Investigational New Drugs最新文献

{"title":"The analysis of molecular classification of pulmonary neuroendocrine tumors and relationship between YAP1 and efficacy.","authors":"Meihui Li, Xinyuan Wang, Jiali Gong, Hongyang Lu","doi":"10.1007/s10637-024-01492-6","DOIUrl":"10.1007/s10637-024-01492-6","url":null,"abstract":"<p><p>A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET). Clinical and survival data for PNET patients were gathered from January 2008 to December 2020. Immunohistochemical analysis was employed to evaluate the expression. The relationship between YAP1 expression and outcomes in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) was examined. Data from low-grade PNET patients who had previously undergone immunotherapy were retrospectively gathered and analyzed. The ASCL1 positive rate was markedly elevated in SCLC (7.1% vs. 60%; P < 0.001) and LCNEC patients (7.1% vs. 38.5%; P = 0.034) compared to PC patients. The YAP1-positive rate was elevated in LCNEC compared to SCLC (43.6% vs. 20%, P = 0.028) and pulmonary carcinoid (PC) patients (43.6% vs. 21.4%; P = 0.021). The DLL3-positive rate in SCLC patients was greater than in SCLC and PC patients (37.1% vs. 23.1% vs. 0%; P = 0.028, P = 0.021). A significant level of tumor heterogeneity was noted, with SCLC and LCNEC patients exhibiting markedly higher heterogeneity than PC patients (65.7% vs. 56.3% vs. 21.4%; P = 0.005, P = 0.025). In patients with LCNEC, YAP1 positivity exhibited no correlation with PD-L1 expression (17.1% vs. 45.7%, P = 0.518). Tumor heterogeneity was also noted in transformed SCLC, with no significant differences in the expression levels of transcription factors between transformed and traditional SCLC. In 13 LCNEC patients with a history of ICI application, YAP1 exhibited no significant effect on PFS (P = 0.331) or OS (P = 0.17) in the subgroup analysis of LCNEC patients. Among the 14 patients with low-grade PNET who underwent immunotherapy, the disease control rate was 85.7%. Patients with high-grade PNET have high levels of expression of ASCL1 and DLL3, whereas patients with LCNEC have high levels of expression of YAP1. With regard to the transcription factor level, it was found that patients with SCLC and LCNEC had a much higher degree of tumor heterogeneity than those with PC. In patients with LCNEC who were receiving monotherapy of ICIs or chemotherapy in combination with ICIs, the expression of YAP1 did not appear to have any clear impact on the prognosis. This is due to the limited sample size of the study, which requires additional investigation. When compared to the expression of TFs in regular SCLC, the expression of TFs in converted SCLC is comparable.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"108-117"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of ramucirumab combined with erlotinib or osimertinib in untreated EGFR-mutated NSCLC patients with asymptomatic brain metastases: insights from molecular biomarkers in the RELAY-brain trial.","authors":"Hiroyasu Kaneda, Haruko Daga, Asuka Okada, Yuki Nakatani, Yoko Tani, Takako Oka, Kenji Sawa, Kazuko Sakai, Kazuto Nishio, Tomoya Kawaguchi","doi":"10.1007/s10637-025-01505-y","DOIUrl":"10.1007/s10637-025-01505-y","url":null,"abstract":"<p><strong>Background: </strong>The RELAY-Brain trial examined the clinical utility and survival impacts of ramucirumab (RAM) combined with epidermal growth factor receptor (EGFR)-TKI in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with brain metastases. Although RAM combined with erlotinib (ERL) is known to have clinical benefits, the benefits in patients with baseline brain metastases remain unclear. This report examined the long-term follow-up data (Japan Registry of Clinical Trials: jRCTs2051190027) of the same patients, analyzing relevant biomarkers from tumor and plasma samples.</p><p><strong>Patients and methods: </strong>The six patients enrolled in the RELAY-Brain trial received RAM plus ERL or osimertinib (OSM). Our long-term follow-up observational study assessed patient survival, treatment status, and genetic biomarkers. Tumor and plasma samples were analyzed at baseline, during treatment, and at disease progression using next-generation sequencing and droplet digital PCR, to identify gene alterations and EGFR-TKI-resistant mutations.</p><p><strong>Results: </strong>After median follow-up of 44.2 months, the first site of disease progression in three of the patients was the brain metastases. In the RAM + ERL group, two patients with the T790M mutation subsequently received OSM. Progression-free survival (PFS) and overall survival ranged from 10.46 to 42.07 months and from 30.14 to 52.25 months, respectively. Gene alterations included TP53 mutations in three patients and ERBB2 and PIK3CA mutations in two. TP53 mutations were associated with shorter PFS.</p><p><strong>Conclusion: </strong>RAM with ERL or OSM achieved significant clinical benefits for patients with EGFR-mutated NSCLC with asymptomatic brain metastases. These positive outcomes and the identification of related biomarkers support the therapeutic potential of these combinations.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"147-156"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manganese improves anti-PD-L1 immunotherapy via eliciting type I interferon signaling in melanoma.","authors":"Xiaoxin Zhang, Jianhua Deng, Renjie Wu, Jian Hu","doi":"10.1007/s10637-024-01484-6","DOIUrl":"10.1007/s10637-024-01484-6","url":null,"abstract":"<p><p>The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl₂. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl₂ on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl₂ via combining treatment with anti-PD-L1 and MnCl₂. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4⁺ T cells and CD8⁺ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl₂ significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl₂ displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl₂ is a promising therapeutic strategy for melanoma.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"685-693"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142728747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma.","authors":"Cong Fu, Haoran Gu, Lin Sun, Zhouyu Wang, Qin Zhang, Ningning Luo, Dongsheng Chen, Tong Zhou","doi":"10.1007/s10637-024-01477-5","DOIUrl":"10.1007/s10637-024-01477-5","url":null,"abstract":"<p><p>Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"623-634"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting MDM2-mediated suppression of p53 with idasanutlin: a promising therapeutic approach for acute lymphoblastic leukemia.","authors":"Seyda Gungordu, Erhan Aptullahoglu","doi":"10.1007/s10637-024-01473-9","DOIUrl":"10.1007/s10637-024-01473-9","url":null,"abstract":"<p><p>Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"603-611"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-ovarian cancer migration and toxicity characteristics of a platinum(IV) pro-drug with axial HDAC inhibitor ligands in zebrafish models.","authors":"Salma Begum, Scheldon D Irvin, Carol K Cox, Zhouyang Huang, Justin J Wilson, Jerry D Monroe, Yann Gibert","doi":"10.1007/s10637-024-01479-3","DOIUrl":"10.1007/s10637-024-01479-3","url":null,"abstract":"<p><p>Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"644-654"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of immune checkpoint inhibitor rechallenge in initial immunotherapy responders with advanced non-small cell lung cancer: A single-center retrospective study.","authors":"Manyi Xu, Yanhua Wang, Ke Wang, Yue Hao, Chunwei Xu, Lei Shi, Zhengbo Song","doi":"10.1007/s10637-024-01483-7","DOIUrl":"10.1007/s10637-024-01483-7","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune rechallenge in patients with advanced non-small cell lung cancer (NSCLC) who responded well to initial immune checkpoint inhibitor (ICI) treatment is becoming a research hotspot. This study was aimed at describing the survival and clinical characteristics after immune rechallenge in initial immunotherapy responders.</p><p><strong>Patients and methods: </strong>We retrospectively identified 104 patients with advanced NSCLC who responded well in the first ICI and were rechallenged with immunotherapy to treat progression between January 2018 and June 2023 at Zhejiang Cancer Hospital. Progression-free survival (PFS) 2 and overall survival (OS) were defined as the time from the first day of the second ICI to the date of progression, death, or last follow-up.</p><p><strong>Results: </strong>Of 104 enrolled patients, 33 received immune monotherapy, and 71 were rechallenged with combination therapy (34 combined with anti-angiogenesis therapy). Patients with an initial immunotherapy duration exceeding 12 months, compared with a duration within 12 months, achieved a significantly prolonged mPFS2 and mOS (PFS2: 9.2 vs. 3.4 months, P < 0.001; OS: 25.5 vs. 10.7 months, P = 0.006). Patients rechallenged with combination therapy had significantly longer PFS2 than those receiving monotherapy (5.8 vs. 2.5 months, P = 0.040), and showed a favorable OS trend (15.9 vs. 10.1 months, P = 0.301). A significant difference in PFS2, particularly for patients receiving combined treatment with anti-angiogenesis therapy (8.7 vs. 4.6 months, P = 0.011), and a tendency toward longer OS (25.3 vs. 13.7 months, P = 0.090), were observed. Multivariate analysis identified long-term treatment duration (P = 0.005) and combined treatment with anti-angiogenesis therapy (P = 0.030) as independent positive factors associated with PFS after rechallenge.</p><p><strong>Conclusion: </strong>Immune rechallenge is recommend for responders with a prolonged initial immunotherapy duration. Combination therapy, particularly that including anti-angiogenic therapy, is an alternative effective approach to immune rechallenge.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"703-715"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase II study of ME2136 (Asenapine Maleate) plus standard antiemetic therapy for patients, including diabetic patients, receiving cisplatin-based chemotherapy.","authors":"Satoshi Hamauchi, Hirofumi Yasui, Tomoya Yokota, Takahiro Tsushima, Kunihiro Fushiki, Tateaki Naito, Akira Ono, Nobuhiro Kado, Yusuke Onozawa, Haruyasu Murakami, Toshiaki Takahashi, Yasuyuki Hirashima, Keita Mori, Kentaro Yamazaki","doi":"10.1007/s10637-024-01480-w","DOIUrl":"10.1007/s10637-024-01480-w","url":null,"abstract":"<p><p>Olanzapine combined with the neurokinin-1 receptor antagonist, palonosetron and dexamethasone is the standard treatment for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). However, the use of olanzapine poses challenges in patients with diabetes mellitus (DM) due to the potential risk of hyperglycemia. ME2136, antipsychotic similar to olanzapine, is associated with a lower risk of hyperglycemia. This study investigated the antiemetic efficacy and safety of ME2136 for HEC. This single-arm phase 2 study examined the safety and efficacy of ME2136 5 mg for 4 days in combination with triplet-combination antiemetic therapy. Two cohorts were established for the safety assessment: DM and non-DM. Eligible patients had malignant tumors and were receiving cisplatin-based chemotherapy for the first time. The primary endpoint was the complete response (CR) rate, defined as the percentage of patients without vomiting and not requiring rescue medications in the delayed phase (24-120 h). Between December 2020 and January 2022, 40 patients were enrolled, with 20 in each cohort. All patients were included in the safety analysis and 35 in the efficacy analysis. The CR rate in the delayed phase was 71.4% [60% CI 63.1-78.6%] for all patients, 66.7% in the DM cohort, and 76.5% in the non-DM cohort. No treatment-related adverse events ≥ grade 3, including hyperglycemia, were reported. ME2136, when combined with standard triplet-combination antiemetic therapy, is expected to exert similar antiemetic effects to the standard treatment for CINV due to HEC. Currently, ME2136-02 trial is underway to examine the safety and efficacy of triplet-combination antiemetic therapy and a 5-day treatment with ME2136. This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020. Clinical trial registration: This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"655-663"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical research progress of fruquintinib in the treatment of malignant tumors.","authors":"Shihao Zhao, Wenhui Wang, Jingyi Li, Zhigang Li, Zhanbo Liu, Shunchao Zhang, Zhaoqi Chen, Hongling Wang, Xiangqi Wang, Juntao Wang","doi":"10.1007/s10637-024-01476-6","DOIUrl":"10.1007/s10637-024-01476-6","url":null,"abstract":"<p><p>Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"612-622"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial.","authors":"Mathilde Morisseau, Carlos Gomez-Roca, Marie Viala, Audrey Rabeau, Delphine Loirat, Nadia Munsch, Kristell Thomas, Cécile Pages, Iphigenie Korakis, Vincent Sibaud, Jean-Pierre Delord, Thomas Filleron, Bastien Cabarrou","doi":"10.1007/s10637-024-01481-9","DOIUrl":"10.1007/s10637-024-01481-9","url":null,"abstract":"<p><p>The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"664-674"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}