Eric Van Cutsem, Joelle Collignon, Rikke L Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Dirk Arnold, Edita Baltruskeviciene, Per Pfeiffer, Jeffrey Yachnin, Susanne Magnusson, Camilla Rydberg Millrud, Annika Sanfridson, Nedjad Losic, Ignacio Garcia-Ribas, Dominique Tersago, Ahmad Awada
{"title":"抗IL1RAP抗体纳度诺利单抗（CAN04）联合吉西他滨和纳布-紫杉醇治疗晚期/转移性胰腺癌患者的疗效和安全性。","authors":"Eric Van Cutsem, Joelle Collignon, Rikke L Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Dirk Arnold, Edita Baltruskeviciene, Per Pfeiffer, Jeffrey Yachnin, Susanne Magnusson, Camilla Rydberg Millrud, Annika Sanfridson, Nedjad Losic, Ignacio Garcia-Ribas, Dominique Tersago, Ahmad Awada","doi":"10.1158/1078-0432.CCR-24-0645","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).</p><p><strong>Patients and methods: </strong>Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.</p><p><strong>Results: </strong>Seventy-six patients were enrolled; the median age was 63 years (range, 43-89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0-15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2-7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS.</p><p><strong>Conclusions: </strong>Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5293-5303"},"PeriodicalIF":10.0000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609625/pdf/","citationCount":"0","resultStr":"{\"title\":\"Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer.\",\"authors\":\"Eric Van Cutsem, Joelle Collignon, Rikke L Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Dirk Arnold, Edita Baltruskeviciene, Per Pfeiffer, Jeffrey Yachnin, Susanne Magnusson, Camilla Rydberg Millrud, Annika Sanfridson, Nedjad Losic, Ignacio Garcia-Ribas, Dominique Tersago, Ahmad Awada\",\"doi\":\"10.1158/1078-0432.CCR-24-0645\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).</p><p><strong>Patients and methods: </strong>Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.</p><p><strong>Results: </strong>Seventy-six patients were enrolled; the median age was 63 years (range, 43-89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0-15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2-7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS.</p><p><strong>Conclusions: </strong>Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.</p>\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\" \",\"pages\":\"5293-5303\"},\"PeriodicalIF\":10.0000,\"publicationDate\":\"2024-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609625/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.CCR-24-0645\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.CCR-24-0645","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：白细胞介素（IL）-1通路上调与胰腺导管腺癌（PDAC）的进展、耐药性和存活率有关。Nadunolimab是一种IL-1受体附属蛋白（IL1RAP）靶向抗体，具有增强的抗体依赖性细胞毒性，可阻断IL-1α/IL-1β信号传导。我们研究了纳度尼单抗与吉西他滨/纳布-紫杉醇（GN）联合治疗PDAC的疗效和安全性：既往未经治疗的局部晚期/转移性PDAC患者接受纳武利单抗（1.0-7.5 mg/kg）治疗，每两周一次，同时接受标准GN治疗。首要目标是安全性；次要目标是抗肿瘤反应、无进展生存期（PFS）和总生存期（OS）。研究还探讨了血清和肿瘤生物标志物与临床反应之间的相关性：入组患者76人，中位年龄63岁（43-89岁），42%为女性，97%为转移性疾病，9%接受过辅助化疗。最常见的≥3级不良反应是中性粒细胞减少（66%），通常发生在第一周期。29%的患者出现输液相关反应（3级，3%）。76名患者中只有1人出现3级或以上的周围神经病变。四个剂量组之间在安全性或疗效方面没有观察到明显的剂量依赖性差异。总体中位生存期为13.2个月（95%CI 10.6-15.5），1年生存率为58%。中位 iPFS（iRECIST）为 7.2 个月（95%CI 5.2-8.5）。肿瘤基线IL1RAP高表达患者的疗效高于低表达患者（OS 14.2个月 vs 10.6个月，P=0.026）。治疗过程中血清IL-8的降低与OS的延长相关：结论：纳度利单抗与GN联合治疗局部晚期/转移性PDAC具有良好的疗效和可控的安全性。肿瘤基线IL1RAP表达越高，预后越好。
Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer.
Purpose: IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).
Patients and methods: Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.
Results: Seventy-six patients were enrolled; the median age was 63 years (range, 43-89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0-15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2-7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS.
Conclusions: Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.
期刊介绍：
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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