Tom 8, Nr 3 (2022)
Artykuł przeglądowy
Opublikowany online: 2021-03-26
Pobierz cytowanie

Inhibitory kinaz 4/6 zależnych od cyklin — podobieństwa i różnice

Agnieszka Jagiełło-Gruszfeld1, Aleksandra Konieczna1, Roman Dubiański1, Zbigniew Nowecki1
Onkol Prakt Klin Edu 2022;8(3):178-187.
Afiliacje
  1. Klinika Nowotworów Piersi i Chirurgii Rekonstrukcyjnej, Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie — Państwowy Instytut Badawczy w Warszawie

dostęp płatny

Tom 8, Nr 3 (2022)
PRACE PRZEGLĄDOWE (REVIEW ARTICLES)
Opublikowany online: 2021-03-26

Streszczenie

Leczenie hormonozależnego HER2-ujemnego raka piersi ewoluuje w zależności od ciągłego poznawania mechaniz mów regulujących w komórkach rakowych rozwój hormonooporności. Aktualnie opcje terapeutyczne w zaawansowanym ER-dodatnim HER-2 ujemnym raku piersi są dość szerokie i umożliwiają długoletnie przeżycia z zachowaniem dobrej jakości życia. Dotychczasowym standardem była hormonoterapia w monoterapii. Przełomowym odkryciem okazały się inhibitory kinaz zależnych od cyklin, które weszły do leczenia standardowego i zmieniły praktykę kliniczną w I linii leczenia przerzutowego raka piersi. Po pozytywnych wynikach badań w zakresie czasu całkowitego przeżycia i czasu wolnego od progresji w przerzutowym raku piersi, rozpoczęto badania nad skutecznością inhibitorów w różnych podtypach raka piersi oraz w leczeniu neo- bądź adjuwantowym w konfiguracjach z dotychczas znanym leczeniem. W niniejszej pracy omówiono badania kliniczne, które przyczyniły się do rejestracji inhibitorów CDK 4/6. Porównano także poszczególne inhibitory pod kątem wyników skuteczności stosowanej terapii oraz możliwej toksyczności leczenia. Omówiono także profil bezpieczeństwa leczenia szczególnej grupy chorych jaką są osoby starsze.

Streszczenie

Leczenie hormonozależnego HER2-ujemnego raka piersi ewoluuje w zależności od ciągłego poznawania mechaniz mów regulujących w komórkach rakowych rozwój hormonooporności. Aktualnie opcje terapeutyczne w zaawansowanym ER-dodatnim HER-2 ujemnym raku piersi są dość szerokie i umożliwiają długoletnie przeżycia z zachowaniem dobrej jakości życia. Dotychczasowym standardem była hormonoterapia w monoterapii. Przełomowym odkryciem okazały się inhibitory kinaz zależnych od cyklin, które weszły do leczenia standardowego i zmieniły praktykę kliniczną w I linii leczenia przerzutowego raka piersi. Po pozytywnych wynikach badań w zakresie czasu całkowitego przeżycia i czasu wolnego od progresji w przerzutowym raku piersi, rozpoczęto badania nad skutecznością inhibitorów w różnych podtypach raka piersi oraz w leczeniu neo- bądź adjuwantowym w konfiguracjach z dotychczas znanym leczeniem. W niniejszej pracy omówiono badania kliniczne, które przyczyniły się do rejestracji inhibitorów CDK 4/6. Porównano także poszczególne inhibitory pod kątem wyników skuteczności stosowanej terapii oraz możliwej toksyczności leczenia. Omówiono także profil bezpieczeństwa leczenia szczególnej grupy chorych jaką są osoby starsze.

Pobierz cytowanie

Słowa kluczowe

rak piersi; inhibitory CDK4/6; hormonoterapia

Informacje o artykule
Tytuł

Inhibitory kinaz 4/6 zależnych od cyklin — podobieństwa i różnice

Czasopismo

Onkologia w Praktyce Klinicznej - Edukacja

Numer

Tom 8, Nr 3 (2022)

Typ artykułu

Artykuł przeglądowy

Strony

178-187

Opublikowany online

2021-03-26

Wyświetlenia strony

2050

Wyświetlenia/pobrania artykułu

516

Rekord bibliograficzny

Onkol Prakt Klin Edu 2022;8(3):178-187.

Słowa kluczowe

rak piersi
inhibitory CDK4/6
hormonoterapia

Autorzy

Agnieszka Jagiełło-Gruszfeld
Aleksandra Konieczna
Roman Dubiański
Zbigniew Nowecki

Referencje (79)
  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424.
  2. Krajowy Rejestr Nowotworów. http://onkologia.org.pl/nowotwory-piersi-kobiet/.
  3. Brufsky AM. Long-term management of patients with hormone receptor-positive metastatic breast cancer: Concepts for sequential and combination endocrine-based therapies. Cancer Treat Rev. 2017; 59: 22–32.
  4. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)†. Ann Oncol. 2018; 29(8): 1634–1657.
  5. National Comprehensive Cancer Network. NCC Clinical Practice guidelines in Oncology. Breast Cancer. Version 4.2107. 2017. https://www.nccn.org/professionals/physiciangls/pdf/breast (18.12.2018).
  6. Rugo HS, Rumble RB, Macrae E, et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016; 34(25): 3069–3103.
  7. 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): 1623–1649.
  8. Scott SC, Lee SS, Abraham J. Mechanisms of therapeutic CDK4/6 inhibition in breast cancer. Semin Oncol. 2017; 44(6): 385–394.
  9. Chan FK, Zhang J, Cheng L, et al. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol. 1995; 15(5): 2682–2688.
  10. Tamura K. Differences of cyclin-dependent kinase 4/6 inhibitor, palbociclib and abemaciclib, in breast cancer. Jpn J Clin Oncol. 2019; 49(11): 993–998.
  11. Gelbert LM, Cai S, Lin Xi, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014; 32(5): 825–837.
  12. Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res. 2014; 20(14): 3763–3774.
  13. Braal CL, Jongbloed EM, Wilting SM, et al. Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences. Drugs. 2020 [Epub ahead of print].
  14. van Dyk M, Marshall JC, Sorich MJ, et al. Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries. Eur J Clin Pharmacol. 2018; 74(7): 913–920.
  15. Im SA, Mukai H, Park InH, et al. Palbociclib plus letrozole as first-line therapy in postmenopausal asian women with metastatic breast cancer: results from the phase III, randomized PALOMA-2 study. J Glob Oncol. 2019; 5: 1–19.
  16. Gelbert LM, Cai S, Lin Xi, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014; 32(5): 825–837.
  17. Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res. 2014; 20(14): 3763–3774.
  18. O'Brien N, Conklin D, Beckmann R, et al. Preclinical activity of abemaciclib alone or in combination with antimitotic and targeted therapies in breast cancer. Mol Cancer Ther. 2018; 17(5): 897–907.
  19. Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos. 2015; 43(9): 1360–1371.
  20. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, nonsmall cell lung cancer, and other solid tumors. Cancer Discov. 2016; 6(7): 740–753.
  21. de Gooijer MC, Zhang P, Thota N, et al. P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib. Invest New Drugs. 2015; 33(5): 1012–1019.
  22. Martínez-Chávez A, van Hoppe S, Rosing H, et al. P-glycoprotein limits ribociclib brain exposure and CYP3A4 restricts its oral bioavailability. Mol Pharm. 2019; 16(9): 3842–3852.
  23. Chong QY, Kok ZH, Bui NL, et al. A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib. Pharmacol Res. 2020; 156: 104686.
  24. Goetz M, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology. 2017; 35(32): 3638–3646.
  25. Summary of Product Characteristics palbociclib. Food and Drug Administration. https://www.fda.gov/drugs /infor mationondr ugs/appro veddr ugs/ucm54 9978.htm (15.12.2020).
  26. Summary of Product Characteristics abemaciclib. Food and Drug Administration. https://www.fda.gov/drugs /infor mationondr ugs/appro veddr ugs/ucm57 8081.htm (15.12.2020).
  27. Summary of Product Characteristics ribociclib. Food and Drug Administration. https://www.fda.gov/drugs /infor matio nondrugs/appro veddr ugs/ucm54 6438.htm.
  28. Yu Y, Loi CM, Hoffman J, et al. Physiologically based pharmacokinetic modeling of palbociclib. J Clin Pharmacol. 2017; 57(2): 173–184.
  29. Chen P, Lee NV, Hu W, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther. 2016; 15(10): 2273–2281.
  30. Infante JR, Cassier PA, Gerecitano JF, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016; 22(23): 5696–5705.
  31. Tate SC, Sykes AK, Kulanthaivel P, et al. A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients. Clin Pharmacokinet. 2018; 57(3): 335–344.
  32. Samant TS, Dhuria S, Lu Y, et al. Ribociclib bioavailability is not affected by gastric pH changes or food intake: in silico and clinical evaluations. Clin Pharmacol Ther. 2018; 104(2): 374–383.
  33. Finn RS, Crown JP, 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.
  34. Rugo HS, Diéras V, Gelmon KA, et al. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018; 29(4): 888–894.
  35. Rugo HS, Finn RS, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016; 375(20): 1925–1936.
  36. Turner NC, Ro J, André F, et al. PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015; 373(3): 209–219.
  37. Awada A. Faculty Opinions recommendation of Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2019.
  38. Serra F, Lapidari P, Quaquarini E, et al. Palbociclib in metastatic breast cancer: current evidence and real-life data. Drugs Context. 2019; 8: 212579.
  39. 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): 1738–1748.
  40. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018; 29(7): 1541–1547.
  41. Tripathy D, Im SA, Colleoni M, et al. Abstract 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. Poster Spotlight Session Abstracts. 2021.
  42. Im SA, Lu YS, Bardia A. Ribociclib plus endocrine therapy for premonopausal women with hormon-receptor-positive, advanced breast cancer (MONALEESA-7): A randomisem phase III trial. Lancet Oncol. 2018; 19: 904–915.
  43. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018; 36(24): 2465–2472.
  44. 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): 514–524.
  45. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2019; 382(6): 514–524.
  46. Sledge GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 2019 [Epub ahead of print].
  47. Sledge G, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Journal of Clinical Oncology. 2017; 35(25): 2875–2884.
  48. http://www.radiologytutor.com/index.php/cases/oncol/139-recist.
  49. Sledge GW, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019 [Epub ahead of print].
  50. Neven P, Johnston S, Toi M, et al. MONARCH 2: Subgroup analysis of patients receiving abemaciclib + fulvestrant as first- and second-line therapy for HR+, HER2- advanced breast cancer. Journal of Clinical Oncology. 2020; 38(15_suppl): 1061–1061.
  51. Kaufman PA, Toi M, Neven P, et al. Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist. 2020; 25(2): e243–e251.
  52. 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; 5: 5.
  53. Martin M, Johnston S, Huober J, et al. MONARCH-3: Updated time to chemotherapy and disease progression following abemaciclib plus aromatase inhibitor in HR+, HER2-advanced breast cancer. ESMO 2019, Poster #326P.
  54. O'Shaughnessy J, Goetz M, Sledge G, et al. Abstract CT099: The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3. Clinical Trials. 2018.
  55. 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; 5: 5.
  56. Goetz MP, Martin M, Tokunaga E, et al. Health-related quality of life in MONARCH 3: abemaciclib plus an aromatase inhibitor as initial therapy in HR+, HER2-advanced breast cancer. Oncologist. 2020; 25(9): e1346–e1354.
  57. Harbeck N, Iyer S, Turner N, et al. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016; 27(6): 1047–1054.
  58. Verma S, O'Shaughnessy J, Burris HA, et al. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018; 170(3): 535–545.
  59. Diéras V, Harbeck N, Joy AA, et al. Palbociclib with letrozole in postmenopausal women with ER+/HER2- advanced breast cancer: hematologic safety analysis of the randomized PALOMA-2 Trial. Oncologist. 2019; 24(12): 1514–1525.
  60. Rugo HS, Huober J, García-Sáenz JA, et al. Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3. Oncologist. 2021; 26(1): e53–e65.
  61. Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018; 101: 123–133.
  62. Goetz MP, Okera M, Wildiers H. Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with HR+, HER2- advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. SABCS. 2019(P1-19-10).
  63. Johnston SRD, Harbeck N, Hegg R, et al. monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high risk,early breast cancer (monarchE). J Clin Oncol. 2020; 38(34): 3987–3998.
  64. Mayer EL, Gnant MI, DeMichele A, et al. LBA12 PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. Annals of Oncology. 2020; 31: S1145.
  65. Di Cosimo S, Porcu L, Cardoso F. CDK 4/6 inhibitors mired in uncertainty in HR positive and HER2 negative early breast cancer. Breast. 2021; 55: 75–78.
  66. Matikas A, Lambertini M. ESMO20 YO for YO: highlights on adjuvant CDK4/6 inhibitors in early hormone receptor-positive/HER2-negative breast cancer. ESMO Open. 2020 [Epub ahead of print]; 6(1): 100014.
  67. Slamon D, Fasching P, Patel R, et al. NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC). Journal of Clinical Oncology. 2019; 37(15_suppl): TPS597–TPS597.
  68. Johnston SRD, Harbeck N, Hegg R, et al. monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020; 38(34): 3987–3998.
  69. Ma CX, Gao F, Luo J, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011; 13(2): R21–4065.
  70. Johnston S, Puhalla S, Wheatley D, et al. Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. J Clin Oncol. 2019; 37(3): 178–189.
  71. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). https ://doi.org/10.1200/JCO.2020.38.15_suppl .505 (15.12.2020).
  72. Hurvitz SA, Martin M, Press MF, et al. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR/HER2 Breast Cancer. Clin Cancer Res. 2020; 26(3): 566–580.
  73. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020; 21(1): 33–43.
  74. Zheng J, Wu J, Wang C, et al. Combination cyclin-dependent kinase 4/6 inhibitors and endocrine therapy versus endocrine monotherapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: A systematic review and meta-analysis. PLoS One. 2020; 15(6): e0233571.
  75. 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): 307–316.
  76. de Melo Gagliato D, C Buzaid A, Perez-Garcia JM, et al. CDK4/6 Inhibitors in Hormone Receptor-Positive Metastatic Breast Cancer: Current Practice and Knowledge. Cancers (Basel). 2020; 12(9).
  77. Liu S, Sun X, Xu X, et al. 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): 460–483.
  78. Bisi JE, Sorrentino JA, Jordan JL, et al. Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget. 2017; 8(26): 42343–42358.
  79. Krastev B, Rai R, Bulat I, et al. 278MO cfDNA analysis from phase I/II study of lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients. Annals of Oncology. 2020; 31: S351–S352.

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