Ceralasertib plus durvalumab in melanoma progressed on anti-PD-1 treatment

Modulating the DNA damage response (DDR) and repair pathways is a promising strategy to boost cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related, which is crucial to the DDR. This phase 2 trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma (MM) who had failed anti-PD-1 therapy. Among a total of 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Median progression-free survival was 7.1 months (95% confidence interval [CI], 3.6-10.6), and median overall survival was 14.2 months (95% CI, 9.3-19.1). Common adverse events were largely hematologic, and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to study treatment. We conclude that ceralasertib in combination with durvalumab had promising anti-tumor activity in patients with MM after failing anti-PD1 therapy, a population of unmet need.