1012P - Safety, tolerability, and efficacy of nadunolimab in combination with pembrolizumab in patients with solid tumors

Background

Lack of response or treatment resistance to checkpoint inhibitors can be caused by profound immunosuppression from myeloid cells within the tumor microenvironment. Interleukin-1 Receptor Accessory Protein (IL1RAP) plays a pivotal role in IL-1 signaling and is expressed on tumor cells and infiltrating cells, regulating their activity. Nadunolimab, a fully humanized ADCC-enhanced antibody, targets IL1RAP and blocks IL-1α/β signaling. Here, we investigated nadunolimab with pembrolizumab in patients with solid tumors.

Methods

The Phase 1b trial enrolled patients with metastatic/locally advanced cancers that had progressed after ≥3 months of PD-(L)1 inhibitor-containing therapy. Patients received 5 mg/kg nadunolimab in combination with pembrolizumab. Primary objective was safety. Additional objectives included assessment of biomarkers and anti-tumor response using iRECIST.

Results

15 patients with stage IV cancer were enrolled: 9 HNSCC, 5 NSCLC and 1 melanoma. There was 1 DLT: G3 febrile neutropenia; only one G3 AE (dysphagia) was reported in > 1 patient. Responses included 1 PR (in HNSCC, DoR of 17.4 mo), 8 SD and 6 PD. Median iPFS was 3.4 mo (95% CI 1.4–8.6), median OS was 19.7 mo (95% CI 4.3–28.7) and 1-year survival 67%. There were no apparent differences between responses in NSCLC or HNSCC patients. IL1RAP was expressed on tumor, stroma and immune cells at screening in 11/12 available tumor biopsies. PD-L1 was detected on tumor (7/11 biopsies) and immune cells (9/11 biopsies). IL1RAP or PD-L1 expression was not consistently altered by treatment. Interestingly, patients with high levels of NKp46⁺ NK cells and CD163⁺ macrophages in the tumor had significantly longer survival, consistent with the mechanism of action of nadunolimab (targeting myeloid immune suppression and inducing ADCC). Additionally, these patients showed reduced on-treatment levels of circulating IL-6, a downstream effector of IL-1.

Conclusions

Nadunolimab with pembrolizumab was safe and well tolerated in patients with advanced solid tumors. Prolonged survival was observed in a subset of patients with a distinct biomarker profile. The results support further development of nadunolimab in combination with PD-(L)1 inhibitor therapy.

Clinical trial identification

NCT04452214; June 30, 2020.

Editorial acknowledgement

Legal entity responsible for the study

Cantargia AB.

Funding

Cantargia AB.

Disclosure

R. Cohen: Financial Interests, Institutional, Funding: Innate Pharma, Xencor, AstraZeneca, F-Star Biotechnology, Chugai Pharma, Cantargia; Financial Interests, Personal, Advisory Role: Ono Pharmaceutical, Actuate Therapeutics. S. Jauhari: Financial Interests, Personal, Full or part-time Employment: Merus NV. A. Jimeno: Financial Interests, Personal, Speaker, Consultant, Advisor: Bluedot Bio, Purple Biotech; Financial Interests, Institutional, Local PI: Cantargia AB, DebioPharm, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, SQZ. L. Sun: Financial Interests, Personal, Advisory Board: Sanofi Genzyme, Regeneron, GenMab, Seagen; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Institutional, Local PI: Blueprint, Seagen, IO Biotech, Erasca. M. Wallen Öhman, A. Sanfridson, N. Losic: Financial Interests, Personal, Full or part-time Employment: Cantargia AB; Financial Interests, Personal, Stocks/Shares: Cantargia AB. D. Tersago: Financial Interests, Personal, Speaker, Consultant, Advisor: Cantargia AB. All other authors have declared no conflicts of interest.