Cyclin-dependent kinase 4/6 inhibitors beyond progression in hormone receptor-positive, HER2-negative advanced breast cancer: a systematic review and meta-analysis (REIGNITE study)

Adding cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy (ET) is considered the first-line treatment of advanced HR-positive/HER2-negative breast cancer. However, with the recent approval of several additional targeted agents, the optimal treatment sequencing remains uncertain, and it is unclear whether the benefits of CDK4/6i extend beyond progression on first-line therapy. We conducted a systematic review and meta-analysis to evaluate the efficacy of CDK4/6i in the second-line setting after progression on CDK4/6i in the first line, with a particular focus on patients who had either PIK3CA or ESR1 mutation. We included randomized clinical trials (RCTs) comparing CDK4/6i combined with ET to ET alone in patients who experienced tumor progression on CDK4/6i treatment in the first-line setting. The results were pooled using a random-effects model with 95% confidence interval (CI). Five RCTs encompassing 1184 patients were included. Overall, CDK4/6i plus ET significantly improved progression-free survival (PFS) versus ET alone, yielding a hazard ratio of 0.73 (95% CI 0.56-0.94, P < 0.05), with a more prominent benefit in patients who switched the CDK4/6i (hazard ratio 0.61, 95% CI 0.48-0.77, P < 0.05). The benefit was consistent in patients with somatic PIK3CA mutations (hazard ratio 0.71, 95% CI 0.52-0.98, P < 0.05), and ESR1 mutations (hazard ratio 0.66, 95% CI 0.49-0.89, P < 0.05). The toxicity profile was compatible with the known side effects from CDK4/6i. Our results support the strategy of switching the CDK4/6i in the second-line setting and demonstrate persistent benefit even in patients with PIK3CA or ESR1 mutations.