Влияние ингибиторов CDK4/6 на общую выживаемость пациенток с распространенным HR+/HER2- РМЖ во всей популяции и в особых клинических подгруппах неблагоприятного прогноза

Гречухина К.С., Калугин М.В., Просвирнов А.А., Сухова М.В., Жукова Л.Г. Влияние ингибиторов CDK4/6 на общую выживаемость пациенток с распространенным HR+/HER2- РМЖ во всей популяции и в особых клинических подгруппах неблагоприятного прогноза. Современная Онкология. 2023;25(1):55–62.
DOI: 10.26442/18151434.2023.1.202180

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Grechukhina KS, Kalugin MV, Prosvirnov AA, Sukhova MV, Zhukova LG. The effect of CDK4/6 inhibitors on the overall survival in patients with advanced HR+/HER2- BC in the entire population and in special clinical subgroups of unfavorable prognosis: A review. Journal of Modern Oncology. 2023;25(1):55–62.
DOI: 10.26442/18151434.2023.1.202180

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Аннотация

Увеличение медианы выживаемости без прогрессирования при использовании ингибиторов циклин-зависимых киназ 4/6 в комбинации с ингибиторами ароматазы привело к большим ожиданиям от анализа общей выживаемости пациенток с HR+/HER2- метастатическим раком молочной железы. По трем препаратам группы окончательные данные получены в исследованиях MONALEESA-2 и PALOMA-2, при этом статистически значимая разница в медиане общей выживаемости достигнута только при использовании рибоциклиба. В обзоре проанализированы возможные факторы, которые могли повлиять на финальные результаты представленных исследований, а также влияние рибоциклиба на общую выживаемость в клинически неблагоприятных прогностических подгруппах (например, среди пациентов с висцеральными метастазами) и на выживаемость без прогрессирования в зависимости от экспрессии молекулярно-генетических факторов, ухудшающих выживаемость (Rb, p16, Ki-67, CDKN2A, CCND1, ESR1). Комбинация рибоциклиба и ингибиторов ароматазы доказала свое преимущество в терапии пациенток с HR+/HER2- метастатическим раком молочной железы с точки зрения увеличения выживаемости без прогрессирования и общей выживаемости. Доказана эффективность в подгруппах с клиническими и молекулярными неблагоприятными прогностическими факторами.

Ключевые слова: рак молочной железы, iCDK4/6, рибоциклиб, палбоциклиб, висцеральные метастазы, прогностические факторы

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An increase in the median progression-free survival when using cyclin-dependent kinase 4/6 inhibitors in combination with aromatase inhibitors led to high expectations from the analysis of the overall survival of patients with HR+/HER2- metastatic breast cancer. Of the three drugs in the group, the final data were obtained in the MONALEESA-2 and PALOMA-2 studies, while a statistically significant difference in median overall survival was achieved only with the use of ribociclib. The review discusses possible factors that could affect the final results of the presented studies. The effect of ribociclib on the value of OS in clinically unfavorable prognostic subgroups (for example, patients with visceral metastases) and on progression-free survival depending on the expression of molecular genetic factors that worsen patient survival (such as Rb, p16, Ki-67, CDKN2A, CCND1, ESR1) was analyzed.The combination of ribociclib and aromatase inhibitors has proven to be an advantage in the treatment of patients with HR+/HER2- metastatic breast cancer in terms of increasing both progression-free survival and overall survival. Efficacy has been proven in subgroups with clinical and molecular adverse prognostic factors.

Keywords: breast cancer, iCDK4/6, ribociclib, palbociclib, visceral metastases, prognostic factors

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30. Sutherland RL, Watts CK, Musgrove EA. Cyclin gene expression and growth control in normal and neoplastic human breast epithelium. J Steroid Biochem Mol Biol. 1993;47(1-6):99-106. DOI:10.1016/0960-0760(93)90062-2
31. Neven P, Petrakova K, Bianchi GV, et al. Ribociclib (RIB) + fulvestrant (FUL) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-3 biomarker analyses. Ann Oncol. 2018;29(Suppl. 8):viii113-114. DOI:10.1093/annonc/mdy272.336
32. Lu YS, Hurvitz SA, Su F, et al. In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial. J Clin Oncol. 2019;37:1018. DOI:10.1200/JCO.2019.37.15_suppl.1018
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________________________________________________

1. Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020;31(12):1623-49. DOI:10.1016/j.annonc.2020.09.010
2. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-46. DOI:10.1200/JCO.2017.75.6155
3. Goetz MP, Toi M, Huober J, et al. LBA15 – MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC). Ann Oncol. 2022;33(Suppl. 7):S808-69. DOI:10.1016/annonc/annonc1089
4. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-46. DOI:10.1200/JCO.2017.75.6155
5. Finn RS, Rugo HS, Dieras VC, 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(Suppl. 17):LBA100. DOI:10.1200/JCO.2022.40.17_suppl.LBA1003
6. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925-36. DOI:10.1056/NEJMoa1607303
7. Im SA, Lu YS, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019;381(4):307-16. DOI:10.1056/NEJMoa1903765
8. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18):1738-48. DOI:10.1056/NEJMoa1609709
9. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021;32(8):1015-24. DOI:10.1016/j.annonc.2021.05.353
10. Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382(6):514-24. DOI:10.1056/NEJMoa1911149
11. Lu YS, Im SA, Colleoni M, et al. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022;28(5):851-9. DOI:10.1158/1078-0432.CCR-21-3032
12. Tripathy D, Im SA, 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
13. Hortobagyi GN, Stemmer SM, Burris HA, 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
14. Hart LL, Bardia A, Beck JT, et al. Impact of ribociclib (RIB) dose modifications (mod) on overall survival (OS) in patients (pts) with HR+/HER2- advanced breast cancer (ABC) in MONALEESA(ML)-2. J Clin Oncol. 2022;40(Suppl. 16):1017. DOI:10.1200/JCO.2022.40.16_suppl.1017
15. Song F, Harvey I, Lilford R. Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions. J Clin Epidemiol. 2008;61(5):455-63. DOI:10.1016/j.jclinepi.2007.06.006
16. Thom H, Jugl SM, Palaka E, Jawla S. Matching adjusted indirect comparisons to assess comparative effectiveness of therapies: usage in scientific literature and health technology appraisals. Value in Health. 2016;19(3):A100-1. DOI:10.1016/j.jval.2016.03.1723
17. Korotaeva TV. Results of evaluating the efficacy of secukinumab versus adalimumab in treating psoriatic arthritis by using the matching-adjusted indirect comparison method. Sovremennaya Revmatologiya=Modern Rheumatology Journal. 2016;10(4):57-63 (in Russian). DOI:10.14412/1996-7012-2016-4-57-63
18. 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):S2-3. DOI:10.1016/S0959-8049(22)01353-3
19. Hamilton E, Spring LM, Fasching PA, et al. P4-01-42: Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2- advanced breast cancer in the MONALEESA-2, -3, and -7 studies. Cancer Res. 2023;83(Suppl. 5):P4-01-42. DOI:10.1158/1538-7445.SABCS22-P4-01-42
20. Woodford RG, Zhou DDX, Kok PS, et al. The validity of progression-free survival 2 as a surrogate trial end point for overall survival. Cancer. 2022;128(7):1449-57. DOI:10.1002/cncr.34085
21. Tripathy D, Im SA, Colleoni M, et al. PD2-04. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Cancer Res. 2021;81(Suppl. 4):PD2-04-PD2-04. DOI:10.1158/1538-7445.SABCS20-PD2-04
22. Slamon DJ, Neven P, Chia SKL, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). J Clin Oncol. 2021;39(Suppl. 15):1001. DOI:10.1200/JCO.2021.39.15_suppl.1001
23. Carter GC, Mohanty M, Stenger K, et al. Prognostic factors in hormone receptor-positive/human epidermal growth factor receptor 2-negative (Hr+/her2-) advanced breast cancer: A systematic literature review. Cancer Manag Res. 2021;13:6537-66. DOI:10.2147/CMAR.S300869
24. Lu YS, Im SA, Colleoni M, et al. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022;28(5):851-9. DOI:10.1158/1078-0432.CCR-21-3032
25. Yardley DA, Yap YS, Azim HA, et al. 205P Pooled exploratory analysis of survival in patients (pts) with HR+/HER2- advanced breast cancer (ABC) and visceral metastases (mets) treated with ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) trials. Ann Oncol. 2022;33(Suppl. 7):S629. DOI:10.1016/j.annonc.2022.07.239
26. Konecny GE. Cyclin-dependent kinase pathways as targets for women’s cancer treatment. Curr Opin Obstet Gynecol. 2016;28(1):42-8. DOI:10.1097/GCO.0000000000000243
27. Weinberg RA. The Biology of Cancer. 2nd ed. W.W. Norton & Company, 2013.
28. Krämer A, Schultheis B, Bergmann J, et al. Alterations of the cyclin D1/pRb/p16INK4A pathway in multiple myeloma. Leukemia. 2002;16(9):1844-51. DOI:10.1038/sj.leu.2402609
29. Abdelmalak M, Singh R, Anwer M, et al. The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance. Cancers (Basel). 2022;14(21):5388. DOI:10.3390/cancers14215388
30. Sutherland RL, Watts CK, Musgrove EA. Cyclin gene expression and growth control in normal and neoplastic human breast epithelium. J Steroid Biochem Mol Biol. 1993;47(1-6):99-106. DOI:10.1016/0960-0760(93)90062-2
31. Neven P, Petrakova K, Bianchi GV, et al. Ribociclib (RIB) + fulvestrant (FUL) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-3 biomarker analyses. Ann Oncol. 2018;29(Suppl. 8):viii113-114. DOI:10.1093/annonc/mdy272.336
32. Lu YS, Hurvitz SA, Su F, et al. In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial. J Clin Oncol. 2019;37:1018. DOI:10.1200/JCO.2019.37.15_suppl.1018
33. Andre F, Stemmer SM, Campone M, et al. Abstract CT045: Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers. Cancer Res. 2017;77(Suppl. 13):CT045. DOI:10.1158/1538-7445.AM2017-CT045
34. NCCN. National Comprehensive Cancer Network. Breast Cancer, ver.2.2023. Available at: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419. Accessed: 25.02.2023.

Авторы

К.С. Гречухина*, М.В. Калугин, А.А. Просвирнов, М.В. Сухова, Л.Г. Жукова

ГБУЗ «Московский клинический научно-практический центр им. А.С. Логинова» Департамента здравоохранения г. Москвы, Москва, Россия
*dr.grechukhina@gmail.com

________________________________________________

Katerina S. Grechukhina*, Maxim V. Kalugin, Andrey A. Prosvirnov, Margarita V. Sukhova, Liudmila G. Zhukova

Loginov Moscow Clinical Scientific Center, Moscow, Russia
*dr.grechukhina@gmail.com

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