613P - Phase I/II study with CXCL12 inhibitor NOX-A12 and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer

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. Patients received 300mg 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 300mg NOX-A12 and 200mg pembrolizumab until progression or intolerable toxicity. 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. 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. NCT03168139. The authors. NOXXON Pharma AG. 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 emp