Abstract 329P
Background
PDAC is characterized by a fibro-inflammatory tumor microenvironment (TME) in which oncogenic KRAS signaling and inflammatory pathways interact. Interleukin-1 (IL-1) signaling is a key component of that TME and also plays a role in chemotherapy induced peripheral neuropathy (CIPN). Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting IL1RAP, inducing ADCC of IL1RAP-expressing tumor cells and inhibiting tumor-promoting signals mediated by IL-1α/β. We present new analyses from the phase IIa CANFOUR trial highlighting the role of IL1RAP blockade by nadunolimab when combined with nab-paclitaxel and gemcitabine (GN) in previously untreated, unresectable, locally advanced or metastatic PDAC.
Methods
73 PDAC patients received nadunolimab at doses between 1 mg/kg and 7.5mg/kg in combination with GN. Tumor biopsies were available from 49 patients, allowing IL1RAP subgroup analysis as well as exploratory correlative analysis of KRAS mutation with IL-1 signalling. Relationship of dose and adverse events indicative of CIPN were investigated.
Results
Overall, median OS was 13.2 months (m), iPFS 7.2 m, ORR 33% and DCR 71%. All available tumors expressed IL1RAP, and patients with high IL1RAP expressing tumors showed more benefit compared to low IL1RAP tumors with median OS: 14.2 vs. 10.6 m, iPFS: 7.4 vs. 5.8 m and ORR: 48 vs. 30%. High IL1RAP tumor expression was also more beneficial in patients continuing on nadunolimab monotherapy after GN (OS 15.6 vs. 11.3 m high vs. low IL1RAP). This was also observed in late stage patients receiving nadunolimab as a single agent. In a subset of tumors for which KRAS was measured IL1α expression was higher in KRAS-mutated tumor cells than wild-type, suggesting signaling pathway crosstalk. Regarding safety and effects of IL1RAP blockade, only 1 of 73 patients reported a grade ≥ 3 peripheral neuropathy. The pooled 2.5-7.5 mg/kg dose groups compared to the 1 mg/kg dose group showed a lower incidence of any-grade CIPN; 36% vs 60% and a significantly longer time to onset; median not estimable vs 112 days.
Conclusions
Blockade of IL1RAP by nadunolimab may combine antitumor activity in the oncogenic KRAS signaling driven inflammatory TME of PDAC with reduction of CIPN.
Clinical trial identification
EUDRACT number 2017-001111-36; NCT03267316.
Legal entity responsible for the study
Cantargia AB.
Funding
Cantargia AB.
Disclosure
E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, Agenus, ALX, Arcus Biosciences, Astellas, AstraZeneca, Bayer, BeiGene, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm, Elmedix, Eisai, GSK, Hoopika Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Seattle Genetics, Servier, Simcere, Takeda, Taiho, Terumo; Financial Interests, Personal, Invited Speaker: Amgen, Pfizer. S. Ochsenreither: Financial Interests, Personal, Advisory Board: MSD, BMS, Janssen, Ipsen, Immunocore, Genemab, Pfizer; Financial Interests, Personal, Invited Speaker: MSD, Merck, Immunocore, Janssen; Financial Interests, Personal, Other, Support for travel/meeting: Janssen, Pfizer; Financial Interests, Personal, Invited Speaker, Patent of T-cell therapy target: Fred Hutchinson cancer Research Center. R.L. Eefsen: Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS. C. Rydberg-Millrud: Financial Interests, Personal, Full or part-time Employment: Cantargia; Financial Interests, Personal, Stocks/Shares: Cantargia. N. Losic: Financial Interests, Personal, Full or part-time Employment: Cantargia; Financial Interests, Personal, Stocks/Shares: Cantargia; Financial Interests, Personal, Leadership Role: Cantargia. D. Tersago: Financial Interests, Personal, Full or part-time Employment, Consultant: Cantargia; Financial Interests, Personal, Leadership Role: Cantargia. All other authors have declared no conflicts of interest.