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. 2024 Dec 2;30(23):5293-5303.
doi: 10.1158/1078-0432.CCR-24-0645.

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

Eric Van Cutsem  1 , Joelle Collignon  2 , Rikke L Eefsen  3 , Sebastian Ochsenreither  4 , Zanete Zvirbule  5 , Audrius Ivanauskas  6 , Dirk Arnold  7 , Edita Baltruskeviciene  8 , Per Pfeiffer  9 , Jeffrey Yachnin  10 , Susanne Magnusson  11 , Camilla Rydberg Millrud  11 , Annika Sanfridson  11 , Nedjad Losic  11 , Ignacio Garcia-Ribas  11 , Dominique Tersago  11 , Ahmad Awada  12
Affiliations

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

Eric Van Cutsem et al. Clin Cancer Res. .

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.

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Conflict of interest statement

E. Van Cutsem reports personal fees from Cantargia AB during the conduct of the study, as well as personal fees from AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas, AstraZeneca, Bayer, BeiGene, Bexon Clinical, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm, ElmediX, Eisai, Galapagos, GSK, Hookipa Biotech, Incyte, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Simcere, Takeda, Taiho, and Terumo outside the submitted work. S. Ochsenreither reports other support from Cantargia AB during the conduct of the study, as well as personal fees from MSD, Bristol Myers Squibb, Pfizer, Janssen, Merck, and Immunocore and grants from Bayer outside the submitted work. D. Arnold reports personal fees from Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, Astellas, Arcus Biosciences, Servier, Takeda, Taiho, Janssen, Daiichi Sankyo, Boston Scientific, GSK, and various CME Providers outside the submitted work. E. Baltruskeviciene reports personal fees from Cantargia AB during the conduct of the study, as well as personal fees and other support from Servier and personal fees from Amgen, Roche, Takeda, and MSD outside the submitted work. S. Magnusson reports employment with Cantargia AB and ownership of stock in Cantargia AB. C. Rydberg Millrud reports employment with Cantargia AB and ownership of stock in Cantargia AB. A. Sanfridson reports employment with Cantargia AB and ownership of stock in Cantargia AB. N. Losic reports employment with Cantargia AB and ownership of stock in Cantargia AB. I. Garcia-Ribas reports personal fees and other support from Cantargia AB during the conduct of the study, as well as personal fees from Oncomatryx, Shionogi, and Zumutor Biologics outside the submitted work. D. Tersago reports personal fees and other support from Cantargia AB during the conduct of the study. A. Awada reports personal fees and other support from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Genomic Health, Ipsen, Leo Pharma, Eli Lilly and Company, Merck, MSD, Novartis, Pfizer, and Seattle Genetics, other support from Hengrui, Innate, and Menarini, personal fees from Hikma, and grants from Bristol Myers Squibb and Roche outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Study design.
Figure 2.
Figure 2.
OS and iPFS (months; mITT population). mITT population, modified intention-to-treat population.
Figure 3.
Figure 3.
Baseline tumor IL1RAP expression is associated with deeper and more durable response to nadunolimab and GN. Screening biopsies, archival or study specific, were collected from 49 patients and stained for IL1RAP by IHC. A, Representative images are shown of IL1RAP-positive tumor cells (left), cancer-associated fibroblasts (center), and infiltrating immune cells (right). B, Tumor cell expression of IL1RAP was quantified by H-score and the distribution plotted; IL1RAP high was defined as ≥150 and IL1RAP low as <150. Representative images of tumor sections with low and high IL1RAP H-score are shown. C, The correlation between IL1RAP expression and OS was analyzed with a Kaplan–Meier analysis and IL1RAP-high and IL1RAP-low subgroups compared using the log-rank test. D, Clinical responses in the IL1RAP-high and IL1RAP-low groups were visualized in a waterfall (top) and a swimmer plot (bottom). iCPD, immune confirmed progressive disease; iPR, immune partial response; iSD, immune stable disease; iUPD, immune unconfirmed progressive disease.
Figure 4.
Figure 4.
Lower baseline CRP and a decrease in IL8 and CA 19-9 while on treatment with nadunolimab plus GN predict prolonged OS. Serum samples were collected from all patients before start of treatment (baseline) and throughout the study. CRP and CA 19-9 levels were analyzed at local laboratories, IL8 by MSD at a central laboratory, and OS compared using the Kaplan–Meier method. A, Baseline CRP (n = 73) was divided according to the median. Low baseline CRP is a prognostic biomarker for OS. B, Lowest IL8 post-baseline value during the first 50 days (nadir) was divided with the baseline IL8 value (nadir/baseline ratio; n = 69). The nadir/baseline ratio was divided on the median into two groups corresponding to those with an increase in IL8 levels and those with a decrease. IL8 reduction by nadunolimab and GN was associated with a significantly prolonged OS. C, There were 16 patients (24% of 67 patients with baseline CA 19-9) who had ≥90% decrease in CA 19-9 from baseline over the study period. A ≥90% decrease in CA 19-9 was associated with significantly prolonged survival.
See this image and copyright information in PMC

References

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