This study will evaluate safety, tolerability, drug levels, molecular effects and clinical activity of MRTX849 (adagrasib) in combination with BI 1701963 in patients with advanced solid tumors that have a KRAS G12C mutation.

开始日期2021-08-12

申办/合作机构

Mirati Therapeutics, Inc.

[+1]

NCT04973163 / Active, not recruiting临床1期

A Phase Ia/Ib, Open-label, Multicentre Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of BI 1823911 as a Monotherapy and in Combination With Other Anti-cancer Therapies in Patients With Advanced or Metastatic Solid Tumours Expressing KRAS G12C Mutation

This study is open to adults with different types of advanced or metastatic cancer (including lung cancer, colorectal cancer, pancreatic cancer, and bile duct cancer). This study is for people for whom previous treatment was not successful or no treatment exists.
People who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes tumours grow faster. BI 1823911 and BI 1701963 are medicines that may turn off KRAS, each in a different way. In this study, BI 1823911 is given to people for the first time.
The purpose of this study is to find the highest dose of BI 1823911 that people can tolerate when taken alone and together with BI 1701963. The most suitable dose is used to find out whether BI 1823911 alone and in combination with BI 1701963 can make tumours shrink.
Participants can stay in the study as long as they benefit from treatment and can tolerate it.
During this time, participants take tablets of BI 1823911 alone or in combination with BI 1701963 once a day. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participant's health.

开始日期2021-08-03

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 KRAS G12D x KRAS G12V 相关的临床结果

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100 项与 KRAS G12D x KRAS G12V 相关的转化医学

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0 项与 KRAS G12D x KRAS G12V 相关的专利（医药）

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项与 KRAS G12D x KRAS G12V 相关的文献（医药）

2024-10-01·Molecular Carcinogenesis

Triiodothyronine (T3) suppresses hepatic tumorigenesis and development by inhibiting the phosphorylation of ERK

Article

作者: Zhang, Nan ; Wang, Aiguo ; Mao, Nan ; Dong, Lili ; Li, Huiling ; Dong, Penghui ; Chen, Jun

AbstractThe effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild‐type mice [WT] and mouse models of HCC [HrasG12Vand KrasG12Dtransgenic mice (Hras‐Tg and Kras‐Tg)]) systems were used to investigate the effect of T3 on p‐ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p‐ERK in hepatoma cells within 30 min. However, p‐ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p‐ERK in liver tissues of WT. In Hras‐Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, HrasG12V, and p‐ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p‐MEK. Especially, the inhibitory effect of T3 on p‐ERK and hepatic tumorigenesis and development without influence on the levels of KrasG12D and p‐MEK was further confirmed in Kras‐Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.

2024-09-01·Cancer Letters

Driver mutation subtypes involve with differentiated immunophenotypes influencing pancreatic cancer outcomes

Article

作者: Jiang, Lingxi ; Deng, Xiaxing ; Cheng, Xueyan ; Chen, Hao ; Zhan, Qian ; Jiang, Cen ; Wen, Chenlei ; Zou, Siyi ; Zhang, Jiao ; Lin, Lin ; Deng, Lisha ; Zhang, Lei ; Shen, Baiyong ; Li, Fanlu ; Yang, Ying

Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRAS^non-G12DTP53^wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4⁺ T cell) in KRAS^G12DTP53^mut patients, KRAS^G12VTP53^wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRAS^G12VTP53^wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.

2024-06-01·Journal of Biological Chemistry

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

Article

作者: Hindul, Naushin L ; Hirota, Kouji ; Abbott, Lauren R ; Tanaka, Kayoko ; Adan, Sumaya M D ; Fry, Andrew M ; Straatman, Kornelis R

About 18% of all human cancers carry a mutation in the KRAS gene making it among the most sought-after anticancer targets. However, mutant KRas protein has proved remarkably undruggable. The recent approval of the first generation of RAS inhibitors therefore marks a seminal milestone in the history of cancer research. It also raises the predictable challenges of limited drug efficacies and acquired resistance. Hence, new approaches that improve our understanding of the tumorigenic mechanisms of oncogenic RAS within more physiological settings continue to be essential. Here, we have used the near-diploid hTERT RPE-1 cells to generate isogenic cell lines in which one of the endogenous KRAS alleles carries an oncogenic KRAS mutation at glycine 12. Cells with a KRAS^G12V/+, KRAS^G12C/+, or KRAS^G12D/+ genotype, together with WT KRAS^G12G(WT)/+ cells, reveal that oncogenic KRAS.G12X mutations increase cell proliferation rate and cell motility and reduced focal adhesions in KRAS^G12V/+ cells. Epidermal growth factor -induced phosphorylation of ERK and AKT was comparable between KRAS^G12V/+, KRAS^G12C/+, KRAS^G12D/+, and KRAS^G12G(WT)/+ cells. Interestingly, KRAS^G12X/+ cells showed varying responses to distinct inhibitors with the KRAS^G12V/+ and KRAS^G12D/+ cells more sensitive to hydroxyurea and MEK inhibitors, U0126 and trametinib, but more resistant to PI3K inhibitor, PIK-90, than the KRAS^G12G(WT)/+ cells. A combination of low doses of hydroxyurea and U0126 showed an additive inhibition on growth rate that was greater in KRAS^G12V/+ than WT cells. Collectively, these cell lines will be a valuable resource for studying oncogenic RAS signaling and developing effective anti-KRAS reagents with minimum cytotoxicity on WT cells.

项与 KRAS G12D x KRAS G12V 相关的新闻（医药）

2024-10-25

·EndPoints

Revolution Medicines breaks ground in challenging pancreatic cancer with two RAS drugs

In an interview Friday, Revolution Medicines CEO Mark Goldsmith, who says he prefers to understate rather than exaggerate, floated a lofty goal: cure pancreatic cancer — or get close. “That’s our aim, and we don’t think that’s right around the corner, but we’re off to a very good start,” he told Endpoints News. It’s an ambitious vision, given that the five-year survival rate for pancreatic cancer is 13%, according to the American Cancer Society. Revolution is developing a suite of RAS inhibitors, and the company’s shares have more than doubled in the past 12 months because of excitement over their potential to treat solid tumors, particularly pancreatic cancer. The Redwood City, CA-based company reported results this week from early-stage trials of two of its experimental treatments in pancreatic cancer, where more than 90% of cases harbor RAS mutations. In a late-breaking presentation Friday, Revolution Medicines said that 12 of 40 previously treated pancreatic cancer patients who received a 1,200 mg daily dose of its KRAS G12D inhibitor, called RMC-9805, saw their tumors shrink at least 30%. (The company included confirmed responses as well as unconfirmed responses still on treatment.) That’s good for a 30% response rate, and the company said it would use a 1,200 mg dose in a Phase 2 trial for pancreatic cancer. The data, presented at what’s known as the Triple Meeting, were the first clinical results from RMC-9805. They’re from a broader Phase 1/1b study looking at the drug in patients with solid tumors harboring KRAS G12D mutations who had received a median of two previous treatments. The company, which informally goes by RevMed, said that 179 patients have been dosed with the drug. At the 1,200 mg daily dose, with which 99 patients have been treated, the most common side effects were nausea, diarrhea and vomiting and rash. It described those adverse events as low-grade and limited, though there was one grade 3 case of elevated liver enzymes. The company also has a multi-RAS inhibitor that can tackle a range of mutations in a Phase 3 trial. Known as RMC-6236, RevMed announced it dosed a first pancreatic cancer patient in that trial on Monday. The study will include a core population of pancreatic cancer patients with RAS G12X mutations, as well as other mutations. RevMed shared updated results from 127 patients in an earlier Phase 1/1b study of RMC-6236. In that study, overall survival rates were 14.5 months in both previously treated pancreatic cancer patients with any RAS mutation, as well as with those with a mutation at codon 12 (which is referred to as KRAS G12X). While the study didn’t have a control arm, Jefferies analyst Kelly Shi said the benchmark for survival in those patients with chemotherapy is about six to seven months. Grade 3 or greater side effects related to the drug were rash (which impacted 8% of patients), stomatitis and diarrhea, and 35% of patients required dose modifications because of side effects, but none dropped out because of that. Goldsmith said the two experimental compounds have “overlapping but also distinct profiles, and two overlapping but also distinct ranges of target.”

临床结果临床2期临床1期临床3期

2024-10-23

·药明康德

“癌症之王”总生存率超90%！靶向多种KRAS突变小分子临床试验结果亮眼

▎药明康德内容团队编辑今日，Revolution Medicines宣布，其在研泛RAS抑制剂RMC-6236在经治胰腺导管腺癌（PDAC）患者中展现出令人鼓舞的抗肿瘤活性和安全性。分析显示，RMC-6236单药作为二线疗法可改善携带任意RAS突变PDAC患者的中位无进展生存期（PFS）与总生存期（OS），患者在第6个月的总生存率高达91%。目前该疗法的3期临床试验RASolute 302正在进行中。致癌RAS蛋白驱动高达30%的所有人类癌症，尤其是在PDAC、非小细胞肺癌（NSCLC）和结直肠癌（CRC）中最为显著。PDAC是所有主要癌症中RAS突变率最高的癌症，超过90%的患者的肿瘤携带RAS突变，而RAS突变是驱动PDAC疾病进展的主要因素。在人类癌症中，RAS G12突变（如G12D、G12V和G12C）为主要的RAS突变种类。然而目前获批的KRAS靶向疗法仅针对一种特定的KRAS突变，即在GDP结合（不具活性，OFF）状态下的KRAS G12C。 RMC-6236-001是一项1/1b期多中心、开放标签、剂量递增和剂量扩展研究，旨在评估RMC-6236作为单药治疗携带RAS突变或野生型RAS晚期实体瘤患者的效果。截至2024年7月23日，共有127名PDAC患者接受了RMC-6236治疗，剂量范围为每日160 mg至300 mg。 RMC-6236在每日剂量160 mg至300 mg范围内显示出持久的抗肿瘤活性。在二线治疗中，携带KRAS G12X突变PDAC患者的中位PFS为8.5个月（95% CI：5.3–11.7个月），中位OS为14.5个月（95% CI：8.8–不可估计）。携带任意RAS突变的PDAC患者在二线治疗中的中位PFS为7.6个月（95% CI：5.9–11.1个月），中位OS为14.5个月（95% CI：8.8–不可估计）。携带KRAS G12X突变与携带任意RAS突变的PDAC患者在6个月的总生存率分别为89%与91%。在二线治疗组中，携带KRAS G12X突变患者的客观缓解率为29%，在三线及以上治疗组（3L+）中为22%，这些患者的疾病控制率分别为91%和89%。KRAS G12X指的是KRAS蛋白第12位的甘氨酸因为基因突变，转换成其它氨基酸。 RMC-6236在每日160 mg至300 mg剂量范围内总体耐受性良好，其安全性数据与此前报告的结果一致，未观察到新的安全信号。最常见的治疗相关不良事件（TRAEs）为皮疹和胃肠道毒性，主要为1级或2级。报告的最常见≥3级TRAEs为皮疹（8%）、口腔炎（3%）和腹泻（2%）。由于TRAEs导致的剂量调整发生在35%的患者中，但无患者因TRAEs而终止治疗。 ▲RMC-6236抑制与GTP结合的RAS蛋白（图片来源：参考资料[3]） RMC-6236是一款口服、可靶向突变和野生型RAS在GTP结合（具活性，ON）状态下的选择性抑制剂。在去年欧洲肿瘤内科学会（ESMO）大会上，Revolution Medicines公布RMC-6236用于治疗NSCLC患者的早期临床结果。在携带KRAS G12D，G12V，G12R，G12A，或G12S的经治NSCLC患者中，客观缓解率达到38%，包括一名获得完全缓解的患者，疾病控制率为85%。除了RMC-6236，Revolution Medicines旗下还有一款潜在“first-in-class”的口服KRAS G12D突变选择性共价抑制剂RMC-9805。该疗法正在临床1/1b期试验中接受评估，旨在研究其作为单药或与RMC-6236联合使用时，对携带KRAS G12D突变的实体瘤患者的疗效和安全性。目前该试验正处于患者招募阶段。除了已获批的adagrasib与sotorasib，目前产业界还有多项KRAS靶向疗法处于临床试验阶段。其中较受人瞩目的有罗氏（Roche）所研发的KRAS G12C抑制剂divarasib。该疗法在1期临床试验中，分别在NSCLC与CRC患者中达到53.4%与29.1%的确认缓解。此外，默沙东（MSD）在今年4月宣布已启动一项3期临床试验，旨在检视其在研口服选择性KRAS G12C共价抑制剂MK-1084，与重磅PD-1抑制剂Keytruda联用，一线治疗携带KRAS G12C突变且高度表达PD-L1的转移性NSCLC患者。去年，加科思药业公布了KRAS G12C抑制剂格来雷塞（glecirasib）与SHP2抑制剂JAB-3312联用，一线治疗NSCLC患者的临床试验结果。结果显示，格来雷塞/JAB-3312组合达到65.5%的客观缓解率。今年5月，BridgeBio Oncology Therapeutics也宣布正在致力推动BBO-8520的临床进展。这是一款可与KRAS G12C突变体的激活构象和失活构象结合的抑制剂，目前正在1期临床试验中用于治疗携带KRAS G12C突变的NSCLC患者。该公司旗下的一款泛KRAS抑制剂BBO-11818，则可靶向多种KRAS G12X突变体的激活和失活状态，预计在2025年初递交IND申请。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Revolution Medicines Presents Updated Data from RMC-6236 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved October 23, 2024 from https://www.globenewswire.com/en/news-release/2024/10/23/2967583/0/en/Revolution-Medicines-Presents-Updated-Data-from-RMC-6236-Monotherapy-Study-in-Patients-with-Advanced-Pancreatic-Ductal-Adenocarcinoma.html [2] Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors. Retrieved October 23, 2024 from https://clinicaltrials.gov/study/NCT06040541?intr=RMC-9805%20&rank=1[3] RMC-6236: Pancreatic Cancer Update to Support Pivotal Phase 3 Trial. Retrieved July 15, 2024 from https://ir.revmed.com/static-files/eeeb0690-0ef4-44b8-b5fe-8d11d8df3c9a 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床3期临床结果临床终止

2024-10-04

·药明康德

高效降解13种常见KRAS突变体，创新PROTAC分子登《科学》

▎药明康德内容团队编辑 KRAS基因突变是人类癌症中最常见的基因突变之一。然而KRAS蛋白也是著名的难于成药靶点，虽然近年来针对KRAS G12C突变体的共价抑制剂获得FDA的批准上市，打破了KRAS的不可成药性，然而仍然有多种其它类型的KRAS基因突变能够激活KRAS的活性，这给利用小分子药物抑制多种KRAS突变体的活性带来了挑战。近日，邓迪大学（University of Dundee）和勃林格殷格翰（Boehringer Ingelheim）公司的科学家合作，开发了一种能够降解多种KRAS突变体的广谱靶向蛋白降解疗法，为治疗多种难治性癌症提供了新选择。这项研究已经发表在顶尖科学期刊《科学》上。在这项研究中，科学家们利用称为蛋白降解靶向嵌合体（PROTAC）的治疗模式来靶向多种不同的KRAS突变体。PROTAC是近年来小分子药物开发的热点领域之一，它是一种双功能分子，一端可以与靶点蛋白结合，另一端与E3泛素连接酶结合，促使泛素连接酶在靶点蛋白上添加泛素的“标签”。而被泛素装饰的蛋白会被送到细胞自身的蛋白酶体中降解，从而降低了靶点蛋白的水平。这款名为ACBI3的PROTAC分子基于勃林格殷格翰公司已经开发的一款泛KRAS抑制剂BI-2865。它在临床前研究中已经表现出抑制多种KRAS突变体和野生型KRAS蛋白的活性。这款泛KRAS抑制剂的临床前研究已于去年发表在《自然》杂志上。在这项发表在《科学》上的研究中，勃林格殷格翰公司和邓迪大学的科学家合作，将BI-2865与可以和E3泛素连接酶VHL结合的基团连接在一起，生成了可以将VHL招募到KRAS突变体附近的候选PROTAC化合物。研究团队然后解析了KRAS、VHL和候选PROTAC化合物构成的复合体的晶体结构，基于从中发现的洞见对候选化合物进行了一步步优化，最终生成了ACBI3。在临床前研究中，这款PROTAC分子能够选择性、高效降解17种最常见KRAS突变体中的13种突变体。此外，在小鼠癌症模型中，ACBI3有效抑制了表达KRAS G12D和KRAS G12V突变体肿瘤的生长。 ▲ACBI3在动物模型中展现降解KRAS G12D和KRAS G12V突变体的活性（图片来源：参考资料[3]）研究人员指出，KRAS突变在多种具有高度未满足医疗需求的癌症中出现，包括35%的肺癌，45%的结直肠癌和高达90%的胰腺癌。ACBI3广泛降解多种KRAS突变体的活性为治疗这些疾病，克服KRAS突变产生的耐药性提供了有力的工具。勃林格殷格翰公司同时表示，将通过其开源科学通道opnMe让全球的科学家都可免费获得ACBI3，从而加速针对KRAS的未来研究。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Degrader takes out many forms of KRas. Retrieved October 4, 2024, from https://cen.acs.org/pharmaceuticals/drug-discovery/Degrader-takes-forms-KRas/102/web/2024/09?sc=230901_cenrssfeed_eng_latestnewsrss_cen [2] University of Dundee research shows potential breakthrough for hard to treat cancers. Retrieved October 4, 2024, from https://www.dundee.ac.uk/stories/university-dundee-research-shows-potential-breakthrough-hard-treat-cancers [3] Popow et al., (2024). Targeting cancer with small-molecule pan-KRAS degraders. Science, DOI: 10.1126/science.adm8684 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

蛋白降解靶向嵌合体临床结果