Modeling the impact of CDK4 / 6 inhibitors on reducing cancer mortality

Background. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (abemaciclib, palbociclib, ribociclib) plus aromatase inhibitors (AI) are the modern standard-of-care of the first-line treatment of hormone-dependent (HR+) HER2-negative (HER2–) advanced breast cancer (ABC).

Aim. To evaluate the effects of using CDK4/6 inhibitors for treating patients with HR+/HER2– ABC on reducing overall cancer mortality in Russia.

Materials and methods. Proposed mathematical model describes duration of therapy and treatment outcomes for AI alone or in combination with CDK4/6 inhibitors in patients with HR+/HER2– ABC. The model was based on overall survival and progression-free survival data from clinical trials and matching-adjusted indirect comparison. Frequency of drug prescriptions in both current and forecast practices was derived from regional surveys. The model was used to estimate the number of lives saved and healthcare system costs when transitioning from current practice to the forecast one by 2030, considering the number of adult patients with HR+/HER2– ABC, who may start considered therapy annually in Russia.

Results. Annually, up to 10,794 patients with HR+/HER2– ABC in Russia are diagnosed and indicated for first-line therapy using CDK 4/6 inhibitors in combination with AI. However, 30 % of them are prescribed suboptimal AI monotherapy. Expanding CDK4/6 inhibitor usage in combination with AI to 83 % with the increase of using ribociclib and reallocating the prescription of drugs according to the forecast practice may lead to reduction in mortality from malignant neoplasms by 934 cases by 2030. Transitioning to the forecast therapy practice will require a 20 % increase in funding.

Conclusion. The use of CDK4/6 inhibitors in patients with HR+/HER2– ABC has a significant and quantifiable impact on reducing cancer-related mortality in Russia.

1. Malignant tumors in Russia in 2023 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow: Moskovskiy nauchno-issledovatelskiy onkologicheskiy institut im. P.A. Gertsena – filial FGBU “Natsionalnyy medicinskiy issledovatelskiy tsentr radiologii” Minzdrava Rossii, 2024. 276 p. (In Russ.).

2. Resolution of the Government of the Russian Federation No. 2161 of November 29, 2022. (In Russ.).

3. Clinical guidelines “Breast cancer”. 2021. Available at: https://cr.minzdrav.gov.ru/recomend/379. (In Russ.).

4. The state of oncological care for the population of Russia in 2023. Ed. by A.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow: Moskovskiy nauchno-issledovatelskiy onkologicheskiy institut im. P.A. Gertsena – filial FGBU “Natsionalnyy medicinskiy issledovatelskiy tsentr radiologii” Minzdrava Rossii, 2024. 262 p. (In Russ.).

5. Andrahennadi S., Sami A., Manna M. et al. Current landscape of targeted therapy in hormone receptor-positive and HER2-negative breast cancer. Curr Oncol 2021;28(3):1803–22. DOI: 10.3390/curroncol28030168

6. Elias A.D. Management of small T1a/bN0 breast cancers. American Society of Clinical Oncology Educational Book 2012;32(1):10–9.

7. Pan H., Gray R., Braybrooke J. et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 2017;377(19):1836–46. DOI: 10.1056/NEJMoa1701830

8. Chakraborty A., Kumar Bose Ch., Basak J. et al. Determinants of lymph node status in women with breast cancer: A hospital based study from eastern India. Indian J Med Res 2016;143(Suppl):S45–51. DOI: 10.4103/0971-5916.191761

9. Kolyadina I.V., Poddubnaya I.V., Pavlikova O.A. et al. Evolution of the neoadjuvant approach in primary resectable breast cancer in the last decade: a fashionable trend or real clinical practice. Sovremennaya onkologiya = Modern Oncology 2017;19(1):9–16. (In Russ.).

10. Sultanbaev A.V., Fatyhov R.I., Gladkov O.A. et al. Pharmacotherapy regimens for patients with hormone-receptor positive (HR+), human epidermal growth factor 2 negative (HER2–) metastatic breast cancer in routine clinical practice (results of non-interventional retrospective study). Meditsinskiy alfavit = Medical Alphabet 2022;(31):7–14. (In Russ.). DOI: 10.33667/2078-5631-2022-31-7-14

11. Perevodchikova N.I. Neoadjuvant therapy of patients with locally advanced inoperable breast cancer. Effektivnaya farmakoterapiya = Effective Pharmacotherapy 2012;34:21–5. (In Russ.).

12. Instructions for medical use of the drug Risarg. Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=1c78799f-78b4-4eb6-bcb9-3b081d786cb6&t=. (In Russ.).

13. Instructions for medical use of the drug Itulsi 13. Instructions for medical use of the drug Itulsi. Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=e28f2eb4-476d-4074-bd8d-8ee882fbdc27&t=. (In Russ.).

14. Instructions for medical use of the drug Zenlistik. Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=cfcecfd9-dc39-4b21-beb8-183f75f9cf2b&t=. (In Russ.).

15. Instructions for medical use of the drug Anastrozole. Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=359a40f4-38e0-4f35-b3ec-f55d39aabe44&t=. (In Russ.).

16. 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

17. Jhaveri K. Matching adjusted indirect comparison of PFS & OS comparing ribociclib + letrozole vs palbociclib + letrozole as firstline treatment of HR+/HER2– ABC: Analysis based on updated PFS & final OS results of MONALEESA-2 & PALOMA-2. Eur J Cancer 2022;175:S2, S3.

18. Finn R.S., Rugo H., Dieras V. et al. Overall survival (OS) with firstline 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. JCO 2022;40:LBA1003.

19. Hortobagyi G.N., Stemmer S.M., Burris H.A. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptorpositive, HER2-negative advanced breast cancer. Ann Oncol 2018;29(7):1541–7. DOI: 10.1093/annonc/mdy155

20. Avxentyev N.A., Zhuravleva M.V., Pazukhina E.M. et al. Pharmacoeconomic evaluation of ribociclib for the first-line treatment of HR-positive HER2-negative advanced breast cancer. Opukholi zhenskoy reproduktivnoy systemy = Tumors of female reproductive system 2018;15(2):21–35. (In Russ.).

21. Methodological recommendations for the use of mathematical modeling in clinical and economic research and research using budget impact analysis. Available at: https://rosmedex.ru/wpcontent/uploads/2020/07/mr-po-isp.matem.modelir.v-kei-i-issl.s-isp.-analiza-vliyan.na-byudzhet.pdf. (In Russ.).

22. Avxentyev N.A., Sisigina N.N., Frolov M.Yu., Makarov A.S. Assessment of the contribution of the use of modern antitumor drugs to achieving the goals of the federal project to combat cancer. Voprosy onkologii = Issues of Oncology 2021;67(6):768–76. (In Russ.).

23. Avxentyev N.A. Updated assessment of the impact of the use of modern drugs for the treatment of lung cancer on the key indicators of the Federal Project “Fight against cancer”. Voprosy onkologii = Issues of Oncology 2023;69(2). (In Russ.).

24. Ministry of Health of Russia. List of drugs. Available at: https://plp.minzdrav.gov.ru. (In Russ.).

25. Goetz M.P., Toi M., Huober J. et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2-advanced breast cancer: Final overall survival results of MONARCH 3. Ann Oncol 2024;35(8):718–27. DOI: 10.1016/j.annonc.2024.04.013

26. Avxentyev N.A., Andreyashkina N.A., Artamonova E.V. et al. Effectiveness of cyclin-dependent kinase 4 and 6 inhibitors for the treatment of hormone-sensitive HER2-negative metastatic breast cancer in first-line therapy: A systematic literature review. Opukholi zhenskoy reproduktivnoy systemy = Tumors of Female Reproductive System 2024;20(1):64–81. (In Russ.). DOI: 10.17650/1994-4098-2024-20-1-64-81

27. Goryainova A.Yu., Stukan A.I., Murashko R.A. et al. Evolution of the CDK4/6 inhibitor abemaciclib: From palliative to adjuvant therapy. Clinical experience with abemaciclib in patients with hormone receptor-positive HER2-negative breast cancer. Meditsinskiy sovet = Medical Council 2022;16(9):40–8. (In Russ.).

28. Goryainova A.Yu., Murashko R.A., Sharov S.V. et al. Analysis of regional clinical practice of using the CDK4/6 inhibitor ribociclib as a mechanism for integrating a research approach into the organization of drug provision. Meditsinskiy sovet = Medical Council 2023;17(11):119–31. (In Russ.). DOI: 10.21518/ms2023-201