Abstract
Background: The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression are variable. Here, we report a pooled analysis of this strategy. Methods: A systematic review identified reports of both observational and clinical studies, which evaluated the continuation of CDK4/6i beyond progression. The mean overall response rate (ORR) and progression-free survival (PFS) weighted by the study sample size were calculated. Meta-regression comprising linear regression weighted by the sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and the benefit from continuing CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Results: Thirteen studies comprising 1530 patients were included. The median age was 58 years, 50.8% had visceral metastases, and 48% had ESR1 mutations; the median lines of prior therapies were 1 (range 1-5), and 96.3% received palbociclib as the initial CDK4/6i. Eight studies tested a CDK4/6i switch as the intervention. The median PFS was 5.3 months, and the ORR was 14%. In randomized studies, statistically significant differences were observed between CDK4/6i continuation and control, although it is uncertain whether the magnitude of the effect is clinically meaningful. Increasing age, lack of prior chemotherapy, no visceral metastasis or ESR1 mutations, and a switch to a non-palbociclib CDK4/6i were associated with better outcomes. Conclusion: Continuing a CDK 4/6i + ET beyond progression yields modest benefits. Switching CDK4/6i likely results in improved ORR and PFS. Continuing palbociclib beyond progression is likely ineffectual.