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Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer

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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: Van Cutsem, Eric, Collignon, Joëlle, Eefsen, Rikke L, Ochsenreither, Sebastian, Zvirbule, Zanete, Ivanauskas, Audrius, Arnold, Dirk, Baltruskeviciene, Edita, Pfeiffer, Per, Yachnin, Jeffrey, Magnusson, Susanne, Rydberg Millrud, Camilla, Sanfridson, Annika, Losic, Nedjad, Garcia-Ribas, Ignacio, Tersago, Dominique, Awada, Ahmad
Source: Clin Cancer Res
Publisher Information: American Association for Cancer Research (AACR), 2024.
Publication Year: 2024
Subject Terms: Male, Pancreatic Neoplasms/pathology, Oncologie, Carcinoma, Pancreatic Ductal/drug therapy, Deoxycytidine, ACTIVATION, Deoxycytidine/analogs & derivatives, Pancreatic Neoplasms/drug therapy, Antineoplastic Combined Chemotherapy Protocols, Paclitaxel/adverse effects, Human health sciences, Neoplasm Metastasis, Aged, 80 and over, CHEMORESISTANCE, Carcinoma, Pancreatic Ductal/immunology, Medicine (all), Middle Aged, Treatment Outcome, Oncology, Antibodies, Monoclonal, Humanized/adverse effects, Female, Pancreatic Neoplasms/immunology, Life Sciences & Biomedicine, Albumins/administration & dosage, Antibodies, Monoclonal, Humanized/administration & dosage, Carcinoma, Pancreatic Ductal, Adult, Paclitaxel, Clinical Trials: Targeted Therapy, Carcinoma, Pancreatic Ductal/pathology, Antibodies, Monoclonal, Humanized, Sciences de la santé humaine, POOR-PROGNOSIS, Paclitaxel/administration & dosage, 3211 Oncology and carcinogenesis, Albumins, Biomarkers, Tumor, Pancreatic Neoplasms/mortality, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Deoxycytidine/administration & dosage, Aged, Albumins/adverse effects, Science & Technology, Antineoplastic Combined Chemotherapy Protocols/adverse effects, IL1RAP protein, human, 3202 Clinical sciences, 130-nm albumin-bound paclitaxel, Gemcitabine, Pancreatic Neoplasms, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Interleukin-1 Receptor Accessory Protein, Deoxycytidine/therapeutic use
Description: 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.
Document Type: Article
Other literature type
Language: English
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-24-0645
Access URL: https://pubmed.ncbi.nlm.nih.gov/39385434
https://lirias.kuleuven.be/handle/20.500.12942/769085
https://doi.org/10.1158/1078-0432.ccr-24-0645
https://hdl.handle.net/2268/333840
https://doi.org/10.1158/1078-0432.CCR-24-0645
Rights: CC BY NC ND
URL: http://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
Accession Number: edsair.doi.dedup.....fe06f836a151dfd67594e9e40a5edb5c
Database: OpenAIRE
Description
Abstract: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.
ISSN:15573265
10780432
DOI:10.1158/1078-0432.ccr-24-0645