Palbociclib、Ribociclib、Abemaciclib的临床研究进展
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摘要
乳腺癌发病率居女性恶性肿瘤首位。研究表明,Cyclin-CDK-Rb轴的调节异常经常发生在乳腺癌中。目前,已经有3个CDK4/6抑制剂在美国上市,分别为Palbociclib(哌柏西利,2018年在中国上市)、Ribociclib以及Abemaciclib,用于治疗ER阳性的转移性乳腺癌。本文对这3个药物最新的临床研究进行了综述。
Breast cancer(BC) is the most common cancer in women.In BC,the Cyclin-CDK-Rb pathway is often deregulated.Three CDK4/6 inhibitors are approved for use in ER-positive MBC in the USA:palbociclib,which is approved for market in China,ribociclib and abemaciclib.In this paper,the clinical trials and applications of the three drugs are summarized.
Breast cancer(BC) is the most common cancer in women.In BC,the Cyclin-CDK-Rb pathway is often deregulated.Three CDK4/6 inhibitors are approved for use in ER-positive MBC in the USA:palbociclib,which is approved for market in China,ribociclib and abemaciclib.In this paper,the clinical trials and applications of the three drugs are summarized.
引文
[1] Jemal A,Siegel R,Xu J,et al.Cancer statistics,2010[J].CA Cancer J Clin,2010,60(5):277-300.
[2] National Cancer Institute.SEER Cancer Statistics Factsheets:female breast cancer-cancer stat facts[EB/OL].[2018-5-29].https://seer.cancer.gov/statfacts/html/breast.html.
[3] Gong Y,Liu YR,Ji P,et al.Impact of molecular subtypes on metastatic breast cancer patients:a SEER population-based study[J].Sci Rep,2017,7:45411.
[4] Satyanarayana A,Kaldis P.Mammalian cell-cycle regulation:severalCdks,numerous cyclins and diverse compensatory mechanisms[J].Oncogene,2009,28(33):2925-2939.
[5] Sherr CJ,Roberts JM.CDK inhibitors:positive and negative regulators of G1-phase progression[J].Genes Dev,1999,13(12):1501-1512.
[6] Malumbres M,Barbacid M.Cell cycle,CDKs and cancer:a changing paradigm[J].Nat Rev Cancer,2009,9(3):153-166.
[7] O′Leary B,Finn RS,Turner NC.Treating cancer with selective CDK4/6 inhibitors[J].Nat Rev Clin Oncol,2016,13(7):417-430.
[8] Ortiz AB,Garcia D,Vicente Y,et al.Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma[J].PLoS One,2017,12(11):e0188068.
[9] Comprehensive molecular portraits of human breast tumours[J].Nature,2012,490(7418):61-70.
[10] Zwijsen RM,Wientjens E,Klompmaker R,et al.CDK-independent activation of estrogen receptor by cyclin D1[J].Cell,1997,88(3):405-415.
[11] Shapiro GI.Cyclin-dependent kinase pathways as targets for cancer treatment[J].J Clin Oncol,2006,24(11):1770-1783.
[12] Torres-Guzmán R,Calsina B,Hermoso A,et al.Preclinical characterization of Abemaciclib in hormone receptor positive breast cancer[J].Oncotarget,2017,8(41):69493-69507.
[13] Finn RS,Dering J,Conklin D,et al.PD 0332991,a selective cyclin D kinase 4/6 inhibitor,preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro[J].Breast Cancer Res,2009,11(5):R77.
[14] Yu Q,Sicinska E,Geng Y,et al.Requirement for CDK4 kinase function in breast cancer[J].Cancer Cell,2006,9(1):23-32.
[15] Lee RJ,Albanese C,Fu M,et al.Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway[J].Mol Cell Biol,2000,20(2):672-683.
[16] Herrera Abreu MT,Asghar US,Elliot R,et al.86OPI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis[J].Ann Oncol,2015,26(suppl 3):iii29.
[17] Flaherty KT,Lorusso PM,Demichele A,et al.PhaseI,dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991,administered using a 21-day schedule in patients with advanced cancer[J].Clin Cancer Res,2012,18(2):568-576.
[18] DeMichele A,Clark AS,Tan KS,et al.CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer:phase II activity,safety,and predictive biomarker assessment[J].Clin Cancer Res,2015,21(5):995-1001.
[19] 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[J].Lancet Oncol,2015,16(1):25-35.
[20] Finn RS,Crown J,Lang I,et al.Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2-advanced breast cancer (PALOMA-1;TRIO-18)[J].Clin Oncol,2017,35(15 suppl):1001.
[21] Finn RS,Martin M,Rugo HS,et al.Palbociclib and letrozole in advanced breast cancer[J].N Engl J Med,2016,375(20):1925-1936.
[22] 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[J].Ann Oncol,2018,29(4):888-894.
[23] Cristofanilli M,Turner NC,Bondarenko I,et al.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[J].Lancet Oncol,2016,17(4):425-439.
[24] Shah A,Bloomquist E,Tang S,et al.FDAapproval:Ribociclib for the treatment of postmenopausal women with hormone receptor-positive,HER2-negative advanced or metastatic breast cancer[J].Clin Cancer Res,2018,24(13):2999-3004.
[25] Kim S,Loo A,Chopra R,et al.LEE011:an orally bioavailable,selective small molecule inhibitor of CDK4/6-reactivating Rb in cancer[J].Mol Cancer Ther,2013,12(Supple 11):PR02.
[26] Barroso-Sousa R,Shapiro GI,Tolaney SM.Clinical development of the CDK4/6 inhibitors Ribociclib and Abemaciclib in breast cancer[J].Breast Care (Basel),2016,11(3):167-173.
[27] 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[J].Clin Cancer Res,2016,22(23):5696-5705.
[28] DiPippo AJ,Patel NK,Barnett CM.Cyclin-dependent kinase inhibitors for the treatment of breast cancer:past,present,and future[J].Pharmacotherapy,2016,36(6):652-667.
[29] O′Brien NA,Tomaso ED,Ayala R,et al.In vivo efficacy of combined targeting of CDK4/6,ER and PI3K signaling in ER+ breast cancer[J].Cancer Res,2014,74(Suppl 19):4756.
[30] Juric D,Munster PN,Campone M,et al.Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+),HER2-negative (HER2-) advanced breast cancer (aBC):phase Ibsafety,preliminary efficacy and molecular analysis[J].J Clin Oncol,2016,34(suppl 15):568.
[31] Hortobagyi GN,Stemmer SM,Burris HA,et al.Ribociclib as first-line therapy for hr-positive,advanced breast cancer[J].N Engl J Med,2016,375(18):1738-1748.
[32] 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[J].Lancet Oncol,2018,19(7):904-915.
[33] 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].J Clin Oncol,2018,36(24):2465-2472.
[34] Gelbert LM,Cai S,Lin X,et al.Preclinical characterization of the CDK4/6 inhibitor LY2835219:in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine[J].Invest New Drugs,2014,32(5):825-837.
[35] 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[J].Drug Metab Dispos,2015,43(9):1360-1371.
[36] Sanchezmartinez C,Gelbert LM,Shannon H,et al.LY2835219,a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts[J].Mol Cancer Ther,2015,10:B234.
[37] Parrish KE,Pokorny J,Mittapalli RK,et al.Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model[J].J Pharmacol Exp Ther,2015,355(2):264-271.
[38] Shapiro G,RosenLS,Tolcher AW,et al.A first-in-human phase I study of the CDK4/6 inhibitor,LY2835219,for patients with advanced cancer[J].Lancet,2013,1(7276):330.
[39] Patnaik A,Rosen LS,Tolaney SM,et al.CT232:clinical activity of LY2835219,a novel cell cycle inhibitor selective for CDK4 and CDK6,in patients with metastatic breast cancer[J].Cancer Res,2014,74(Suppl 19):CT232.
[40] Dickler MN,Tolaney SM,Rugo HS,et al.MONARCH 1,A Phase II study of Abemaciclib,a CDK4 and CDK6 inhibitor,as a single agent,in patients with refractory HR+/HER2-metastatic breast cancer[J].Clin Cancer Res,2017,23(17):5218-5224.
[41] Sledge GW,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[J].J Clin Oncol,2017,35(25):2875-2884.
[42] Goetz MP,Toi M,Campone M,et al.MONARCH 3:Abemaciclib as initial therapy for advanced breast cancer[J].J Clin Oncol,2017,35(32):3638-3646.
[2] National Cancer Institute.SEER Cancer Statistics Factsheets:female breast cancer-cancer stat facts[EB/OL].[2018-5-29].https://seer.cancer.gov/statfacts/html/breast.html.
[3] Gong Y,Liu YR,Ji P,et al.Impact of molecular subtypes on metastatic breast cancer patients:a SEER population-based study[J].Sci Rep,2017,7:45411.
[4] Satyanarayana A,Kaldis P.Mammalian cell-cycle regulation:severalCdks,numerous cyclins and diverse compensatory mechanisms[J].Oncogene,2009,28(33):2925-2939.
[5] Sherr CJ,Roberts JM.CDK inhibitors:positive and negative regulators of G1-phase progression[J].Genes Dev,1999,13(12):1501-1512.
[6] Malumbres M,Barbacid M.Cell cycle,CDKs and cancer:a changing paradigm[J].Nat Rev Cancer,2009,9(3):153-166.
[7] O′Leary B,Finn RS,Turner NC.Treating cancer with selective CDK4/6 inhibitors[J].Nat Rev Clin Oncol,2016,13(7):417-430.
[8] Ortiz AB,Garcia D,Vicente Y,et al.Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma[J].PLoS One,2017,12(11):e0188068.
[9] Comprehensive molecular portraits of human breast tumours[J].Nature,2012,490(7418):61-70.
[10] Zwijsen RM,Wientjens E,Klompmaker R,et al.CDK-independent activation of estrogen receptor by cyclin D1[J].Cell,1997,88(3):405-415.
[11] Shapiro GI.Cyclin-dependent kinase pathways as targets for cancer treatment[J].J Clin Oncol,2006,24(11):1770-1783.
[12] Torres-Guzmán R,Calsina B,Hermoso A,et al.Preclinical characterization of Abemaciclib in hormone receptor positive breast cancer[J].Oncotarget,2017,8(41):69493-69507.
[13] Finn RS,Dering J,Conklin D,et al.PD 0332991,a selective cyclin D kinase 4/6 inhibitor,preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro[J].Breast Cancer Res,2009,11(5):R77.
[14] Yu Q,Sicinska E,Geng Y,et al.Requirement for CDK4 kinase function in breast cancer[J].Cancer Cell,2006,9(1):23-32.
[15] Lee RJ,Albanese C,Fu M,et al.Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway[J].Mol Cell Biol,2000,20(2):672-683.
[16] Herrera Abreu MT,Asghar US,Elliot R,et al.86OPI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis[J].Ann Oncol,2015,26(suppl 3):iii29.
[17] Flaherty KT,Lorusso PM,Demichele A,et al.PhaseI,dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991,administered using a 21-day schedule in patients with advanced cancer[J].Clin Cancer Res,2012,18(2):568-576.
[18] DeMichele A,Clark AS,Tan KS,et al.CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer:phase II activity,safety,and predictive biomarker assessment[J].Clin Cancer Res,2015,21(5):995-1001.
[19] 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[J].Lancet Oncol,2015,16(1):25-35.
[20] Finn RS,Crown J,Lang I,et al.Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2-advanced breast cancer (PALOMA-1;TRIO-18)[J].Clin Oncol,2017,35(15 suppl):1001.
[21] Finn RS,Martin M,Rugo HS,et al.Palbociclib and letrozole in advanced breast cancer[J].N Engl J Med,2016,375(20):1925-1936.
[22] 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[J].Ann Oncol,2018,29(4):888-894.
[23] Cristofanilli M,Turner NC,Bondarenko I,et al.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[J].Lancet Oncol,2016,17(4):425-439.
[24] Shah A,Bloomquist E,Tang S,et al.FDAapproval:Ribociclib for the treatment of postmenopausal women with hormone receptor-positive,HER2-negative advanced or metastatic breast cancer[J].Clin Cancer Res,2018,24(13):2999-3004.
[25] Kim S,Loo A,Chopra R,et al.LEE011:an orally bioavailable,selective small molecule inhibitor of CDK4/6-reactivating Rb in cancer[J].Mol Cancer Ther,2013,12(Supple 11):PR02.
[26] Barroso-Sousa R,Shapiro GI,Tolaney SM.Clinical development of the CDK4/6 inhibitors Ribociclib and Abemaciclib in breast cancer[J].Breast Care (Basel),2016,11(3):167-173.
[27] 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[J].Clin Cancer Res,2016,22(23):5696-5705.
[28] DiPippo AJ,Patel NK,Barnett CM.Cyclin-dependent kinase inhibitors for the treatment of breast cancer:past,present,and future[J].Pharmacotherapy,2016,36(6):652-667.
[29] O′Brien NA,Tomaso ED,Ayala R,et al.In vivo efficacy of combined targeting of CDK4/6,ER and PI3K signaling in ER+ breast cancer[J].Cancer Res,2014,74(Suppl 19):4756.
[30] Juric D,Munster PN,Campone M,et al.Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+),HER2-negative (HER2-) advanced breast cancer (aBC):phase Ibsafety,preliminary efficacy and molecular analysis[J].J Clin Oncol,2016,34(suppl 15):568.
[31] Hortobagyi GN,Stemmer SM,Burris HA,et al.Ribociclib as first-line therapy for hr-positive,advanced breast cancer[J].N Engl J Med,2016,375(18):1738-1748.
[32] 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[J].Lancet Oncol,2018,19(7):904-915.
[33] 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].J Clin Oncol,2018,36(24):2465-2472.
[34] Gelbert LM,Cai S,Lin X,et al.Preclinical characterization of the CDK4/6 inhibitor LY2835219:in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine[J].Invest New Drugs,2014,32(5):825-837.
[35] 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[J].Drug Metab Dispos,2015,43(9):1360-1371.
[36] Sanchezmartinez C,Gelbert LM,Shannon H,et al.LY2835219,a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts[J].Mol Cancer Ther,2015,10:B234.
[37] Parrish KE,Pokorny J,Mittapalli RK,et al.Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model[J].J Pharmacol Exp Ther,2015,355(2):264-271.
[38] Shapiro G,RosenLS,Tolcher AW,et al.A first-in-human phase I study of the CDK4/6 inhibitor,LY2835219,for patients with advanced cancer[J].Lancet,2013,1(7276):330.
[39] Patnaik A,Rosen LS,Tolaney SM,et al.CT232:clinical activity of LY2835219,a novel cell cycle inhibitor selective for CDK4 and CDK6,in patients with metastatic breast cancer[J].Cancer Res,2014,74(Suppl 19):CT232.
[40] Dickler MN,Tolaney SM,Rugo HS,et al.MONARCH 1,A Phase II study of Abemaciclib,a CDK4 and CDK6 inhibitor,as a single agent,in patients with refractory HR+/HER2-metastatic breast cancer[J].Clin Cancer Res,2017,23(17):5218-5224.
[41] Sledge GW,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[J].J Clin Oncol,2017,35(25):2875-2884.
[42] Goetz MP,Toi M,Campone M,et al.MONARCH 3:Abemaciclib as initial therapy for advanced breast cancer[J].J Clin Oncol,2017,35(32):3638-3646.