# Continuing Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Advanced Breast Cancer: A Meta-Analysis

## TL;DR

This study finds that continuing CDK4/6 inhibitors beyond progression in advanced breast cancer provides modest benefits, with better outcomes when switching to a non-palbociclib CDK4/6i.

## Contribution

A meta-analysis revealing that switching CDK4/6 inhibitors after progression may improve outcomes more than continuing the same drug.

## Key findings

- Switching CDK4/6 inhibitors after progression is associated with better outcomes than continuing the same drug.
- Older patients, those without visceral metastases, and those with ESR1 mutations benefit more from continuing CDK4/6i beyond progression.
- Continuing palbociclib beyond progression is likely ineffective.

## Abstract

Advanced endocrine-driven breast cancer (i.e., cancer which is estrogen/progesterone receptor-positive and HER2-negative) is treated with targeted therapy, consisting of a cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) and endocrine therapy first, which is a highly effective and well-tolerated treatment. After the cancer stops responding to this strategy, some studies have evaluated continuing the same or switching to a different CDK 4/6i with/without a change in endocrine therapy, with mixed results. We sought to systematically review the evidence and then pool the data in a weighted manner to arrive at a conclusion. We found that this strategy results in modest improvement in outcomes, and certain subgroups (older patients, no chemotherapy, absence of any cancer involvement of the organs, certain mutations like ESR1 mutations, and non-use of palbociclib as the CDK4/6i) did better. This can help to inform clinical decision making and in choosing the right patient for this approach.

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.