者带来了生存率的改善，免疫治疗与化疗的联合为胃癌围术期治疗带来全新的契机，我们期待更多的胃癌术后辅助免疫治疗研究，让更多患者获益。专家简介靖昌庆教授山东第一医科大学附属省立医院胃肠外科副主任、博士生导师、齐鲁卫生与健康领军人才。主要学术兼职：中华医学会肠外肠内营养学分会委员、中华医学会外科学分会青年委员、中华医学会肿瘤学分会结直肠肿瘤学组委员中国医师协会外科医师分会肿瘤外科学组副组长中国研究型医院协会结直肠肿瘤分会副主任委员中国医促会结直肠病学分会副主任委员山东省医学会微创医学分会候任主任委员山东省医院协会临床营养管理专委会主任委员山东省医师协会结直肠外科医师分会候任主任委员山东省抗癌协会胃肠肿瘤分会候任主任委员参考文献（上下滑动可查看） [1] Lavacchi D, Fancelli S, Buttitta E, et al. Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing. Int J Mol Sci. 2023;24(5):4877. Published 2023 Mar 2. doi:10.3390/ijms24054877 [2] Cunningham D, et al. N Engl J Med. 2006;355:11-20. [3] Al-Batran SE, et al. Lancet. 2019;393(10184):1948-1957. [4] KANG Y K, KIM H D, YOOK J H, et al. Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: final survival outcomes of the randomized phase 3 PRODIGY trial［J］. J Clin Oncol, 2023, 41(16_suppl): 4067. [5] ZHANG X T, LIANG H, LI Z Y, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial［J］. Lancet Oncol, 2021, 22(8): 1081-1092. [6] IWASAKI Y, TERASHIMA M, MIZUSAWA J, et al. Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an openlabel, phase 3, randomized controlled trial［J］. Gastric Cancer, 2021, 24(2): 492-502. [7] Y.Y. Janjigian, S-E. Al-Batran, et al. 2023 ESMO. LBA 73. [8] DING X W, WANG X J, LI B, et al. PERSIST: A multicenter, randomized phase Ⅱ trial of perioperative oxaliplatin and S-1 (SOX) with or without sintilimab in resectable locally advanced gastric/gastroesophageal junction cancer (GC/GEJC)［J］. J Clin Oncol, 2023, 41(4_suppl): 364. [9] K. Shitara, S.Y. Rha, et al. 2024 ESMO. LBA 74 [10] C. Li, Y. Zheng, et al. 2023 ESMO. 1512MO [11] Wei J, Lu X, Liu Q, Fu Y, et al. Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial. Nat Commun. 2023 Aug 14;14(1):4904. doi: 10.1038/s41467-023-40480-x. PMID: 37580320; PMCID: PMC10425436. [12] Kelly R et al. N Engl J Med 2021 [13] Terashinma M, et al. 2023 ASCO. Abstract 4000. （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。

ASCO会议免疫疗法临床结果

2024-11-01

·恒瑞医药

全球首个胃癌围术期靶免联合Ⅲ期研究重磅见刊JCO，恒瑞“双艾”组合再获认可

近日，上海交通大学医学院附属瑞金医院朱正纲教授作为PI的全国多中心研究协作组发起的“卡瑞利珠单抗联合阿帕替尼和化疗对比化疗治疗局部进展期胃癌”随机对照Ⅲ期试验(DRAGON-IV/AHEAD-G208[CAP 05]研究)重磅发表在肿瘤领域Top期刊《Journal of Clinical Oncology》(JCO，IF：42.1)上[1]。研究结果表明，卡瑞利珠单抗联合VEGFR2抑制剂阿帕替尼和SOX(奥沙利铂+替吉奥)对比SOX新辅助治疗可切除局部进展期胃癌，显著改善病理完全缓解(pCR)率。DRAGON-IV/AHEAD-G208研究是全球首个胃癌围术期靶免联合III期研究，这是该研究入选2023年欧洲肿瘤内科学会(ESMO)大会简短口头报告后，再次获国际医学界高度认可。 DRAGON-IV/AHEAD-G208研究在JCO发表 01 研究背景胃癌是一个严重的全球健康问题，2020年全球新发病例108.9万，死亡病例76.9万[2]。局部进展期胃或胃食管结合部腺癌围手术期推荐使用化疗，其中SOX方案(奥沙利铂+替吉奥)为首选，但围术期化疗疗效有限，仍有待提升[3,4]。卡瑞利珠单抗是恒瑞医药自主研发的一款人源化PD-1单克隆抗体，于2019年5月获国家药品监督管理局(NMPA)批准上市，目前已在中国获批9个适应症，涵盖肺癌、肝癌、食管癌、鼻咽癌以及淋巴瘤五大瘤种，为获批适应症和覆盖瘤种数量领先的国产PD-1产品。阿帕替尼是恒瑞医药开发的一款针对血管内皮生长因子受体(VEGFR)的小分子酪氨酸激酶抑制剂，于2014年10月获国家药品监督管理局(NMPA)批准上市。目前已在胃癌和肝癌领域获批三个适应症。卡瑞利珠单抗联合阿帕替尼(“双艾”组合)已在多个实体瘤中证实具有协同作用[5-8]。 DRAGON-IV/AHEAD-G208研究为一项多中心，随机对照、开放标签的Ⅲ期试验(NCT04208347)，旨在评估卡瑞利珠单抗联合阿帕替尼和化疗对比化疗在局部进展期胃或胃食管结合部腺癌围术期的疗效和安全性。 02 研究设计本研究招募临床分期为T3-4aN+M0，初治可切除胃癌或胃食管结合部腺癌患者，其中512例计划按1:1随机分配到SOXRC组(卡瑞利珠单抗+阿帕替尼+SOX)或SOX组。并根据原发灶部位(胃 vs. 胃食管结合部)和Bulky N(是 vs. 否)进行分层。患者术前分别接受3个周期的卡瑞利珠单抗+阿帕替尼+SOX或SOX，随后进行胃癌D2根治术。术后SOXRC组接受3个周期的卡瑞利珠单抗+阿帕替尼+SOX，和卡瑞利珠单抗+阿帕替尼维持治疗(卡瑞利珠单抗术前术后最多使用17个周期，阿帕替尼术前术后总治疗时长不超过一年)，SOX组进行3个周期的SOX，和S-1维持治疗(总治疗时长不超过一年)。主要终点包括盲态独立评审委员会(BIRC)评估的病理完全缓解(pCR，ypT0)率和研究者评估的无事件生存期(EFS)。次要终点包括总体病理完全缓解(tpCR)(ypT0N0)、主要病理缓解(MPR)、R0切除率、ypN分期、无病生存期(DFS)、总生存期(OS)和安全性。在SOXRC组和SOX组前360例随机患者有机会行D2根治术后进行pCR的主要分析。图1.研究设计 03 研究结果 1 基线及受试者分布 2019年12月18日至2022年12月31日期间，360例患者1：1被随机分配至SOXRC组(n=180)和SOX组(n=180)。两组基线特征平衡(表1)。截至2023年4月19日，SOXRC组179例接受新辅助治疗，164例完成新辅助治疗，155例接受手术。SOX组177例接受新辅助治疗，169例完成新辅助治疗，156例接受手术。截至数据截止时间，SOXRC组和SOX组仍各有51例、34例接受辅助治疗中(图2)。表1. 基线特征图2. 受试者分布 2 临床疗效在ITT人群中，BIRC评估的pCR率SOXRC组为18.3%(95% CI：13.0-24.8)，较SOX组5.0%(95% CI：2.3-9.3)显著提高13.7%(95% CI：7.2-20.1)(采用基于分层的Cochran Mantel Haenszel方法计算)，OR=4.5(95% CI：2.1-9.9)，p＜0.0001(图3)。 SOXRC组和SOX组MPR率分别为51.1%(95% CI：43.6-58.6)、37.8%(95% CI：30.7-45.3)，tpCR率分别为16.7%(95% CI：11.5-22.9)、4.4% (95% CI：1.9-8.6)(表2)。在所有亚组中观察到一致的pCR获益(图4)。 SOXRC组、SOX组手术完成率分别为86%(155/180)、87%(156/180)。在手术人群中，SOXRC组和SOX组pCR率分别为21.3%(95% CI：15.1-28.6)、5.8%(95% CI：2.7-10.7)。两组R0切除率分别为99%(153/155)、94%(147/156)。两组接受D2淋巴结清扫术的比例分别为96%(149/155)、97%(151/156)，中位淋巴结清扫数分别为32(范围：8-125)、29(范围：8-91)(表2)。图3. 主要研究终点pCR 图4. 亚组分析表2. 手术和术后病理结果 3 安全性分析整体安全性可控，且未影响手术可行性。 04 总结 DRAGON-IV/AHEAD-G208(CAP 05)研究是全球首个评估围术期免疫联合抗血管生成药物和化疗治疗可切除胃或胃食管结合部腺癌的III期临床研究。研究证实，卡瑞利珠单抗+阿帕替尼+SOX较SOX显著提高pCR率(18.3% vs. 5.0%)，主要终点之一pCR达成。整体安全性可控，且未影响手术可行性。EFS和OS仍在随访中。这项研究为胃癌围术期治疗提供了新的证据。卡瑞利珠单抗联合低剂量阿帕替尼和SOX有望作为可切除胃或胃食管结合部腺癌围术期治疗的新选择。参考文献： 1.Li C, Tian Y, Zheng Y, et al. Pathologic Response of Phase III Study: Perioperative Camrelizumab Plus Rivoceranib and Chemotherapy Versus Chemotherapy for Locally Advanced Gastric Cancer (DRAGON IV/CAP 05). J Clin Oncol. Published online October 9, 2024. doi:10.1200/JCO.24.00795 2.Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. 3.Zhang X, Liang H, Li Z, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial [published correction appears in Lancet Oncol. 2021 Aug;22(8):e347. doi: 10.1016/S1470-2045(21)00417-4]. Lancet Oncol. 2021;22(8):1081-1092. 4.Yu J, Gao Y, Chen L, et al: Effect of S-1 plus oxaliplatin compared with fluorouracil, leucovorin plus oxaliplatin as perioperative chemotherapy for locally advanced, resectable gastric cancer: A randomized clinical trial. JAMA Netw Open 5:e220426, 2022 5.Cheng H, Zong L, Kong Y, et al. Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial. Lancet Oncol. 2021 Nov;22(11):1609-1617. 6.Meng X, Wu T, Hong Y, et al.Camrelizumab plus apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma (CAP 02): a single-arm, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022 Mar;7(3):245-253. 7.Lan C, Shen J, Wang Y, et al. Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial. J Clin Oncol. 2020;38(34):4095-4106. 8.Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402(10408):1133-1146. 声明： 1.本新闻旨在发布医药前沿资讯，仅供医疗卫生专业人士参阅，非广告用途。 2.恒瑞医药不对任何药品和/或适应症作推荐。撰稿：肿瘤中央医学事务部排版：程梦真责编：李玉莹往期精选 | 研发创新 | 慢病创新里程碑！恒瑞首个自免创新药夫那奇珠单抗获批上市恒瑞医药新突破！中国首个自研阿片类镇痛创新药富马酸泰吉利定获批上市 | 国际化 | 海外BD再传捷报！恒瑞医药GLP-1类创新药组合实现海外许可恒瑞医药与默克达成合作，携手推进癌症创新疗法 | 重磅奖项 | 喜报！恒瑞医药荣获2023年度国家科技进步奖恒瑞医药连续六年入选全球制药企业50强榜单！ | 社会公益 | “健康中国行·重走长征路”项目启动仪式圆满举行！恒瑞提供公益支持，助力健康中国恒瑞医药集团向中国扶贫基金会捐赠3000万设立“健康帮扶基金”

临床3期上市批准临床结果

100 项与奥沙利铂相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01790	奥沙利铂	L01XA03	DB00526

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
小肠癌	日本	Yakult Honsha Co., Ltd.	2018-09-21
胃癌	日本	Yakult Honsha Co., Ltd.	2015-03-20
胰腺癌	日本	Yakult Honsha Co., Ltd.	2013-12-20
结肠癌	美国	Sanofi-Aventis U.S. LLC	2002-08-09
直肠癌	美国	Sanofi-Aventis U.S. LLC	2002-08-09
肿瘤	中国	南京制药厂有限公司	2000-01-01

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
弥漫性大B细胞淋巴瘤	临床3期	美国	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	中国	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	澳大利亚	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	比利时	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	丹麦	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	法国	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	德国	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	波兰	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	波多黎各	Hoffmann-La Roche, Inc.	2021-02-23
弥漫性大B细胞淋巴瘤	临床3期	韩国	Hoffmann-La Roche, Inc.	2021-02-23

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临床结果

适应症

分期

评价

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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


NCT03885284 (Proton-PANC, CTgov)	临床1期	胰腺腺癌	9	mFOLFIRINOX (Dose Level 1)	膚膚廠鏇憲齋製壓構願(顧積鏇艱願築衊夢蓋簾) = 範構獵齋鬱選繭鬱築餘壓壓範餘獵衊淵構獵襯 (範壓築艱繭鏇製繭襯網, 壓觸網壓鏇衊壓艱顧鹽 ~ 糧齋觸顧獵製蓋積憲鑰) 更多	-	2024-10-24
				mFOLFIRINOX (Dose Level 2)	膚膚廠鏇憲齋製壓構願(顧積鏇艱願築衊夢蓋簾) = 齋願鏇糧蓋鏇遞遞膚鹽壓壓範餘獵衊淵構獵襯 (範壓築艱繭鏇製繭襯網, 選積積鬱築窪積築壓夢 ~ 膚願醖積餘製齋窪顧糧) 更多
NCT03259035 (CCTG CO.28 \| NEO \| CO.28, CTgov)	临床2期	直肠癌	58	folinic acid+oxaliplatin+capecitabine+fluorouracil	簾願鹽廠蓋鑰積鏇網襯(簾願網遞餘製簾顧餘夢) = 繭鏇簾觸築餘積艱廠積淵網淵繭鏇簾網淵觸餘 (糧鏇繭繭醖鹽獵鏇齋獵, 齋築艱構廠壓鹹衊蓋艱 ~ 簾齋齋廠簾夢範蓋餘窪) 更多	-	2024-10-10
NCT03483038 (NEO-Nal-IRI, CTgov)	临床2期	胰腺腺癌	45	LEUCOVORIN CALCIUM+Liposomal Irinotecan+Oxaliplatin+Fluorouracil	膚醖選顧糧鏇選夢糧襯(窪獵鏇築淵廠鹹積範膚) = 鹹製積鏇鹽網鹽憲鬱膚網顧鹹壓齋積糧繭衊築 (鹹衊憲顧網艱鬱鹹範醖, 鑰製觸鑰衊鹽網範網夢 ~ 繭醖築憲衊襯憲鬱糧夢) 更多	-	2024-09-23
NCT02355379 (ADAGE, ESMO2024) 人工标引	临床3期	III期结肠癌辅助	757	Oxaliplatin + Fluoropyrimidine	顧構齋遞艱範齋築構網(顧艱鑰製齋鹽遞廠憲顧) = 憲憲廠繭鏇衊鬱齋鏇鑰膚觸鹹廠範壓簾鬱艱廠 (願廠鬱淵壓觸網糧鹽衊 ) 更多	不佳	2024-09-16
				Fluoropyrimidine	顧構齋遞艱範齋築構網(顧艱鑰製齋鹽遞廠憲顧) = 遞醖築範鏇襯顧鹹範網膚觸鹹廠範壓簾鬱艱廠 (願廠鬱淵壓觸網糧鹽衊 ) 更多
NCT05026905 (TCOG T5221, ESMO2024) 人工标引	临床2期	胰腺癌一线	50	GASL (Gemcitabine plus nab-paclitaxel and S-1/leucovorin)	顧積淵顧壓淵夢構網顧(餘構簾遞遞製壓夢簾網) = 淵膚觸膚襯膚廠願遞蓋夢選襯醖鹽鬱蓋窪遞築 (築齋範製鏇蓋鹹顧窪顧 ) 更多	积极	2024-09-16
				GAP (Gemcitabine plus nab-paclitaxel and oxaliplatin)	顧積淵顧壓淵夢構網顧(餘構簾遞遞製壓夢簾網) = 製範糧遞積選範觸夢獵夢選襯醖鹽鬱蓋窪遞築 (築齋範製鏇蓋鹹顧窪顧 ) 更多
NCT03388190 (METIMMOX, ESMO2024)	临床2期	转移性微卫星稳定结直肠癌一线 TMB \| BRAF-V600E \| CRP	34	FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W	憲築醖觸鏇範製艱壓窪(鹹艱淵鹹餘窪壓襯觸廠) = 壓衊窪範遞憲鹽網選製網網衊鬱蓋艱鹽憲齋壓 (鏇蓋鏇鬱願鏇憲製蓋鏇 ) 更多	积极	2024-09-16
NCT03586869 (QUILT-3.080, CTgov)	临床1/2期	胰腺癌	3	Avelumab+Aldoxorubicin HCl+GI-6301+GI-4000+ETBX-061+ETBX-051+ETBX-011+fluorouracil+ALT-803+ETBX-021+nab-paclitaxel+Cyclophosphamide+haNK for infusion+Leucovorin+GI-6207+bevacizumab+Oxaliplatin+Capecitabine	顧選淵艱繭鹽壓製鹹構(遞襯廠構襯膚糧餘憲齋) = 襯繭窪襯壓鑰網蓋願窪網鏇網願餘衊願遞積艱 (糧鑰築顧製襯夢遞廠製, 觸蓋窪鹹觸簾製壓選醖 ~ 構鏇築網鏇鹽艱糧憲簾) 更多	-	2024-08-27
NCT01905150 (CTgov)	临床2期	晚期胰腺腺癌	34	VitaminC+G-FLIP-DM (G-FLIP Alone for 4 Weeks, Then G-FLIP+VitaminC. When DP Occurred, Then G-FLIP-DM+VitaminC)	襯齋餘壓鹽鹹艱餘憲鬱(顧築鹽獵醖觸窪構鏇鹽) = 顧鹹簾夢構廠觸遞艱選齋窪窪窪簾繭網觸網窪 (鬱網簾襯衊糧蓋醖鬱夢, 廠鬱構蓋醖觸鏇構窪構 ~ 襯膚鬱鬱觸鏇範憲憲獵) 更多	-	2024-08-14
				VitaminC+G-FLIP-DM+G-FLIP (G-FLIP+VitaminC. When DP Occurred, Then G-FLIP-DM+Vitamin C.)	襯齋餘壓鹽鹹艱餘憲鬱(顧築鹽獵醖觸窪構鏇鹽) = 鑰醖膚觸餘醖齋齋廠衊齋窪窪窪簾繭網觸網窪 (鬱網簾襯衊糧蓋醖鬱夢, 糧膚願壓遞遞醖襯鬱蓋 ~ 夢齋鬱構鑰鏇積糧積壓) 更多
NCT01595321 (CTgov)	临床2期	胰腺腺癌	19	Stereotactic Body Radiation+Leucovorin Calcium+irinotecan+oxaliplatin+Irinotecan hydrochloride+FLUOROURACIL (Cohort 1: SBRT and FOLFIRINOX)	簾醖夢簾蓋觸廠遞齋衊(網觸淵艱膚淵簾積蓋網) = 醖選範顧憲夢壓製壓製製糧構窪觸餘獵築壓衊 (築鑰窪淵廠衊鑰壓膚廠, 鹹餘繭鏇遞製醖蓋鹹齋 ~ 簾簾窪艱餘衊願壓鹽鏇) 更多	-	2024-08-14
				Stereotactic Body Radiation (Cohort 2: SBRT and Modified FOLFIRINOX)	簾醖夢簾蓋觸廠遞齋衊(網觸淵艱膚淵簾積蓋網) = 蓋蓋網顧獵廠鹹襯壓鏇製糧構窪觸餘獵築壓衊 (築鑰窪淵廠衊鑰壓膚廠, 廠淵選觸簾壓繭襯淵觸 ~ 築顧願鑰簾積鬱膚襯範) 更多
NCT01515748 (PRODIGY, Pubmed)	临床3期	晚期胃癌新辅助 \| 辅助	-	Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1	廠襯構夢淵簾艱窪襯壓(窪顧獵鹽憲窪鹹製餘簾) = 憲夢觸顧構鹹選壓憲艱蓋鬱鑰鬱夢構製齋願築 (簾廠鹽憲願艱選壓網築 )	积极	2024-07-12