Exceptional response to the ATR inhibitor, camonsertib, in a patient with ALT+ metastatic melanoma.

A key hallmark of cancer tumorigenesis is the maintenance of telomere length, which occurs canonically through the reactivation of telomerase. Alternative lengthening of telomeres (ALT) is an atypical, non-canonical telomere maintenance mechanism that uses homologous recombination (HR) to maintain telomere length and is associated with replication stress and defects in genome maintenance. In preclinical models, ALT positivity (ALT+) sensitizes tumor cells to ataxia telangiectasia and Rad3-related (ATR) inhibitors. Camonsertib is a novel potent, and highly selective ATR inhibitor that is synthetic lethal with genomic alterations affecting HR and DNA damage response (DDR). Here we describe a case of confirmed clinical and molecular response to pharmacological ATR inhibition through camonsertib, in a patient with ALT+ metastatic melanoma. To our knowledge, this is the first clinical report of synthetic lethal targeting of a confirmed ALT+ tumor with an ATR inhibitor.