Effectiveness of cyclin-dependent kinase 4 and 6 inhibitors for the treatment of hormonesensitive HER2-negative metastatic breast cancer in first-line therapy: A systematic literature review

At present, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib, and abemaciclib are widely used for the first-line treatment of locally advanced or metastatic breast cancer. However, direct comparisons of these treatment options in randomized studies have not been conducted.

Aim of the work is to gather and analyze published data on the comparative effectiveness of CDK4/6 inhibitors in combination with aromatase inhibitors in postmenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. A systematic review of publications presenting results from original studies on the impact of CDK4/6 inhibitor therapy in combination with aromatase inhibitors on the survival of patients was performed. Nineteen studies with original data on progression-free survival and overall survival were identified. None of the studies found significant differences between different CDK4/6 inhibitors and aromatase inhibitors in terms of progression-free survival. A statistically significant superiority of ribociclib over palbociclib in terms of overall survival was observed in a single matching-adjusted indirect comparison, while seven other studies of various types (real-world data studies, matching-adjusted indirect comparisons, and meta-analyses) did not find significant differences between the investigated drugs in terms of overall survival.

Currently, there is no compelling evidence of the superiority of one CDK4/6 inhibitor over others. The decision on the preference for a specific drug within the class can only be made after conducting direct randomized comparison trials, or accumulating sufficient real-world data on the use of palbociclib, ribociclib, and abemaciclib.

1. World Health Organization, International Agency for Research on Cancer. Breast. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf.

2. Breastcancer.org. Metastatic Breast Cancer. Available at: https://www.breastcancer.org/types/metastatic.

3. National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.

4. Food and Drug Administration. Palbociclib (IBRANCE). Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance.

5. Food and Drug Administration. Ribociclib (Kisqali). Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/ribociclib-kisqali.

6. Food and Drug Administration. FDA approves abemaciclib for HR-positive, HER2-negative breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-hr-positive-her2-negative-breast-cancer.

7. Food and Drug Administration. FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer. Available at: https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-abemaciclib-initialtherapy-hr-positive-her2-negative-metastatic-breast-cancer.

8. Finn R.S., Martin M., Rugo H.S. et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375(20):1925–36. DOI: 10.1056/NEJMoa1607303

9. Hortobagyi G.N., Stemmer S.M., Burris H.A. et al. Ribociclib as firstline therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375(18):1738–48. DOI: 10.1056/NEJMoa1609709

10. Johnston S., Martin M., Di Leo A. et al. MONARCH 3 final PFS: A randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019;17:5. DOI: 10.1038/s41523-018-0097-z

11. Hortobagyi G.N., Stemmer S.M., Burris H.A. et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 2022;386(10):942–50. DOI: 10.1056/NEJMoa2114663.

12. Finn R.S., Boer K., Bondarenko I. et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat 2020;183(2):419–28. DOI: 10.1007/s10549-020-05755-7

13. Finn R.S., Rugo H.S., Dieras V.C. et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL + LET) versus placebo plus letrozole (PBO + LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2- ABC): Analyses from PALOMA-2. J Clin Oncol 2022;40(17 Suppl):LBA1003. DOI: 10.1200/JCO.2022.40.17_suppl.LBA1003

14. The ASCO Post. Abemaciclib Plus AI in Postmenopausal Patients With Advanced Breast Cancer: Final Overall Survival Analysis From MONARCH 3. Available at: https://ascopost.com/news/december-2023/abemaciclib-plus-ai-in-postmenopausal-patientswith-advanced-breast-cancer-final-overall-survival-analysisfrom-monarch-3/.

15. Kahraman S., Erul E., Seyyar M. et al. Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptorpositive/HER2-negative metastatic breast cancer. Future Oncol 2023;19(10):727–36. DOI: 10.2217/fon-2022-1287

16. Cejuela M., Gil-Torralvo A., Castilla M.A. et al. Abemaciclib, palbociclib, and ribociclib in real-world data: A direct comparison of first-line treatment for endocrine-receptor-positive metastatic breast cancer. Int J Mol Sci 2023;24(10):8488. DOI: 10.3390/ijms24108488

17. Queiroz M.M., Sacardo K.P., Ribeiro M.F. et al. Real-world treatment outcomes in HR+ HER2– metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil. Cancer Treat Res Commun 2023;35:100683. DOI: 10.1016/j.ctarc.2023.100683

18. Cabetas M.G.-T., Martinez P.L., Nacher I.J. et al. Real-world experience of palbociclib and ribociclib: Novel oral therapy in metastatic breast cancer. Int J Clin Pharm 2021;43(4):893–9. DOI: 10.1007/s11096-020-01193-z

19. Buller W., Pallan L., Chu T., Khoja L. CDK4/6 inhibitors in metastatic breast cancer, a comparison of toxicity and efficacy across agents in a real-world dataset. J Oncol Pharm Pract 2023;29(8):1825–35. DOI: 10.1177/10781552231163121

20. Ganguly S., Mukherjee N., Mandal S. et al. Efficacy of cyclindependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: A single institutional study from India. Ecancermedicalscience 2022;16:1450. DOI: 10.3332/ecancer.2022.1450

21. Miron A.I., Anghel A.V., Barnonschi A.A. et al. Real-world outcomes of CDK4/6 inhibitors treatment in metastatic breast cancer in Romania. Diagnostics (Basel) 2023;13(11):1938. DOI: 10.3390/diagnostics13111938

22. Tremblay G., Chandiwana D., Dolph M. et al. Matching-adjusted indirect treatment comparison of ribociclib and Palbociclib in HR+, HER2– advanced breast cancer. Cancer Manag Res 2018;10:1319–27. DOI: 10.2147/CMAR.S163478

23. Jhaveri K., O’Shaughnessy J., Fasching P. et al. Matching adjusted indirect comparison of PFS & OS comparing ribociclib + letrozole vs palbociclib + letrozole as first-line treatment of HR+/HER2-ABC: Analysis based on updated PFS & final OS results of MONALEESA-2 & PALOMA-2. Eur J Cancer 2022;175(Suppl 1):2–3. DOI: 10.1016/S0959-8049(22)01353-3

24. Zhao J.J., Fong K.Y., Chan Y.H. et al. Indirect treatment comparison of first-line CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- metastatic breast cancer. Cancers (Basel) 2023;15(18):45–58. DOI: 10.3390/cancers15184558

25. Ayyagari R., Tang D., Patterson-Lomba O. et al. Progression-free survival with first-line endocrine-based therapies among postmenopausal women with HR+/HER2– metastatic breast cancer: A network meta-analysis. Clin Ther 2018;40(4):628–39. DOI: 10.1016/j.clinthera.2018.03.004

26. Zhang T., Feng F., Zhao W. et al. Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: A network meta-analysis. Onco Targets Ther 2018;11:2647–56. DOI: 10.2147/OTT.S165681

27. Giuliano M., Schettini F., Rognoni C. et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: A systematic review and network meta-analysis. Lancet Oncol 2019;20(10):1360–9. DOI: 10.1016/S1470-2045(19)30420-6

28. Petrelli F., Ghidini A., Pedersini R. et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: An adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat 2019;174(3):597–604. DOI: 10.1007/s10549-019-05133-y

29. El Rassy E., Bakouny Z., Assi T., Kattan J. Different inhibitors for the same target in metastatic luminal breast cancer: Is there any difference? Future Oncol 2018;14(9):891–5. DOI: 10.2217/fon-2017-0532

30. Xie N., Qin T., Ren W. et al. Efficacy and safety of cyclindependent kinases 4 and 6 inhibitors in HR+/HER2– advanced breast cancer. Cancer Manag Res 2020;12:4241–50. DOI: 10.2147/CMAR.S254365

31. Liu S., Sun X., Xu X., Lin F. Comparison of endocrine therapies in hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: A network meta-analysis. J Breast Cancer 2020;23(5):460–83. DOI: 10.4048/jbc.2020.23.e55

32. Liu Y., Wu J., Ji Z. et al. Comparative efficacy and safety of dif-ferent combinations of three CDK4/6 inhibitors with endocrine therapies in HR+/HER2– metastatic or advanced breast cancer patients: A network meta-analysis. BMC Cancer 2023;23(1):816. DOI: 10.1186/s12885-023-11322-2

33. Zeng N., Han J., Liu Z. et al. CDK4/6 inhibitors in the first-line treatment of postmenopausal women with HR+/HER2– advanced or metastatic breast cancer: An updated network meta-analysis and cost-effectiveness analysis. Cancers (Basel) 2023;15(13):3386. DOI: 10.3390/cancers15133386

34. Finn R.S., Crown J.P., Lang I. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 2015;16(1):25–35. DOI: 10.1016/S1470-2045(14)71159-3

35. Tripathy D., Im S.A., Colleoni M. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 2018;19(7):904–15. DOI: 10.1016/S1470-2045(18)30292-4