Multicenter phase 3 trial of overall survival with first-line versus second-line CDK4/6 inhibitor use in advanced breast cancer

CDK4/6 inibitors (CDK4/6i) combined with endocrine therapy (ET) are widely used in HR-positive, HER2-negative advanced breast cancer (HR+ HER2- aBC). The multicenter phase 3 SONIA trial in The Netherlands evaluated the optimal timing of CDK4/6i administration, either in the first-line of second-line setting. Patients with HR+ HER2- aBC who did not receive prior treatment for aBC were randomized 1:1 to receive aromatase inhibitor plus CDK4/6i as first-line treatment followed by fulvestrant as second-line treatment (CDK4/6i first-line group; n=524) or aromatase inhibitor as first-line treatment followed by fulvestrant plus CDK4/6i as second-line treatment (CDK4/6i second-line group; n=526). First-line CDK4/6i use did not improve overall survival (OS) compared with second-line use (median, 47.9 months versus 48.1 months; p=0.24). A post hoc subgroup analysis suggested an OS benefit with first-line use in premenopausal patients (HR 0.53; 95% CI 0.32-0.87) but not in postmenopausal patients (1.00; 0.84-1.19; p for interaction = 0.01). First-line CDK4/6i use was associated with more grade 3 or higher adverse than second-line use. The authors conclude that first-line CDK4/6i use did not improve OS compared with second-line use but did increase treatment-related toxic effects, while post hoc analysis suggested an OS benefit with first-line use in premenopausal patients.