Breast cancer; CDK4/6 inhibitors; abemaciclib; meta-analysis; palbociclib; ribociclib
Abstract :
[en] Introduction: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.Areas covered: Here, we analyze the toxicity profiles of palbociclib, ribociclib, and abemaciclib through a systematic review and meta-analysis. Palbociclib and ribociclib showed high rates of hematological toxicity, primarily neutropenia, and were associated with a low rate of severe infections. Abemaciclib was associated with a high rate of gastrointestinal toxicities, primarily diarrhea, of grade 1-2 in most cases. Ribociclib was associated with a high rate of hepatic, and respiratory toxicity and with QTc prolongation. The toxicity rate of ribociclib was higher in metastatic patients than non-metastatic patients, with approximately 33% more grade 3-4 toxicities and 21% more grade 3-4 neutropenic events. A 5% higher risk of diarrhea was observed in postmenopausal patients. Pre-treated patients did not show a higher toxicity rate for palbociclib/ribociclib than previously untreated patients, while a 26% higher risk of any grade neutropenia and 6% higher risk of grade 3-4 diarrhea were observed with abemaciclib.Expert opinion: Considering the similar efficacies and indications of palbociclib, ribociclib, and abemaciclib, the evaluation of their toxicity profiles may facilitate treatment choice.
Walker AJ, Wedam S, Amiri-Kordestani L, et al. FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016 Oct 15; 22 (20): 4968–4972.
Beaver JA, Amiri-Kordestani L, Charlab R, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2015 Nov 1; 21 (21): 4760–4766.
Wedam S, Fashoyin-Aje L, Bloomquist E, et al. FDA approval summary: palbociclib for male patients with metastatic breast cancer. Clin Cancer Res. 2020 Mar 15; 26 (6): 1208–1212.
Shah A, Bloomquist E, Tang S, et al. FDA approval: ribociclib for the treatment of postmenopausal women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Clin Cancer Res. 2018 Jul 1; 24 (13): 2999–3004.
American Association for Cancer Research. FDA OKs abemaciclib for ER+, HER2- breast cancer. Cancer Discov. 2017 Nov; 7 (11): Of1.
Weinberg RA., The retinoblastoma protein and cell cycle control. Cell. 1995 May 5; 81 (3): 323–330.
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nat. 2012 Oct 4; 490 (7418): 61–70.
Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J Clin Oncol. 2005 Jun 20; 23 (18): 4215–4224.
Millar EK, Dean JL, McNeil CM, et al. Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome. Oncogene. 2009 Apr 16; 28 (15): 1812–1820.
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. Breast Cancer Res. 2009; 11 (5): R77.
Altucci L, Addeo R, Cicatiello L, et al. Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinol. 1997 Mar; 138 (3): 978–984.
Geum D, Sun W, Paik SK, et al. Estrogen-induced cyclin D1 and D3 gene expressions during mouse uterine cell proliferation in vivo: differential induction mechanism of cyclin D1 and D3. Mol Reprod Dev. 1997 Apr; 46 (4): 450–458.
Spring LM, Wander SA, Andre F, et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet. 2020 Mar 7; 395 (10226): 817–827.
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 Nov; 68 (6): 394–424.
Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019; 321 (3): 288–300.
Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020 Jun; 21 (6): 763–775.
Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018 Feb; 19 (2): 249–256.
Cottu P, D’Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018 Dec 1; 29 (12): 2334–2340.
Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant Palbociclib, A Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 Or 3 Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2017 Aug 1; 23 (15): 4055–4065.
Goel S, Pernas S, Tan-Wasielewski Z, et al. Ribociclib plus trastuzumab in advanced HER2-positive breast cancer: results of a phase 1b/2 trial. Clin Breast Cancer. 2019 Dec; 19 (6): 399–404.
Clark AS, McAndrew NP, Troxel A, et al. Combination paclitaxel and palbociclib: results of a phase I trial in advanced breast cancer. Clin Cancer Res. 2019 Apr 1; 25 (7): 2072–2079.
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 Jan 20; 37 (3): 178–189.
Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul 21; 6 (7): e1000097.
Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. Bmj. 2016 Oct 12; 355: i4919.
Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019 Aug 28; 366: l4898.
Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr; 174 (3): 719–729.
Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med. 2016 Nov 17; 375 (20): 1925–1936.
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. Lancet Oncol. 2016 Apr; 17 (4): 425–439.
Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015 Jul 16; 373 (3): 209–219.
Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018 Nov 15; 379 (20): 1926–1936.
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 Jan; 16 (1): 25–35.
Park YH, Kim TY, Kim GM, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019 Dec; 20 (12): 1750–1759.
Malorni L, Curigliano G, Minisini AM, et al. Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: tREnd trial. Ann Oncol. 2018 Aug 1; 29 (8): 1748–1754.
Takahashi M, Masuda N, Nishimura R, et al. Palbociclib-letrozole as first-line treatment for advanced breast cancer: updated results from a Japanese phase 2 study. Cancer Med. 2020 May 18;9(14):4929–4940.
Masuda N, Nishimura R, Takahashi M, et al. Palbociclib in combination with letrozole as first-line treatment for advanced breast cancer: a Japanese phase II study. Cancer Sci. 2018 Mar; 109 (3): 803–813.
Mayer EL, DeMichele A, Rugo HS, et al. A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma. Ann Oncol. 2019 Sep 1; 30 (9): 1514–1520.
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. Clin Cancer Res. 2015 Mar 1; 21 (5): 995–1001.
Tamura K, Mukai H, Naito Y, et al. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016 Jun; 107 (6): 755–763.
Stearns V, Brufsky AM, Verma S, et al. Expanded-access study of palbociclib in combination with Letrozole for treatment of postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. Clin Breast Cancer. 2018 Dec; 18 (6): e1239–e1245.
Ban M, Miše BP, Majić A, et al. Efficacy and safety of palbociclib in heavily pretreated patients with HR+/HER2- metastatic breast cancer. Future Oncol. 2018 Mar; 14 (6): 537–544.
Maurer C, Ferreira AR, Martel S, et al. Endocrine therapy and palbociclib within a compassionate use program in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer. Breast. 2018; 39: 14–18.
Bui TBV, Burgers DM, Agterof MJ, et al. Real-world effectiveness of palbociclib versus clinical trial results in patients with advanced/metastatic breast cancer that progressed on previous endocrine therapy. Breast Cancer (Auckl). 2019; 13: 1178223418823238.
Pizzuti L, Giordano A, Michelotti A, et al. Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: a real-world experience. J Cell Physiol. 2019 Jun; 234 (6): 7708–7717.
Watson GA, Deac O, Aslam R, et al. Real-world experience of palbociclib-induced adverse events and compliance with complete blood count monitoring in women with hormone receptor-positive/HER2-negative metastatic breast cancer. Clin Breast Cancer. 2019 Feb; 19 (1): e186–e194.
Du Rusquec P, Palpacuer C, Campion L, et al. Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer. Breast Cancer Res Treat. 2018 Apr; 168 (2): 559–566.
Herrscher H, Velten M, Leblanc J, et al. Fulvestrant and palbociclib combination in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer patients. Breast Cancer Res Treat. 2020 Jan; 179 (2): 371–376.
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 Jul 1; 29 (7): 1541–1547.
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3; 375 (18): 1738–1748.
Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020 Feb 6; 382 (6): 514–524.
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 Aug 20; 36 (24): 2465–2472.
Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019 Jul 25; 381 (4): 307–316.
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 Jul; 19 (7): 904–915.
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 Jan; 21 (1): 33–43.
Sledge GW, Jr., 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 Sep 29; 6 (1): 116–124.
Sledge GW, Jr., 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 Clin Oncol. 2017 Sep 1; 35 (25): 2875–2884.
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.
Goetz MP, Toi M, Campone M, et al. Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10; 35 (32): 3638–3646.
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. Clin Cancer Res. 2017 Sep 1; 23 (17): 5218–5224.
Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015 Feb; 14 (2): 130–146.
Laurenti E, Frelin C, Xie S, et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell. 2015 Mar 5; 16 (3): 302–313.
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. Invest New Drugs. 2014 Oct; 32 (5): 825–837.
Kassem L, Shohdy KS, Lasheen S, et al. Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer. 2018 Jan; 25 (1): 17–27.
Costa R, Costa RB, Talamantes SM, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: palbociclib and ribociclib. Breast. 2017; 35: 1–7.
Shohdy KS, Lasheen S, Kassem L, et al. Gastrointestinal adverse effects of cyclin-dependent kinase 4 and 6 inhibitors in breast cancer patients: a systematic review and meta-analysis. Ther Adv Drug Saf. 2017 Nov; 8 (11): 337–347.
Messina C, Cattrini C, Buzzatti G, et al. CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat. 2018 Nov; 172 (1): 9–21.
Hamilton EP, Cortés J, Ozyilkan O, et al. 273O nextMONARCH: final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2- metastatic breast cancer. Ann Oncol. 2020; 31: S348.
Martin M, Hurvitz S, Chan D, et al. Abstract PD5-01: final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC). Cancer Res. 2018; 78 (4 Supplement): PD5-01-PD5–01.
Mayer E, DeMichele A, Gnant M, et al. Abstract OT3-05-08: PALLAS: pALbociclib collaborative adjuvant study: A randomized phase 3 trial of palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for HR+/HER2- early breast cancer. Cancer Res. 2018; 78 (4 Supplement): OT3-05-08-OT3-05–08.
Slamon DJ, Fasching PA, 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). J Clin Oncol. 2019; 37 (15_suppl): TPS597–TPS597.
Rastogi PTM, Martin M, O’Shaughnessy J, et al. Abstract OT2-02-02: MONARCH E: A phase 3 study of standard adjuvant endocrine therapy with or without abemaciclib in patients with high risk, node positive, hormone-receptor positive, human epidermal growth factor receptor 2-negative early-stage breast cancer. Cancer Res. 2020;(80)(4 Supplement):OT2-02-02.
von Minckwitz GBH, Bonnefoi H, Colleoni M, et al. Abstract OT2-6-11: PENELOPE: phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13). Cancer Res. 2013;(73)(24 Supplement):OT2-6-11.
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. Ann Oncol. 2020; 31: S1145.
Johnston SRD, Harbeck N, Hegg R, et al. 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.
Foidart P, Yip C, Radermacher J, et al. Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy. Clin Cancer Res. 2019 Mar 15; 25 (6): 1838–1850.
Barton VN, D’Amato NC, Gordon MA, et al. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol Cancer Ther. 2015 Mar; 14 (3): 769–778.
Asghar US, Barr AR, Cutts R, et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res. 2017 Sep 15; 23 (18): 5561–5572.
Liu CY, Lau KY, Hsu CC, et al. Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells. PLoS One. 2017; 12 (12): e0189007.
Sharifi M, Wisinski K, Burkard M, et al. Abstract OT1-02-01: phase I trial of bicalutamide and ribociclib in androgen receptor-positive triple negative breast cancer. Cancer Res. 2019; 79 (4 Supplement): OT1-02-01-OT1-02–01.
