LAUSR

Abstract Background NOX-A12 is an inhibitor of the chemokine CXCL12 which prevents receptor engagement and blocks the formation of chemotactic CXCL12 concentration gradients. The Opera study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination with pembrolizumab in metastatic microsatellite-stable (MSS) colorectal (CRC) and pancreatic (PaC) cancer where PD-1 inhibition alone has not shown clinical benefit. Methods Patients received 300 mg NOX-A12 twice weekly during a 2-week monotherapy phase. Biopsies were taken from liver metastases before and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In a combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. Results 11 of the patients had CRC and 9 PaC. All patients were heavily pretreated with 5 (CRC) and 3 median lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for 95% of patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. At baseline, mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. 2 weeks of NOX-A12 monotherapy induced Th1 cytokines (IFNγ, IL-2, IL-16) in approx. half of the patients. Although there were no objective responses, 25% of patients achieved stable disease; 7 patients showed prolonged time on treatment vs. the prior line of therapy. Median progression-free survival was 1.87 months, overall survival was 42% at 6 months and 19% at 12 months. Conclusions In patients with MSS metastatic PaC and CRC cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Clinical trial identification NCT03168139. Legal entity responsible for the study The authors. Funding NOXXON Pharma AG. Disclosure N. Halama: Research grant / Funding (institution): NOXXON Pharma AG; Shareholder / Stockholder / Stock options, Officer / Board of Directors: Navitect Bio. A. Froemming: Full / Part-time employment: NOXXON Pharma AG. D. Beyer: Full / Part-time employment: NOXXON Pharma AG. D. Eulberg: Full / Part-time employment, Officer / Board of Directors: NOXXON Pharma AG. J.U. Jungnelius: Full / Part-time employment, Officer / Board of Directors: NOXXON Pharma AG. A. Mangasarian: Full / Part-time employment, Officer / Board of Directors: NOXXON Pharma AG. All other authors have declared no conflicts of interest.