MDM2-p53 拮抗剂 Brigimadlin (BI 907828) 对晚期胆管癌患者的疗效和安全性：病例系列

IF 2.7 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

OncoTargets and therapy Pub Date : 2024-03-29 DOI:10.2147/ott.s440979

Noboru Yamamoto, Anthony Tolcher, Navid Hafez, Iwona Lugowska, Rodryg Ramlau, Teresa Macarulla, Junxian Geng, Jian Li, Michael Teufel, Angela Märten, Patricia LoRusso

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引用次数: 0

摘要

背景：在晚期胆道癌（BTC）患者中，一线化疗加免疫治疗可改善疗效；然而，仍需要能反映该疾病分子异质性的二线治疗方案。MDM2是一个新出现的靶点，在约5%-8%的BTC病例中MDM2被扩增：方法：这是对正在进行的两项 Ia/Ib 期试验的子集分析，评估患者接受 brigimadlin（BI 907828；一种高效口服 MDM2-p53 拮抗剂）± ezabenlimab（PD-1 抑制剂）± BI 754111（抗 LAG-3；n = 1）治疗的情况：结果：12 名 BTC 患者的治疗结果（单一疗法：n = 6/联合疗法：n = 6）。六名患者获得部分应答（单药治疗：n = 2/联合治疗：n = 4），四名患者病情稳定；应答持久。布瑞吉玛林的安全性可控。7名患者因不良反应而减少了剂量，但没有因治疗相关不良反应而终止治疗：Brigimadlin在MDM2-扩增的晚期BTC患者中显示出抗肿瘤活性，值得进一步研究。白话摘要：胆道癌（BTC）是一种影响胆管的癌症，胆管是消化系统的一部分。通常，晚期胆管癌（即无法通过手术切除和/或已经扩散）的首选治疗方法是化疗联合免疫疗法。但是，如果化疗不起作用或停止起作用，二线治疗的选择就很少了。因此，目前正在进行深入研究，试图找到有效的药物。其中一种潜在药物名为布瑞吉玛林（或 BI 907828），是一种能激活肿瘤细胞中一种名为 p53 的分子的药片。p53 的正常功能是在细胞开始癌变时杀死它们。然而，如果 p53 因基因突变或其他机制而被关闭，那么癌症就会发展。虽然 p53 在 BTC 肿瘤中很少发生突变，但它会被另一种叫做 MDM2 的分子灭活，而 MDM2 通常在 BTC 中存在异常高的水平。Brigimadlin 可阻止 MDM2 和 p53 之间的相互作用。这将激活 p53 并导致癌症死亡。目前有两项临床试验正在评估 Brigimadlin 对包括 BTC 在内的一系列癌症的治疗效果，目的是确定一个安全剂量，以便在更大规模的试验中进行更详细的检查。迄今为止，已有 12 名 BTC 患者接受了治疗。其中六名患者的肿瘤明显缩小，另外四名患者的肿瘤保持稳定。副作用符合预期，可以通过暂停治疗或降低剂量来缓解。这些结果表明，应在晚期 BTC 患者中进一步测试布瑞吉玛林。

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Efficacy and Safety of the MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced Biliary Tract Cancer: A Case Series

Background: In patients with advanced biliary tract cancer (BTC), first-line chemotherapy plus immunotherapy has improved outcomes; however, second-line options that reflect the disease’s molecular heterogeneity are still needed. One emerging target is MDM2, amplified in ~5– 8% of BTC cases.
Methods: This is a subset analysis of two ongoing Phase Ia/Ib trials assessing patients treated with brigimadlin (BI 907828; a highly potent, oral MDM2–p53 antagonist) ± ezabenlimab (PD-1 inhibitor) ± BI 754111 (anti-LAG-3; n = 1).
Results: Results from 12 patients with BTC are shown (monotherapy: n = 6/combination: n = 6). Six patients achieved partial response (monotherapy: n = 2/combination: n = 4), four had stable disease; responses were durable. Brigimadlin had a manageable safety profile. Seven patients had dose reductions due to adverse events, but no treatment-related adverse events led to treatment discontinuation.
Conclusion: Brigimadlin demonstrated anti-tumor activity in patients with advanced MDM2-amplified BTC, and warrants further investigation.

Plain Language Summary: Biliary tract carcinoma (BTC) is a cancer that affects the bile ducts which are part of the digestive system. Usually, the first treatment for advanced BTC (ie cannot be removed surgically and/or has spread) is chemotherapy in combination with immunotherapy. However, if chemotherapy does not work, or stops working, there are few treatment options available in second-line. Accordingly, intensive research is ongoing to try and find effective drugs. One potential medicine, called brigimadlin (or BI 907828), is a tablet that activates a molecule in tumor cells called p53. The normal function of p53 is to kill cells when they first start to become cancerous. However, if p53 is turned off by genetic mutations, or other mechanisms, then cancer can develop. Although p53 is rarely mutated in BTC tumors, it is inactivated by another molecule called MDM2 which is usually present at abnormally high levels in BTC. Brigimadlin prevents interaction between MDM2 and p53. This activates p53 and causes the cancer to die. Two clinical trials are currently assessing brigimadlin in a range of cancers, including BTC, with the aim of identifying a safe dose that can be examined in more detail in larger trials. So far, 12 patients with BTC have been treated. The patients’ tumors significantly shrank in six of these patients and remained stable in a further four patients. Side effects were as expected and could be tolerated by pausing treatment or lowering the dose. These results show that brigimadlin should be tested further in patients with advanced BTC.

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来源期刊

OncoTargets and therapy BIOTECHNOLOGY & APPLIED MICROBIOLOGY-ONCOLOGY

CiteScore

9.70

自引率

0.00%

发文量

221

审稿时长

1 months

期刊介绍： OncoTargets and Therapy is an international, peer-reviewed journal focusing on molecular aspects of cancer research, that is, the molecular diagnosis of and targeted molecular or precision therapy for all types of cancer. The journal is characterized by the rapid reporting of high-quality original research, basic science, reviews and evaluations, expert opinion and commentary that shed novel insight on a cancer or cancer subtype. Specific topics covered by the journal include: -Novel therapeutic targets and innovative agents -Novel therapeutic regimens for improved benefit and/or decreased side effects -Early stage clinical trials Further considerations when submitting to OncoTargets and Therapy: -Studies containing in vivo animal model data will be considered favorably. -Tissue microarray analyses will not be considered except in cases where they are supported by comprehensive biological studies involving multiple cell lines. -Biomarker association studies will be considered only when validated by comprehensive in vitro data and analysis of human tissue samples. -Studies utilizing publicly available data (e.g. GWAS/TCGA/GEO etc.) should add to the body of knowledge about a specific disease or relevant phenotype and must be validated using the authors’ own data through replication in an independent sample set and functional follow-up. -Bioinformatics studies must be validated using the authors’ own data through replication in an independent sample set and functional follow-up. -Single nucleotide polymorphism (SNP) studies will not be considered.