Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the CDK4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of HR+/HER2- advanced breast cancer. Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in advanced breast cancer to date, we identified potential biomarkers of response to ribociclib.

PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival was performed to identify potential biomarkers of response to ribociclib.

RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater progression-free survival benefit with ribociclib vs placebo. Patients with high tumour mutational burden and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib vs placebo.

CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted.