Dr Posner on the Mechanism of Action of Danivatirsen in HNSCC

Marshall Posner, MD, professor of medicine, director, Head and Neck Medical Oncology, associate director, Center for Personalized Cancer Therapeutics, co-leader, Cancer Clinical Investigation Program, Tisch Cancer Institute, discusses the mechanism of action of danvatirsen (AZD9150) in recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC).

Danvatirsen is a 16-nucleotide, generation 2.5 antisense oligonucleotide designed to down-regulate the expression of human STAT3 mRNA, Posner states. Following intravenous administration, the stabilized antisense oligonucleotide travels through the bloodstream and enters cells, he details. There, it binds to mRNA, which is particularly expressed in tumors, thereby blocking the production of the STAT3 protein in both normal and tumor cells, he explains.

STAT3 is ubiquitously expressed in various tissues throughout the body, Posner continues. When expressed in tumor cells, it plays a critical role in promoting an immuno-suppressive microenvironment and the survival of tumor cells, he says, adding that this protein also promotes the growth of the tumor through angiogenesis and reduction of pro-inflammatory cytokines.

Accordingly, the administration of danvatirsen is designed to reduce the supportive infrastructure of the tumor that is not malignant, and to directly attack the tumor cells by inhibiting the production of cytokines and other factors that promote tumor growth, Posner explains. It function is similar to that of a bispecific antibody, as it promotes tumor suppression through cytokine inhibition and enhances tumor immunity by improving the immune milieu around the tumor, he notes.

The ongoing phase 2 PEMDA-HN study (NCT05814666) is evaluating the addition of danvatirsen to pembrolizumab (Keytruda) in patients with recurrent and/or metastatic HNSCC with PD-L1–positive disease. The study will include approximately 81 patients who will receive danvatirsen at either 3 mg/kg on days 1, 3, and 5 of week 1, then 3 mg/kg once per week thereafter, plus pembrolizumab 200 mg once every 3 weeks; or pembrolizumab monotherapy at 200 mg once every 3 weeks. The study's primary end point is investigator-assessed overall response rate per RECIST 1.1 criteria.