Investigational New Drugs最新文献

{"title":"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.","authors":"Petra Henning, Anna Westerlund, Sofia Movérare-Skrtic, Catharina Lindholm, Marcela Márquez-Méndez, Sten Nilsson, Anders R Holmberg, Ulf H Lerner","doi":"10.1007/s10637-024-01427-1","DOIUrl":"10.1007/s10637-024-01427-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"207-220"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996239","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":"A phase 1b open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of py314 in combination with pembrolizumab in patients with advanced renal cell carcinoma.","authors":"Kathryn E Beckermann, Amita Patnaik, Ira Winer, Winston Tan, Babar Bashir, Christos E Kyriakopoulos, Randy F Sweis, Marc Chamberlain, Brian I Rini","doi":"10.1007/s10637-024-01419-1","DOIUrl":"10.1007/s10637-024-01419-1","url":null,"abstract":"<p><p>Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"179-184"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899832","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 multicenter phase Ia study of AbGn-107, a novel antibody-drug conjugate, in patients with advanced gastrointestinal cancer.","authors":"Andrew H Ko, Andrew L Coveler, Benjamin L Schlechter, Tanios Bekaii-Saab, Brian M Wolpin, Jeffrey W Clark, Bruno Bockorny, Li-Yuan Bai, Yu-Chin Lin, Evelyn Chiang, Peter Langecker, Shih-Yao Lin","doi":"10.1007/s10637-024-01430-6","DOIUrl":"10.1007/s10637-024-01430-6","url":null,"abstract":"<p><p>AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"221-228"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028093","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":"Impact of carbamazepine on SMARCA4 (BRG1) expression in colorectal cancer: modulation by KRAS mutation status.","authors":"Aaron Shaykevich, Danbee Chae, Isaac Silverman, Jeremy Bassali, Netanel Louloueian, Alexander Siegman, Gargi Bandyopadhyaya, Sanjay Goel, Radhashree Maitra","doi":"10.1007/s10637-024-01418-2","DOIUrl":"10.1007/s10637-024-01418-2","url":null,"abstract":"<p><p>SMARCA4 is a gene traditionally considered a tumor suppressor. Recent research has however found that SMARCA4 likely promotes cancer growth and is a good target for cancer treatment. The drug carbamazepine, an autophagy inducer, was used on colorectal cancer cell lines, HCT1116 and Hke3 (KRAS mutant and wildtype). Our study finds that Carbamazepine affects SMARCA4 levels and that this effect is different depending on the KRAS mutation status. This study analyzes the effect of carbamazepine on early-stage autophagy via ULK1 as well as simulates the docking of carbamazepine on KRAS, depending on the mutation status. Our study highlights the therapeutic uses of carbamazepine on cancer, and we propose that carbamazepine in conjunction with other chemotherapies may prove useful in targeting KRAS-mutated colorectal cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"229-239"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039329","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":"Targeting LEF1-mediated epithelial-mesenchymal transition reverses lenvatinib resistance in hepatocellular carcinoma.","authors":"Xinxiu Li, Hongmeng Su, Wenqing Tang, Shihui Shu, Luyu Zhao, Jinghan Sun, Hong Fan","doi":"10.1007/s10637-024-01426-2","DOIUrl":"10.1007/s10637-024-01426-2","url":null,"abstract":"<p><p>Acquired resistance is a significant hindrance to clinical application of lenvatinib in unresectable hepatocellular carcinoma (HCC). Further in-depth investigation of resistance mechanisms can help to develop additional therapeutic strategies to overcome or delay resistance. In our study, two lenvatinib-resistant (LR) HCC cell lines were established by treatment with gradient increasing concentration of lenvatinib, named Hep3B-LR and HepG2-LR. Interestingly, continuous lenvatinib treatment reinforced epithelial-mesenchymal transition (EMT), cell migration, and cell invasion. Gene set enrichment analysis (GSEA) enrichment analysis of RNA-sequencing from Hep3B-LR and corresponding parental cells revealed that activation of Wnt signaling pathway was involved in this adaptive process. Active β-catenin and its downstream target lymphoid enhancer binding factor 1 (LEF1) were significantly elevated in LR HCC cells, which promoted lenvatinib resistance through mediating EMT-related genes. Data analysis based on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Program (TCGA) databases suggests that LEF1, as a key regulator of EMT, was a novel molecular target linked to lenvatinib resistance and poor prognosis in HCC. Using a small-molecule specific inhibitor ICG001 and knocking down LEF1 showed that targeting LEF1 restored the sensitivity of LR HCC cells to lenvatinib. Our results uncover upregulation of LEF1 confers lenvatinib resistance by facilitating EMT, cell migration, and invasion of LR HCC cells, indicating that LEF1 is a novel therapeutic target for overcoming acquired lenvatinib resistance.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"185-195"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899833","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-line treatment of driver gene-negative metastatic lung adenocarcinoma with malignant pleural effusion: Should chemotherapy be combined with an immune checkpoint inhibitor or bevacizumab?","authors":"Yuanyuan Zhao, Ting Mei, Feifei Na, Xiaoman Tian, Rui Ao, Xiangyu Long, Qiang Luo, Ping Duan, Jiang Zhu, Yongsheng Wang, Meijuan Huang, Yongmei Liu, Youling Gong","doi":"10.1007/s10637-024-01424-4","DOIUrl":"10.1007/s10637-024-01424-4","url":null,"abstract":"<p><p>Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"196-206"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139931158","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":"PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study.","authors":"Miaomiao Gou, Yong Zhang, Zhikuan Wang, Niansong Qian, Guanghai Dai","doi":"10.1007/s10637-024-01425-3","DOIUrl":"10.1007/s10637-024-01425-3","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC).</p><p><strong>Methods: </strong>This was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients' requirements) in combination with albumin paclitaxel (125 mg/m², intravenously, days 1 and 8, or 250 mg/m², intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1-21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs).</p><p><strong>Results: </strong>From July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9-9.3), and the median OS was 10.1 months (95% CI, 7.5-14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3-4 immune-related liver damage.</p><p><strong>Conclusion: </strong>Second-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC.</p><p><strong>Trial registration: </strong>Clinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"171-178"},"PeriodicalIF":3.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722570","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":"A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors","authors":"Maxime Chénard-Poirier, Aaron R. Hansen, Martin E. Gutierrez, Drew Rasco, Yan Xing, Lin-Chi Chen, Heng Zhou, Andrea L. Webber, Tomoko Freshwater, Manish R. Sharma","doi":"10.1007/s10637-024-01428-0","DOIUrl":"https://doi.org/10.1007/s10637-024-01428-0","url":null,"abstract":"<p>MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and <i>N</i>-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov, NCT03833427.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"87 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140129427","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":"Safety and efficacy of apatinib in combination with chemotherapy with or without immunotherapy versus chemotherapy alone as first-line treatment for advanced gastric cancer","authors":"Lele Chang, Xuemei Zhang, Qian Ma, Lingyang Kong, Yang Yu, Ji Tao, Qingwei Li","doi":"10.1007/s10637-024-01423-5","DOIUrl":"https://doi.org/10.1007/s10637-024-01423-5","url":null,"abstract":"<p>The specific first-line regimen for advanced gastric cancer (GC) is still controversial. The benefit of apatinib for first-line treatment of advanced GC remains unknown and needs to be further explored. Eighty-two patients with advanced GC treated in our institution from October 2017 to March 2023 were retrospectively reviewed. All individuals had her-2 negative GC and had received at least two cycles of first-line treatment, including 44 patients in the combination treatment group (apatinib in combination with chemotherapy with or without immunotherapy) and 38 patients in the simple chemotherapy group. We evaluated the efficacy and safety of apatinib in combination with chemotherapy with or without immunotherapy in the first-line treatment of advanced GC by comparing the efficacy, progression-free survival (PFS), and adverse events in two groups of patients. The median PFS of the simple chemotherapy group was 9.25 months (95% confidence interval (CI), 6.1–11.2 months), and that of the combination treatment group was 10.9 months (95% CI, 7.9–15.8 months), which was 1.65 months longer than the simple chemotherapy group. Statistically significant differences are shown (<i>P</i> = 0.022). The objective response rate (ORR) of the combination treatment group was 65.9%, and 36.8% in the simple chemotherapy group. Statistically significant differences are shown (<i>P</i> = 0.014). No serious (Grade IV) adverse events occurred in either group. Our study indicates that apatinib in combination with chemotherapy with or without immunotherapy as first-line treatment for advanced GC exhibits good anti-tumor activity and is well tolerated by patients.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"17 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139750884","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":"Phase 1 study of pembrolizumab plus chemotherapy in Japanese patients with extensive-stage small-cell lung cancer.","authors":"Naoyuki Nogami, Takaaki Tokito, Yoshitaka Zenke, Miyako Satouchi, Takashi Seto, Hideo Saka, Junko Ohtani, Shirong Han, Kazuo Noguchi, Makoto Nishio","doi":"10.1007/s10637-023-01411-1","DOIUrl":"10.1007/s10637-023-01411-1","url":null,"abstract":"<p><strong>Background: </strong>Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).</p><p><strong>Methods: </strong>Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m²) and etoposide (100 mg/m²; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m²; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).</p><p><strong>Results: </strong>Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).</p><p><strong>Conclusion: </strong>Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov , NCT01840579.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"136-144"},"PeriodicalIF":3.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10891246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650775","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}