CDK4/6 Inhibitor Sequencing in the Metastatic Setting and Maintenance Strategies Following THP Induction

CDK4/6 inhibitor sequencing after adjuvant exposure presents complex decision-making challenges without robust supporting data. When patients experience progression following adjuvant CDK4/6 inhibitor therapy, the benefit of rechallenging with the same class in the metastatic setting remains uncertain. Clinical practice often involves switching between CDK4/6 inhibitors, such as moving from adjuvant abemaciclib to metastatic ribociclib, based on limited data from metastatic studies showing some benefit from continued CDK4/6 inhibition despite progression.

The timing of CDK4/6 rechallenge influences treatment decisions, with greater comfort when more than 12 months have elapsed since completion of adjuvant therapy, though some consideration may be given after 6 months. Supporting evidence comes from metastatic studies including MAINTAIN (showing benefit of switching from palbociclib to ribociclib), postMONARCH (demonstrating abemaciclib efficacy after prior CDK4/6 exposure), and Ember-3 data, though these studies primarily involved metastatic-to-metastatic sequencing rather than adjuvant-to-metastatic scenarios.

This knowledge gap highlights the need for novel targeted therapies, including CAT6 inhibitors, CDK2 inhibitors, and specific PI3K inhibitors, for patients with prior CDK4/6 exposure. The evolving understanding of tumor biology following CDK4/6 resistance, particularly in patients with endocrine-resistant disease, necessitates development of next-generation targeted approaches. Future research must address optimal sequencing strategies and identify predictive biomarkers to guide treatment selection for patients with CDK4/6 inhibitor–resistant disease.