Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer.
Van Cutsem, Eric; Collignon, Joëlle; Eefsen, Rikke Let al.
2024 • In Clinical Cancer Research, 30 (23), p. 5293 - 5303
Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced:Metastatic Pancreatic Cancer.pdf
[en] [en] 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.
Disciplines :
Oncology
Author, co-author :
Van Cutsem, Eric ; University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium
Collignon, Joëlle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Eefsen, Rikke L ; Herlev og Gentofte Hospital, Herlev, Denmark
Ochsenreither, Sebastian ; Department of Hematology, Oncology and Tumor Immunology, Charité Comprehensive Cancer Center, Berlin, Germany
Zvirbule, Zanete ; Riga East Clinical University Hospital, Riga, Latvia
Ivanauskas, Audrius ; Lithuanian University of Health Sciences, Kaunas, Lithuania
Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer.
Publication date :
02 December 2024
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research Inc., United States
Van Cutsem E, Collignon J, Eefsen R, Ochsenreither S, Zvirbule Z, Ivanauskas A, et al. Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel. Cancer Res 2023; 83(Suppl 7):2172.
Genotype-Tissue Expression (GTEx) Project Portal. [cited 2020 Nov 2]. Available from: https://gtexportal.org/home/.
National Cancer Institute. Center for cancer genomics. The Cancer Genome Atlas program (TCGA). [cited 2020 Nov 2]. Available from https://www. cancer.gov/ccg/research/genome-sequencing/tcga.
Zhang Y, Chen X, Wang H, Gordon-Mitchell S, Sahu S, Bhagat TD, et al. Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer. J Hematol Oncol 2022; 15:70.
Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 2013; 39:1003-18.
Mantovani A, Barajon I, Garlanda C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev 2018; 281:57-61.
Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, et al. Tumor-stroma il1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res 2018; 78:1700-12.
Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, et al. IL1-Induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov 2019; 9:282-301.
Dosch AR, Singh S, Dai X, Mehra S, Silva IDC, Bianchi A, et al. Targeting tumor-stromal IL6/STAT3 signaling through IL1 receptor inhibition in pancreatic cancer. Mol Cancer Ther 2021; 20:2280-90.
Zhang D, Li L, Jiang H, Knolhoff BL, Lockhart AC, Wang-Gillam A, et al. Constitutive IRAK4 activation underlies poor prognosis and chemoresistance in pancreatic ductal adenocarcinoma. Clin Cancer Res 2017; 23: 1748-59.
Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 2012; 21:105-20.
Das S, Shapiro B, Vucic EA, Vogt S, Bar-Sagi D. Tumor cell-derived IL1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res 2020; 80:1088-101.
Zhuang Z, Ju HQ, Aguilar M, Gocho T, Li H, Iida T, et al. IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-κB activation. Clin Cancer Res 2016; 22:1432-44.
Fields JK, Kihn K, Birkedal GS, Klontz EH, Sjöström K, Günther S, et al. Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor. Front Immunol 2021; 12:779100.
Rydberg Millrud C, Deronic A, Gronberg C, Jaensson Gyllenback E, von Wachenfeldt K, Forsberg G, et al. Blockade of IL-1alpha and IL-1beta signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer Immunol Immunother 2023; 72:667-78.
Gottschlich A, Endres S, Kobold S. Therapeutic strategies for targeting IL-1 in cancer. Cancers (Basel) 2021; 13:477.
Bengtsson A, Andersson R, Ansari D. The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data. Sci Rep 2020; 10:16425.
National Cancer Institute. Surveillance, epidemiology, and end results program. Cancer Stat Facts: Pancreatic Cancer. [cited 2024 Jan 22]. Available from: https://seer.cancer.gov/statfacts/html/pancreas.html.
Robbrecht D, Jungels C, Sorensen MM, Spanggaard I, Eskens F, Fretland SØ, et al. First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer 2022; 126:1010-7.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-47.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369:1691-703.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364:1817-25.
Wainberg ZA, Melisi D, Macarulla T, Pazo-Cid R, Chandana SR, De La Fouchardiere C, et al. NAPOLI-3: a randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol 2023; 41(Suppl 4):LBA661.
Wainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardière C, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 2023; 402:1272-81.
Pishvaian MJ, Bender RJ, Halverson D, Rahib L, Hendifar AE, Mikhail S, et al. Molecular profiling of patients with pancreatic cancer: initial results from the Know Your Tumor initiative. Clin Cancer Res 2018; 24:5018-27.
Van Cutsem E, Abdilleh K, Datta J, Hidalgo M, Rydberg Millrud C, Skoog P, et al. Interleukin-1 receptor accessory protein (IL1RAP) overexpression is associated with worse prognosis in PDAC and is targetable by nadunolimab. AACR Special Conference. 2023 [cited 2024 May 06]. Available from: https://cantargia.com/en/research-development/publications.
Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci 2011; 48:155-70.
Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 2018; 15:234-48.
Tiainen L, Hämäläinen M, Luukkaala T, Tanner M, Lahdenperä O, Vihinen P, et al. Low plasma IL-8 levels during chemotherapy are predictive of excellent long-term survival in metastatic breast cancer. Clin Breast Cancer 2019; 19: e522-33.
Limpakan Yamada S, Wongsirisin P, Yodkeeree S, Chakrabandhu B, Chongruksut W, Limtrakul Dejkriengkraikul P. Interleukin-8 associated with chemosensitivity and poor chemotherapeutic response to gastric cancer. J Gastrointest Oncol 2019; 10:1120-32.
Fousek K, Horn LA, Palena C. Interleukin-8: a chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther 2021; 219:107692.
Kan M, Imaoka H, Watanabe K, Sasaki M, Takahashi H, Hashimoto Y, et al. Chemotherapy-induced neutropenia as a prognostic factor in patients with pancreatic cancer treated with gemcitabine plus nab-paclitaxel: a retrospective cohort study. Cancer Chemother Pharmacol 2020; 86: 203-10.
Roviello G, Ramello M, Catalano M, D'Angelo A, Conca R, Gasperoni S, et al. Association between neutropenia and survival to nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer. Sci Rep 2020; 10: 19281.
Iwai N, Okuda T, Sakagami J, Harada T, Ohara T, Taniguchi M, et al. Neutrophil to lymphocyte ratio predicts prognosis in unresectable pancreatic cancer. Sci Rep 2020; 10:18758.
Zhou Y, Wei Q, Fan J, Cheng S, Ding W, Hua Z. Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: a meta-analysis containing 8252 patients. Clin Chim Acta 2018; 479:181-9.
Al-Mazidi S, Alotaibi M, Nedjadi T, Chaudhary A, Alzoghaibi M, Djouhri L. Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy. Eur J Pain 2018; 22:810-21.
