Investigational New Drugs最新文献

{"title":"US FDA-accelerated approvals and subsequent withdrawals: influence on Japanese clinical oncology practice guidelines.","authors":"Hayase Hakariya, Akihiko Ozaki, Tetsuya Tanimoto","doi":"10.1007/s10637-025-01524-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01524-9","url":null,"abstract":"<p><p>The US (US) Food and Drug Administration (FDA)-accelerated approval pathway facilitates early access to oncology drugs based on surrogate endpoints, with required confirmatory post-marketing trials. However, regulatory decisions vary globally, with some drugs withdrawn in the US remaining approved in Japan. We conducted a cross-sectional analysis of Japanese professional society guidelines, evaluating recommendations for seven accelerated approval cancer drugs withdrawn from the US market but retained in Japan. We assessed for level of evidence and level of treatment preference ratings with consensus across guidelines issued by the corresponding Japanese professional societies. Four of the seven drugs (57%) were recommended as highly or moderately preferred treatment options in Japanese guidelines: gemtuzumab ozogamicin for acute myeloid leukemia, gefitinib for EGFR-positive non-small cell lung cancer, bevacizumab for HER2-negative metastatic breast cancer, and atezolizumab with nab-paclitaxel for PD-L1-positive triple-negative breast cancer. Detailed analysis of regulatory history and background of guideline recommendation revealed discrepancies in the assessment of clinical benefits: gemtuzumab ozogamicin failed to demonstrate benefits amid safety concerns, while gefitinib, bevacizumab, and atezolizumab were more controversial, although they did not demonstrate improved overall survival in post-marketing trials. Despite regulatory withdrawal in the US due to unproven clinical benefits, drugs retained in Japan received positive guideline recommendations. This finding highlights regional variations in regulatory decisions and different approaches to benefit-risk assessments, suggesting a need for improved transparency in Japan's regulatory decisions and guideline recommendations, with clearer justifications for endorsing drugs that are considered to have unproven clinical benefits in the US.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772401","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":"Rare exon 18 G719A and exon 21 L833V compound EGFR mutations show favorable response to Third-Generation TKI Furmonertinib: A case report and literature review.","authors":"Yuejian, Jijun Zhao, Tao Wu, Dongdong Zhang","doi":"10.1007/s10637-025-01521-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01521-y","url":null,"abstract":"<p><p>EGFR exon 19 deletions and exon 21 point mutations are the most common mutations in lung adenocarcinoma, with patients deriving significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs in rare compound EGFR mutations remains uncertain. We report a case of lung adenocarcinoma with concurrent EGFR exon 18 G719A and exon 21 L833V mutations, showing a favorable response to third-generation TKI treatment. We reported a case of a 63-year-old female patient with brain, bone, and adrenal metastases from lung adenocarcinoma. Next-generation sequencing analysis identified a rare EGFR exon 18 G719A mutation in combination with an EGFR exon 21 L833V mutation. The patient received furmonertinib as first-line treatment and achieved a sustained response lasting over 12 months. This is the first reported case highlighting the efficacy of a third-generation TKI in treating lung adenocarcinoma with this rare compound mutation. Our findings suggest that third-generation TKIs may be a viable therapeutic option for prolonging progression-free survival in this patient subset.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719306","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":"Correction to: 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/s10637-025-01519-6","DOIUrl":"https://doi.org/10.1007/s10637-025-01519-6","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663456","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":"Evaluation of the anti-leukemia activity and underlying mechanisms of the novel perinucleolar compartment inhibitor CTI-2 in acute myeloid leukemia.","authors":"Anran Li, Mingmin Yu, Yue Zhao, Shuangshuang Wu, Guan Wang, Liping Wang","doi":"10.1007/s10637-025-01520-z","DOIUrl":"https://doi.org/10.1007/s10637-025-01520-z","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648448","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 features, treatment, and prognosis of nivolumab induced immune encephalitis.","authors":"Zhaoquan Wu, Haibo Lei, Ronghui Li, Xiang Liu, Chunjiang Wang","doi":"10.1007/s10637-025-01522-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01522-x","url":null,"abstract":"<p><p>Immune encephalitis (IE) is an immune-mediated adverse events (irAEs) linked to nivolumab therapy, and its clinical characteristics remain unclear. This study aimed to analyze the clinical patterns of nivolumab-induced IE to inform diagnosis, treatment, and prevention strategies. We conducted a retrospective analysis of nivolumab-induced IE by reviewing case reports from the database until October 31, 2024. Among the 86 patients (53.5% male), the median age was 64 years (range 17, 83). The median time to the onset of IE was 38 days (range 4, 1430), and the median treatment cycle was 2 cycles (range 1, 18). The most prevalent symptoms included altered mental status (38.4%) and fever (37.2%). Cerebrospinal fluid analysis revealed elevated protein levels, normal glucose, and pleocytosis. Antineuronal antibodies were present in 29.1% of patients. MRI findings typically showed T2/FLAIR hyperintense signals in 52.3%. EEG results indicated diffuse slowing (16.3%). Following drug discontinuation and treatment, 86% of patients exhibited recovery or improvement, while 5.8% unfortunately succumbed to the condition. IE represents a rare yet severe irAEs associated with nivolumab. Clinicians must remain vigilant for signs of IE in patients undergoing nivolumab treatment. Diagnostic tests for nivolumab-induced IE generally do not reveal specific abnormalities. For individuals diagnosed with IE, it is crucial to initiate systemic steroid treatment without delay.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597090","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":"First-in-human, phase 1 dose escalation study of SL-279252, a hexameric PD1-Fc-OX40L fusion protein, in patients with advanced solid tumors and lymphoma.","authors":"Melissa Johnson, David Hong, Irene Braña, Patrick Schöffski, Vladimir Galvao, Fatima Rangwala, Bo Ma, Robert Hernandez, Asha Kamat, Kazunobu Kato, Taylor H Schreiber, Lini Pandite, Lillian L Siu","doi":"10.1007/s10637-025-01518-7","DOIUrl":"https://doi.org/10.1007/s10637-025-01518-7","url":null,"abstract":"<p><p>SL-279252 is a bifunctional hexameric fusion protein adjoining the extracellular domains of PD-1 and OX40L via an inert IgG4 derived Fc domain. A Phase 1 dose escalation study was conducted in patients (pts) with advanced solid tumors or lymphomas. SL-279252 was administered intravenously across 12 dose levels (range: 0.0001-24 mg/kg). Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and anti-tumor activity. Forty-nine pts (48 with solid tumor and 1 with lymphoma) were enrolled (median age 64 years; 53% male; median [range] of 3 [0-5] prior systemic therapies; 61% had been previously treated with PD-1/L1 inhibitors). Most common treatment-related adverse events (AEs) were infusion-related reaction (16%), maculopapular rash (10%), fatigue (6%), and neutropenia (6%). Treatment-related Grade (G) 3 AE was neutropenia (4%). There were no G4 or G5 AEs or DLTs. SL-279252 Cmax and area under the curve (AUC) increased proportionally with dose. T½ was ~ 20 h. Baseline anti-drug antibodies (ADA) were observed in 11/42 pts who had received a PD-1 inhibitor within 250 days. 7/31 pts had a persistent SL-279252 induced ADA response. PD effects consistent with OX40 engagement included dose dependent egress of CD4 + OX40 + cells and increases in Ki67 + CD4 and CD8 central and effector memory cells in the blood. Best response by iRECIST [1] in 46 response evaluable subjects was 1 iPR and 15 iSD. SL-279252 was well tolerated. PD effects consistent with OX40 activation were observed, however, efficacy was limited which may have been due to the disease characteristics, prior treatment with PD-1/L1 inhibitors, neutralization of the PD-1 domain of SL-279252 by circulating PD-1 inhibitors, limited SL-279252 penetration into tumors or other variables. Trial register number NCT03894618. Trial registration date 28-March-2019.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557080","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":"From development to clinical success: the journey of established and next-generation BTK inhibitors.","authors":"Shivani Gupta, Arpit Sharma, Alok Shukla, Abha Mishra, Amit Singh","doi":"10.1007/s10637-025-01513-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01513-y","url":null,"abstract":"<p><p>Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515622","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":"Retrospective analysis of clinical features of nivolumab-induced immune-related pancreatitis.","authors":"Yong Pan, Wei Li, Zhaoquan Wu, Wei Sun, Binsheng He, Chunjiang Wang","doi":"10.1007/s10637-025-01517-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01517-8","url":null,"abstract":"<p><p>To study the clinical features of nivolumab-induced immune-related pancreatitis and to provide evidence for its recognition and treatment. Cases of nivolumab-induced pancreatitis were collected by searching Chinese and English databases until November 30, 2024. Forty-three patients were included, with a median age of 61 years (range 23, 79). The median time to onset of pancreatitis was 120 days (range 1, 990) after initial administration. The main symptoms of the patients were abdominal pain (55.8%), nausea (14.0%), vomiting (11.6%), fever (9.3%), anorexia (9.3%), and asymptomatic (7.0%). Laboratory tests showed elevated lipase and amylase levels, with median values of 391.5 IU/L (range 136, 4050) and 1588 IU/L (range 248, 8788), respectively. Pancreatic biopsy showed inflammatory cell infiltration (18.6%), fibrosis (7.0%), and acinar damage and dropout (4.7%). The main imaging findings were focal or diffuse enlargement of the pancreas and fat stranding. After discontinuation of nivolumab and receiving steroid and immunosuppressive therapy (88.4%), patients' symptoms improved at a median time of 42 days (range 7, 192), and 11.6% of patients died. Immune-related pancreatitis should be alert during nivolumab administration. The lack of specificity of clinical symptoms and laboratory tests confuses the diagnosis of pancreatitis. The diagnosis of immune-associated pancreatitis should be treated promptly.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492116","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 novel anti-HER2/EGFR bispecific antibody-drug conjugate demonstrates promising antitumor efficacy and overcomes resistance to HER2- or EGFR-targeted ADCs.","authors":"Huoying Huang, Yuxin Zhou, Chengzhang Shang, Yifu Zhang, Yuelei Shen","doi":"10.1007/s10637-025-01507-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01507-w","url":null,"abstract":"<p><p>HER2 and EGFR are frequently co-expressed in various tumors. While antibody-drug conjugates (ADCs) targeting HER2, such as T-DM1 and T-Dxd, have shown remarkable antitumor effects in clinical responses, their effectiveness is constrained by drug resistance. EGFR amplification or high expression is one of the factors that lead to resistance against HER2-targeted ADCs. Likewise, the amplification of HER2 may lead to the development of resistance to EGFR-targeted therapies. To overcome these challenges, we, therefore, developed a bispecific antibody (B2C4) that targets HER2 and EGFR. B2C4 exhibited strong binding affinity and internalization activity in tumor cells with high expression of HER2 and EGFR, as well as in those with high expression of either target. B2C4 was then conjugated with vc-MMAE to create a bispecific ADC (B2C4-MMAE) with an average DAR of 4.05. By effectively engaging both arms of the bispecific ADC, B2C4-MMAE demonstrated significant antitumor activity in tumor cells and animal models that were unresponsive HER2- or EGFR-targeted ADCs. B2C4-MMAE could serve as an alternative therapeutic option for tumors that are resistant to single-target treatments. Additionally, B2C4-MMAE exhibited potential in treating tumors resistant to T-Dxd, underscoring its promise as a treatment for challenging cases.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467865","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 I dose-escalation and expansion study of RMX1002, a selective E-type prostanoid receptor 4 antagonist, as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors.","authors":"Dan Liu, Jifang Gong, Jian Zhang, Yongqian Shu, Hao Wu, Tianshu Liu, Yanhua Xu, Lijia Zhang, Min Li, Xichun Hu, Lin Shen","doi":"10.1007/s10637-025-01512-z","DOIUrl":"https://doi.org/10.1007/s10637-025-01512-z","url":null,"abstract":"<p><p>RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (C_max) reached within 2 to 5 h, and dose-dependent increases in C_max and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458025","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}