MiniReview of MONALEESA, PALOMA & CDK Inhibitors

Author: Tuan N. Tran, M.D., Ph.D., Department of Genomic Medicine, Family Hospital.

I. CDK4/6 Inhibitors in Breast Cancer:

CDK4/6 inhibitors have significantly improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by overcoming resistance to traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib, and abemaciclib. These inhibitors work by targeting the Cyclin Dependent Kinase 4 and 6 (CDK 4/6) pathway, which plays a crucial role in cell cycle regulation.

1. Palbociclib:
   • Mechanism: Selective CDK4/6 inhibitor.
   • Clinical Use: Approved for concurrent use with hormonal therapy based on the randomized phase III trial PALOMA.
   • Benefits: Improved progression-free survival (PFS) when combined with anti-estrogen therapy compared to monotherapy.
   • Unique Features: Statistically significant improvement in overall survival in the metastatic setting.
2. Ribociclib:
   • Mechanism: Another selective CDK4/6 inhibitor.
   • Clinical Use: Approved based on the MONALEESA trial.
   • Benefits: Similar improvements in PFS when combined with anti-estrogen therapy.
   • Unique Features: Differences in pharmacology, kinase targets, CNS penetration, and clinical activity as a single agent.
3. Abemaciclib:
   • Mechanism: Third CDK4/6 inhibitor.
   • Clinical Use: Approved based on the MONARCH studies.
   • Benefits: Comparable improvements in PFS.
   • Unique Features: Distinct pharmacological properties and clinical activity.

These agents have revolutionized the treatment landscape for patients with HR-positive, HER2-negative advanced breast cancer. Understanding their differences helps tailor treatment decisions for specific patient subgroups.

II. MONALEESAand PALOMAtrials:

1. MONALEESA Trials:
   • MONALEESA-3:
     • Population: Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.
     • Intervention: Ribociclib (CDK4/6 inhibitor) in combination with fulvestrant.
     • Results:
       • Overall Survival (OS): With a median follow-up of 70.8 months, patients receiving ribociclib plus fulvestrant had a longer OS (67.6 months) compared to placebo plus fulvestrant (51.8 months).
       • Other Benefits: Improved progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS).
       • Safety: No new safety signals observed.
     • Clinical Implications: Ribociclib continues to provide substantial benefit as a first-line treatment for HR+, HER2- advanced breast cancer.
   • MONALEESA-7:
     • Population: Pre- or perimenopausal women under the age of 59.
     • Intervention: Goserelin (endocrine therapy) with or without ribociclib.
     • Clinical Significance: Investigating the efficacy and safety of ribociclib in this younger patient population.
2. PALOMA Trials:
   • PALOMA-2:
     • Population: Postmenopausal women with ER+, HER2- metastatic breast cancer.
     • Intervention: Palbociclib (CDK4/6 inhibitor) in combination with letrozole.
     • Overall Survival (OS): With a median follow-up of 90 months, patients receiving palbociclib plus letrozole had numerically longer OS (53.9 months) compared to placebo plus letrozole (51.2 months), although not statistically significant.
     • Clinical Benefit: Palbociclib transformed the treatment landscape, improving the natural history of HR+ breast cancer.
   • PALOMA-3:
     • Population: Patients with advanced/metastatic HR+, HER2- breast cancer.
     • Intervention: Palbociclib plus fulvestrant.
     • Results: Demonstrated clinical benefit, including delayed time to chemotherapy, maintenance of quality of life, and consistent safety profile.

III. CONCLUSION:

These trials underscore the importance of CDK4/6 inhibitors in improving outcomes for patients with HR+, HER2- advanced breast cancer. While Overall Survival benefits may not always reach statistical significance, the overall impact on patient care remains substantial.

1. SOURCES:
2. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-overall-survival-results-phase-3-paloma-2
3. https://www.onclive.com/view/introduction-and-overview-of-the-monaleesa-7-trial.
4. https://ascopost.com/news/may-2022/updated-overall-survival-results-from-monaleesa-3-show-improved-overall-survival-in-patients-with-hr-positiveher2-negative-breast-cancer/.
5. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1810527?articleTools=true.
6. https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-023-01701-9.
7. Clinical & Pharmacologic Differences of CDK4_6 Inhibitors in BC. George M., et al., Front. Oncol., 12 July 2021, Sec. Breast Cancer, Volume 11 – 2021 | https://doi.org/10.3389/fonc.2021.693104.
8. Clinical considerations of CDK4_6 inhibitors in HER2 positive breast cancer. Cui Zhang, et al., Front. Oncol., 16 January 2024, Sec. Breast Cancer, Volume 13 – 2023 | https://doi.org/10.3389/fonc.2023.1322078.