Professor Man Li:  From Uncertainty to Definitive Evidence—PostMONARCH Study Proves the Benefit of Cross-Line Treatment with CDK4/6 Inhibitors| Man Talks Breast Cancer: ASCO Special

Editor's Note:  In this "Man Talks Breast Cancer: ASCO Special," Professor Man Li's team from The Second Affiliated Hospital of Dalian Medical University has selected the latest ASCO studies on HR+ advanced breast cancer, covering topics such as cross-line treatment with CDK4/6 inhibitors, novel ADCs combined with ICIs, and comparing CDK4/6 inhibitors + ET with chemotherapy in premenopausal women. These can provide more valuable insights for clinical practice.

Study Overview

Background CDK4/6 inhibitors (CDK4/6i) have become the standard for first-line treatment of HR+/HER2- metastatic breast cancer (MBC) and adjuvant intensive therapy for high-risk early breast cancer (EBC). Post-CDK4/6i treatment options are becoming increasingly precise, allowing for the selection of targeted drugs based on mutations such as PIK3CA, AKT, PTEN, ESR1, and BRCA1/2. Considering the solid efficacy data of CDK4/6 inhibitors and the differences between them, cross-line treatment with CDK4/6 inhibitors is a feasible option for patients without detectable mutations or those without conditions to detect mutations. Previous studies like MAINTAIN, PACE, and PALMIRA have shown mixed results, indicating that changing both endocrine therapy and CDK4/6 inhibitors after progression might be more reasonable. However, confirmation from phase III studies is needed.

Design and Results The postMONARCH study is a prospective, phase III, randomized controlled trial enrolling HR+/HER2- advanced breast cancer patients, including premenopausal, postmenopausal women, and men. Patients progressed after initial AI+CDK4/6i treatment or relapsed during or after adjuvant ET+CDK4/6i, and had not received other treatments in the advanced stage. The study involved 368 eligible patients from 16 countries across 96 medical centers, randomly assigned 1:1 to receive abemaciclib + fulvestrant or placebo + fulvestrant, with the primary endpoint being investigator-assessed PFS.

Approximately 62% of enrolled patients had visceral metastases, and nearly all had progressed after CDK4/6i treatment in the advanced stage. Of the patients, 70% had received CDK4/6i treatment for 1 year or more. In the primary analysis, abemaciclib improved PFS, reducing the risk of progression by 27% (HR: 0.73, 95% CI: 0.57-0.95), with median PFS of 6.0 months vs. 5.3 months (P=0.02).

Subgroup analysis showed consistent benefits across various groups, including age, visceral metastases, liver metastases, bone metastases, and different durations of prior CDK4/6i treatment. BICR-assessed PFS was 12.9 months vs. 5.6 months (HR 0.55, P=0.0004), with abemaciclib reducing the risk of progression or death by 45%. ORR was 17% vs. 7% by investigator assessment and 23% vs. 8% by BICR assessment. Key biomarker subgroups with ctDNA evaluation showed benefits regardless of ESR1, PIK3CA, or AKT1/PTEN mutations. Safety was consistent with known abemaciclib profiles, with low discontinuation rates.

Expert Commentary

1. Study Design Interpretation The postMONARCH study is the first and only phase III trial evaluating the benefit of switching CDK4/6 inhibitors after AI+CDK4/6i treatment progression. The significant improvement in PFS with abemaciclib plus fulvestrant provides high-quality evidence for cross-line treatment with CDK4/6 inhibitors. Despite a small absolute benefit in median PFS, the statistically significant HR value (0.73) and the comprehensive assessment over the entire observation period highlight the reliable benefit. BICR-assessed PFS showed even more substantial improvement, possibly due to discrepancies in investigator and BICR assessments.
2. Clinical Practice Interpretation Abemaciclib plus fulvestrant is a feasible treatment option for HR+/HER2- breast cancer patients progressing after AI+CDK4/6i, regardless of biomarker status. The study suggests that switching from palbociclib to abemaciclib or ribociclib after progression can benefit patients, whereas continuing palbociclib with a different endocrine partner may not be effective. The study’s results provide valuable insights for optimizing post-CDK4/6i treatment strategies, supporting the use of targeted therapies for detected mutations, and validating cross-line CDK4/6 inhibitor treatment for those without detectable targets or inaccessible drugs.