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Correction to: CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial. 更正:CXCR2拮抗剂纳瓦利辛与pembrolizumab联合治疗部分晚期实体瘤:一项2期随机试验。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1007/s10637-024-01444-0
Andrew J Armstrong, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H Miller, Aaron R Hansen, Jong-Seok Lee, Frank Tsai, Benjamin J Solomon, Tae Min Kim, Christian Rolfo, Vincent Giranda, Yixin Ren, Fang Liu, Bhargava Kandala, Tomoko Freshwater, Judy S Wang
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引用次数: 0
Association between albumin-bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients. 日本患者白蛋白-胆红素分级与瑞戈非尼及其代谢物M-2和M-5稳态血浆谷浓度之间的关系。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-03-22 DOI: 10.1007/s10637-024-01429-z
Kazuma Fujita, Daiki Taguchi, Koji Fukuda, Taichi Yoshida, Kazuhiro Shimazu, Hanae Shinozaki, Hiroyuki Shibata, Masatomo Miura

The aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.

本研究旨在确定21名接受瑞戈非尼治疗的患者体内瑞戈非尼及其代谢物(N-氧化物代谢物(M-2)和去甲基N-氧化物代谢物(M-5))的血浆谷浓度(C0)是否受白蛋白-胆红素(ALBI)分级的影响。瑞戈非尼的用药剂量为 40 至 160 毫克,每天一次,以 3 周为一个用药周期,1 周为一个停药周期。治疗开始后第8天,采用高效液相色谱法测定瑞戈非尼及其主要代谢物的C0值。与1级患者相比,ALBI 2级患者的瑞戈非尼及其代谢物M-2和M-5的C0值明显降低(P=0.023、0.003和0.017)。1级ALBI患者体内瑞戈非尼及其代谢物的总C0明显高于2级患者(3.489 μg/mL vs. 1.48 μg/mL;P = 0.009)。ALBI2级患者的中位相对剂量强度(RDI)明显低于1级患者(21.9% vs. 62.9%;P = 0.006)。在21名结直肠癌患者中的15名患者中,ALBI 2级患者(n = 9)的中位总生存时间明显短于1级患者(n = 6;P = 0.013)。对ALBI 2级患者施用低剂量瑞戈非尼会降低瑞戈非尼的RDI,降低疗效,因为瑞戈非尼无法维持适当的C0。有必要定期监测瑞戈非尼的C0,以指导剂量调整。
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引用次数: 0
Toxicity burden patterns of MET-selective tyrosine kinase inhibitors: evidence from real-world pharmacovigilance. MET选择性酪氨酸激酶抑制剂的毒性负担模式:来自真实世界药物警戒的证据。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-05-03 DOI: 10.1007/s10637-024-01437-z
Wenjie Li, Wei Wang

MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.

MET第14外显子跳变和MET扩增被认为是癌症患者的致癌和靶向基因变化。MET 选择性酪氨酸激酶抑制剂(TKIs)在这一特定人群中的治疗效果令人鼓舞。然而,目前仍缺乏对这些药物潜在毒性的全面了解。本药物警戒分析利用美国食品药物管理局不良事件报告系统数据库来评估与 MET 选择性 TKIs 相关的显著不良事件。在各类不良事件(AE)中,胃肠功能紊乱、呼吸系统毒性、肝毒性以及代谢和营养紊乱的发生率较高,且具有重要意义。尤其值得注意的是,外周水肿、恶心、吞咽困难、疲劳和呼吸困难成为报告的最主要的五种不良反应。这些不良反应大多出现在开始使用 MET 选择性 TKIs 治疗的最初几个月内,之后持续出现。值得注意的是,我们的调查揭示了使用卡马替尼与听力损失和吞咽困难发生率之间的显著相关性。在管理与MET选择性TKIs相关的毒性,尤其是与胃肠道功能紊乱、呼吸系统毒性、肝毒性和耳毒性相关的毒性时,必须进行严格监测并实施支持性护理策略。
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引用次数: 0
KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer. KEYNOTE-434 B 部分:一项评估日本既往未接受过治疗的晚期非小细胞肺癌患者伊帕卡托司他、pembrolizumab 和化疗联合疗法的 1 期研究。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-03-26 DOI: 10.1007/s10637-024-01422-6
Noboru Yamamoto, Miyako Satouchi, Toshihiko Doi, Yutaka Fujiwara, Noriko Yanagitani, Yoshitaka Kawa, Kiyotaka Yoh, Lance Leopold, Mihaela Munteanu, Takashi Sawada, Shirong Han, Kazuo Noguchi, Makoto Nishio

Background: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).

Methods: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination.

Results: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%.

Conclusion: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.

Trial registration: ClinicalTrials.gov , NCT02862457.

研究背景在非随机、开放标签、1期KEYNOTE-434研究(NCT02862457)的A部分中,日本晚期实体瘤患者对Pembrolizumab联合epacadostat(吲哚胺2,3-二氧合酶-1抑制剂)的耐受性良好。我们报告了B部分的研究结果,该部分评估了日本晚期非小细胞肺癌(NSCLC)患者接受依帕司他联合pembrolizumab和化疗的情况:符合条件的患者年龄≥20岁,组织学或细胞学确诊为IIIB或IV期NSCLC,既往未接受过系统治疗,ECOG表现状态为0或1。患者每天两次口服依帕司他100毫克,每3周静脉注射彭博利珠单抗200毫克,共35个周期,并接受4个周期的化疗(队列1:顺铂加培美曲塞,非鳞癌;队列2:卡铂加培美曲塞,非鳞癌;队列3:卡铂加紫杉醇,鳞癌或非鳞癌)。主要终点是剂量限制性毒性反应(DLT)的发生率。在其他研究出现不利结果后,方案修正案将依帕司他从治疗组合中删除:19名患者中,7名加入了组群1,6名加入了组群2和组群3。中位随访时间为 13.7 个月(4.2-27.8 个月)。17名DLT有效患者中有5名(29%)出现≥1次DLT(队列1,n=1;队列2和队列3,各n=2);最常见的是斑丘疹(3级,n=3)和丙氨酸氨基转移酶升高(2级,n=1;3级,n=2)。所有患者都出现了与治疗相关的不良事件(AEs);58%的患者出现了3级或4级与治疗相关的不良事件。客观反应率为47%:日本晚期NSCLC患者对依帕司他联合pembrolizumab和化疗的耐受性良好:试验注册:ClinicalTrials.gov , NCT02862457。
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引用次数: 0
Evolving or immutable - phase I solid tumor trials in the era of precision oncology. 不断发展还是一成不变--精准肿瘤学时代的实体瘤 I 期试验。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-05-22 DOI: 10.1007/s10637-024-01445-z
Shannon S Stockton, G Dan Ayers, Cody Lee, Heather Laferriere, Satya Das, Jordan Berlin

In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.

在精准肿瘤学(PO)时代,实体瘤患者(pts)的全身疗法已从化疗(CT)转向靶向治疗(TT)和免疫疗法(IO)。本系统调查描述了2010年至2020年间入组试验的特点,重点关注纳入标准、采用的剂量递增方案(DES)类型以及扩增队列(EC)的使用。文献检索确定了12种期刊中2000年1月1日至2020年12月31日发表的针对成人实体瘤的I期研究。我们仅纳入了 2010 年至 2020 年间的研究,以更好地捕捉 PO 时代的研究。两名审稿人对数据进行了摘录;第三名审稿人确定了数据的一致性。在 10,744 项研究中,10,195 项为非局部用药或在 2010 年之前入选;437 项研究被纳入其中。最常见的药物类别是TT(47.6%)、IO(22%)和CT(6.9%)。在报告种族的研究中,患者主要是白人(61.7%)或亚裔(25.7%),其次是黑人(6.5%)或其他种族(6.1%)。在研究纳入标准的报告和说明方面存在异质性。只有40.1%的研究使用了EC,而在使用ECS的研究中,46.6%是通过基因组选择定义的。89%的试验采用了基于规则的DES;80.5%的试验采用了3+3设计。在所有试验药物中,37.5%的药物进入了II期,10.3%的药物获得了监管部门的许可(针对I期试验的适应症)。在 PO 时代,TT 和 IO 已成为 I 期试验中研究最多的药物。基于规则的 DES 更适用于 CT 的升级,但仍主要用于 CT 的升级。
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引用次数: 0
The suppression of cell motility through the reduction of FAK activity and expression of cell adhesion proteins by hAMSCs secretome in MDA-MB-231 breast cancer cells. hAMSCs 分泌组通过降低 MDA-MB-231 乳腺癌细胞中 FAK 的活性和细胞粘附蛋白的表达来抑制细胞的运动性。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-03-27 DOI: 10.1007/s10637-024-01434-2
Fatemeh Safari, Setareh Bararpour, Fatemeh Omidi Chomachaei

Breast cancer is a leading cause of death in women worldwide. Cancer therapy based on stem cells is considered as a novel and promising platform. In the present study, we explore the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through the reduction of focal adhesion kinase (FAK) activity, SHP-2, and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression in MDA-MB-231 breast cancer cells. For this purpose, we employed a co-culture system using 6-well plate transwell. After 72 h, hAMSCs-treated MDA-MB-231 breast cancer cells, the activity of focal adhesion kinase (FAK) and the expression of SHP-2 and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression were analyzed using western blot. The shape and migration of cells were also analyzed. Based on our results, a significant reduction in tumor cell motility through downregulation of the tyrosine phosphorylation level of FAK (at Y397 and Y576/577 sites) and cell adhesion expression in MDA-MB-231 breast cancer cells was demonstrated. Our findings indicate that hAMSCS secretome has therapeutic effects on cancer cell migration through downregulation of FAK activity and expression of cell adhesion proteins.

乳腺癌是全球妇女的主要死因。以干细胞为基础的癌症疗法被认为是一种新颖而有前景的平台。在本研究中,我们探讨了人羊膜间充质基质细胞(hAMSCs)通过降低MDA-MB-231乳腺癌细胞中局灶粘附激酶(FAK)活性、SHP-2和细胞粘附蛋白(如Paxillin、Vinculin、Fibronectin、Talin和整合素αvβ3的表达)的治疗效果。为此,我们采用了6孔板Transwell共培养系统。经 hAMSCs 处理的 MDA-MB-231 乳腺癌细胞 72 h 后,用 Western 印迹法分析了病灶粘附激酶(FAK)的活性、SHP-2 的表达以及 Paxillin、Vinculin、Fibronectin、Talin 等细胞粘附蛋白和整合素 αvβ3 的表达。此外,还分析了细胞的形状和迁移。结果表明,通过下调 FAK 的酪氨酸磷酸化水平(Y397 和 Y576/577 位点)和细胞粘附表达,MDA-MB-231 乳腺癌细胞的肿瘤细胞运动能力显著降低。我们的研究结果表明,hAMSCS 分泌组通过下调 FAK 活性和细胞粘附蛋白的表达,对癌细胞迁移具有治疗作用。
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引用次数: 0
The efficacy and safety of continuous intravenous infusion of rh-endostatin combined with platinum-based doublet chemotherapy for advanced non-small-cell lung cancer. 持续静脉注射rh-恩度他汀联合铂类双联化疗治疗晚期非小细胞肺癌的有效性和安全性。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-05-03 DOI: 10.1007/s10637-024-01439-x
Xinyi Liu, Zihan Guo, Lin Su, Anli Zuo, Min Gao, Xiang Ji, Jiameng Lu, Shuran Yang, Yunxiu Jiang, Degan Lu

Background: Platinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present.

Aim: This study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed.

Methods: This prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210 mg) over a period of 120 h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs).

Results: The mPFS was 6.5 months (95% confidence interval (CI): 3.8-9.1 m) while the mOS was 12.3 months (95% CI: 7.6-18.5 m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS.

Conclusions: The incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients.

Clinicaltrials: GOV: NCT05574998.

背景:铂类双药化疗常用于治疗非小细胞肺癌(NSCLC)。越来越多的证据表明,在铂类化疗中加入抗血管生成药物可提高 NSCLC 患者的生存率。目的:本研究旨在探讨5天连续静脉输注rh-内司他丁联合化疗治疗晚期NSCLC患者的有效性和安全性。方法:这是一项前瞻性单臂多组研究:这项前瞻性、单臂多中心研究在2021年1月至2022年12月期间共招募了48名经组织学或细胞学确诊但之前未接受过任何治疗的晚期NSCLC患者。化疗前,这些患者使用输液泵在120小时内持续静脉输注rh-内司他汀(210毫克)。化疗方案包括铂与培美曲塞或紫杉醇的组合,以21天为一个周期。研究的主要终点是中位无进展生存期(mPFS),次要终点包括中位总生存期(mOS)、客观反应率(ORR)、疾病控制率(DCR)以及不良事件(AEs)评估:mPFS为6.5个月(95%置信区间(CI):3.8-9.1个月),mOS为12.3个月(95%置信区间(CI):7.6-18.5个月)。ORR和DCR分别为52.1%和75.0%。白细胞减少(52.1%)、贫血(33.3%)和血小板减少(20.8%)是最常见的不良反应,这些毒性被认为是可以接受和控制的。此外,血清癌胚抗原(CEA)水平升高与 PFS 和 OS 下降之间存在相关性:结论:在以铂类为基础的双联化疗中连续5天静脉输注rh-内托铂,在晚期NSCLC的治疗中表现出了安全性和有效性。此外,血清中CEA的基线水平有可能作为NSCLC患者联合化疗时rh-endostatin疗效的预测指标:GOV:NCT05574998。
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引用次数: 0
Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer. 奥希替尼早期减量对表皮生长因子受体突变非小细胞肺癌一线治疗疗效的影响
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-03-27 DOI: 10.1007/s10637-024-01432-4
Tomoki Hori, Kazuhiro Yamamoto, Takefumi Ito, Shigeki Ikushima, Tomohiro Omura, Ikuko Yano

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

奥希替尼是表皮生长因子受体(EGFR)突变非小细胞肺癌(NSCLC)患者的一线治疗药物。然而,由于不良事件(AEs)的出现,患者往往需要尽早减少剂量。本研究旨在评估奥希替尼早期减量对疗效和安全性的影响。这是一项回顾性研究,包括2018年8月至2021年12月期间开始使用奥希替尼作为一线疗法的表皮生长因子受体突变NSCLC患者。在开始使用奥希替尼后6个月内剂量降至低于80毫克/天或开始时剂量为40毫克/天的患者被定义为剂量减少组。主要终点是无进展生存期(PFS)。采用 Cox 比例危险模型探讨了影响无进展生存期的因素。本研究共纳入 85 例患者。减量组(25 人)和标准剂量组(60 人)的患者特征无明显差异。与标准剂量组相比,减量组的中位生存期明显延长(26.0 个月对 12.0 个月,P = 0.03)。对84名患者进行的多变量分析(排除了一名脑转移情况不明的患者)显示,表皮生长因子受体外显子21 L858R突变、恶性胸腔积液或胸膜转移、肝转移以及6个月内减量是影响PFS的独立因素。奥希替尼的早期减量是延长EGFR突变NSCLC患者PFS的有效治疗策略。
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引用次数: 0
The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects 食物对中国健康受试者服用不可逆表皮生长因子受体酪氨酸激酶抑制剂马来酸舒替尼胶囊药代动力学的影响
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-11 DOI: 10.1007/s10637-024-01436-0
Bei Cao, Tingting Ma, Yuqiang Zhang, Lei Huang, Hui Lin, Huanhuan Jiang, Yu Zhao, Yan Geng, Yuanxun Yang, Sumin Cao, Juan Li

Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100 mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC0 − inf) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43–95.72 and 75.88–97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69–86.95 and 75.42–93.56), respectively. In addition, the time to maximum plasma concentration (Tmax) of both sutetinib and its metabolite has been prolonged by 2 h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn. The registration No. is CTR20201933, and the date of registration is 2020-10-16).

舒替尼是表皮生长因子受体(EGFR)的不可逆抑制剂,对携带非耐药罕见EGFR突变的局部晚期或转移性非小细胞肺癌(NSCLC)患者具有良好的疗效和安全性。为了评估潜在的食物效应,18 名中国健康受试者参加了一项单中心、随机、开放标签、两序、两期交叉研究。研究人员在空腹或进食条件下单次口服100毫克舒替替尼,每次服药后进行药代动力学采样,并采用经验证的液相色谱/质谱方法进行分析。此外,还对安全性和耐受性进行了评估。摄入食物会轻微降低苏替尼的最大血浆浓度(Cmax)和从时间0到无穷远的血浆浓度-时间曲线下面积(AUC0 - inf)(几何最小二乘平均值[GLSM]比值,80.94%和86.11%;90%置信区间[CI]分别为68.43-95.72和75.88-97.73)及其活性代谢物苏替尼N-氧化物(GLSM比值分别为75.58%和84.00%;90%置信区间[CI]分别为65.69-86.95和75.42-93.56)。此外,在喂养条件下,苏替尼及其代谢物达到最大血浆浓度(Tmax)的时间延长了2小时。研究期间共发生31例不良事件(AE),无严重不良事件(SAE)报告,空腹组和进食组之间未观察到明显差异。我们的研究结果表明,高脂肪和高热量饮食会显著延迟药物吸收,并略微降低药物暴露量。中国健康受试者对舒替替尼的耐受性普遍良好。(本试验已在 http://www.chinadrugtrials.org.cn 注册。注册号为 CTR20201933,注册日期为 2020-10-16)。
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引用次数: 0
The novel cytotoxic polybisphosphonate osteodex decreases bone resorption by enhancing cell death of mature osteoclasts without affecting osteoclastogenesis of RANKL-stimulated mouse bone marrow macrophages. 新型细胞毒性聚双磷酸盐 osteodex 可通过增强成熟破骨细胞的细胞死亡来减少骨吸收,而不影响 RANKL 刺激的小鼠骨髓巨噬细胞的破骨细胞生成。
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-01 Epub Date: 2024-03-01 DOI: 10.1007/s10637-024-01427-1
Petra Henning, Anna Westerlund, Sofia Movérare-Skrtic, Catharina Lindholm, Marcela Márquez-Méndez, Sten Nilsson, Anders R Holmberg, Ulf H Lerner

It has previously been demonstrated that the polybisphosphonate osteodex (ODX) inhibits bone resorption in organ-cultured mouse calvarial bone. In this study, we further investigate the effects by ODX on osteoclast differentiation, formation, and function in several different bone organ and cell cultures. Zoledronic acid (ZOL) was used for comparison. In retinoid-stimulated mouse calvarial organ cultures, ODX and ZOL significantly reduced the numbers of periosteal osteoclasts without affecting Tnfsf11 or Tnfrsf11b mRNA expression. ODX and ZOL also drastically reduced the numbers of osteoclasts in cell cultures isolated from the calvarial bone and in vitamin D3-stimulated mouse crude bone marrow cell cultures. These data suggest that ODX can inhibit osteoclast formation by inhibiting the differentiation of osteoclast progenitor cells or by directly targeting mature osteoclasts. We therefore assessed if osteoclast formation in purified bone marrow macrophage cultures stimulated by RANKL was inhibited by ODX and ZOL and found that the initial formation of mature osteoclasts was not affected, but that the bisphosphonates enhanced cell death of mature osteoclasts. In agreement with these findings, ODX and ZOL did not affect the mRNA expression of the osteoclastic genes Acp5 and Ctsk and the osteoclastogenic transcription factor Nfatc1. When bone marrow macrophages were incubated on bone slices, ODX and ZOL inhibited RANKL-stimulated bone resorption. In conclusion, ODX does not inhibit osteoclast formation but inhibits osteoclastic bone resorption by decreasing osteoclast numbers through enhanced cell death of mature osteoclasts.

之前有研究表明,多聚双膦酸盐骨化酶(ODX)可抑制器官培养小鼠钙骨的骨吸收。在本研究中,我们进一步研究了 ODX 在几种不同的骨器官和细胞培养物中对破骨细胞分化、形成和功能的影响。唑来膦酸 (ZOL) 被用来进行比较。在维甲酸刺激的小鼠钙器官培养物中,ODX 和 ZOL 能显著减少骨膜破骨细胞的数量,但不影响 Tnfsf11 或 Tnfrsf11b mRNA 的表达。ODX 和 ZOL 还能大幅减少从小腿骨分离的细胞培养物和维生素 D3 刺激的小鼠粗骨髓细胞培养物中破骨细胞的数量。这些数据表明,ODX 可通过抑制破骨细胞祖细胞的分化或直接靶向成熟的破骨细胞来抑制破骨细胞的形成。因此,我们评估了在 RANKL 刺激下纯化的骨髓巨噬细胞培养物中破骨细胞的形成是否会受到 ODX 和 ZOL 的抑制,结果发现成熟破骨细胞的初始形成不受影响,但双膦酸盐会增强成熟破骨细胞的细胞死亡。与这些发现一致的是,ODX 和 ZOL 并不影响破骨细胞基因 Acp5 和 Ctsk 以及破骨细胞生成转录因子 Nfatc1 的 mRNA 表达。将骨髓巨噬细胞培养在骨片上时,ODX 和 ZOL 可抑制 RANKL 刺激的骨吸收。总之,ODX 不会抑制破骨细胞的形成,但会通过增强成熟破骨细胞的细胞死亡来减少破骨细胞的数量,从而抑制破骨细胞的骨吸收。
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引用次数: 0
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Investigational New Drugs
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