Nicholas Patrick McAndrew MD, MSCE
Since 1971, after Cole et al reported activity of tamoxifen in patients with late-stage breast cancer, endocrine therapy (ET) has been the cornerstone of systemic treatment for hormone receptor (HR)-positive, HER2-negative breast cancer.1
Starting in the ’90s, aromatase inhibitors (AIs) were developed in the metastatic setting, showing superiority over tamoxifen in postmenopausal patients.2
As tamoxifen and AIs showed benefit in late-stage disease, these drugs also succeeded in the adjuvant setting. They are now routinely used to reduce the risk of distant recurrence.3
Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been changing practice in advanced HR-positive breast cancer, with 3 agents (palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib [Verzenio]) having now FDA-approved indications for use with ET in the first-line setting.4-6
CDK4/6 inhibitors restrict progression through the cell cycle.7
Under normal conditions, the G1 to S phase transition is tightly regulated by the retinoblastoma (Rb) protein to halt abnormal growth. Through their interaction with cyclin proteins, CDK 4 and 6 phosphorylate and inactivate Rb, allowing G1 to S phase conversion. Inhibition of CDK4/6 by these drugs results in dephosphorylation of Rb and subsequent G1 phase arrest.8
Preclinical studies revealed that HR-positive breast cancer cell-line growth was particularly sensitive to CDK4/6 inhibition. These studies also suggested synergism with ET.9
This observation led to a series of phase II and III trials utilizing these agents in the metastatic breast cancer setting.
Through the subsequent PALOMA-2, MONALEESA-2, and MONARCH 3 studies, palbociclib, ribociclib, and abemaciclib, respectively, were shown to drastically improve progression-free survival (PFS) in HR-positive, HER2-negative advanced breast cancer when added to AIs as first-line therapy.10-12
Additionally, PALOMA-3, MONALEESA-3, and MONARCH 2 all demonstrated significant improvement in PFS after progression on prior ET when these agents were added to fulvestrant.13-15
Abemaciclib, because of its increased potency and continuous dosing schedule, was also evaluated as monotherapy in a single-arm, phase II study.16
In addition, these drugs, while generally well tolerated, have similar toxicity profiles, which include fatigue, uncomplicated neutropenia, and diarrhea. QTc prolongation is seen only in ribociclib, and it is isolated to doses ≥600 mg daily.17
These trials are the basis for which the FDA approved these drugs for metastatic breast cancer, and their use has been widely adopted.
Although ET significantly reduces the risk of recurrent HR-positive/HER2-negative early breast cancer, the cumulative risk of distant recurrence has remained steady for decades and is worsened with increased nodal involvement.18
Adjuvant systemic therapy has, therefore, not been optimized for these high-risk patients and it remains a clinically unmet need. In a series of open-label, phase III trials, CDK4/6 inhibitors are now being studied in the high-risk adjuvant setting (Table
Table. Clinical Trials of CDK4/6 Inhibitors in High-Risk Adjuvant Setting
PALLAS (NCT02513394), which opened enrollment in September 2015, is a phase III Alliance Foundation Trials, LLC/Austrian Breast & Colorectal Study Group trial comparing adjuvant palbociclib plus ET of physician’s choice (including tamoxifen) with ET alone in stage II to III HR-positive, HER2-negative breast cancer.19
The dosing of palbociclib in PALLAS is the same as in the metastatic setting and will be administered for 2 years concurrently with ET. The primary endpoint is invasive disease-free survival (iDFS). Patients must enroll within 12 months of diagnosis and within 6 months of beginning adjuvant ET. Also active and enrolling patients is monarchE (NCT03155997), a phase III National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant abemaciclib plus ET (including tamoxifen) with ET alone.20
MonarchE opened in July 2017 and is similar to PALLAS in terms of the primary endpoint, dosing schedule, and study drug administration period. However, monarchE excludes patients with node-negative disease and allows only up to 12 weeks of prior ET.21
NATALEE (NCT03701334) is an international, phase III trial led by Translational Research in Oncology and Novartis that will study adjuvant ET with or without ribociclib. NATALEE, like PALLAS, will include subjects with both anatomic stage II and III breast cancer and assess iDFS as its primary endpoint. However, NATALEE differs from PALLAS and monarchE in that ribociclib will be given over a period of 3 years instead of 2 and at a reduced dose of 400 mg, which may eliminate QTc prolongation.17
Additionally, up to 12 months of prior ET is allowed, and premenopausal women and men will be given a nonsteroidal AI plus goserelin as ET in both arms (excluding tamoxifen). NATALEE opened for enrollment in December 2018 and along with PALLAS and monarchE will clarify the potential role of these agents in helping patients with curable breast cancer remain free of disease.
- Cole MP, Jones CTA, Todd IDH. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25(2):270-275. doi: 10.1030/bjc.1971.33.
- Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst. 2006;98(18):1285-1291. doi: 10.1093/jnci/djj357.
- Dowsett M, Cuzick J, Ingle J, et al. Meta-Analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. Journal of Clinical Oncology. 2010;28(3):509-518. doi: 10.1200/JCO.2009.23.1274.
- Inman S. FDA approves palbociclib for metastatic breast cancer. Onclive website. onclive.com/web-exclusives/fda-approves-palbociclib-for-metastatic-breast-cancer. Published February 3, 2015. Accessed October 16, 2018.
- FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer. FDA website. fda.gov/drugs/informationondrugs/approveddrugs/ucm598404.htm. Published February 26, 2018. Accessed October 20, 2018.
- FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. FDA website. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm613803.htm. Published July 18, 2018. Accessed October 20, 2018.
- Lundberg AS, Weinberg RA. Control of the cell cycle and apoptosis. Eur J Cancer. 1999;35(4):531-539. doi: 10.1016/S0959-8049(99)00046-5.
- Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Molecular Cancer Therapeutics. 2004;3(11):1427-1438. mct.aacrjournals.org/content/3/11/1427.article-info.
- 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. doi: 10.1186/bcr2419.
- Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
- 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. doi: 10.1056/NEJMoa1609709.
- Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. doi:10.1200/JCO.2017.75.6155.
- 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;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0.
- 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. doi: 10.1200/JCO.2018.78.9909.
- 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 Clin Oncol. 2017;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585.
- 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;23(17):5218-5224. doi: 10.1158/1078-0432.CCR-17-0754.
- 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. doi: 10.1158/1078-0432.CCR-16-1248.
- 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):1836-1846. doi: 10.1056/NEJMoa1701830.
- Mayer EL, Demichele AM, Pfeiler G, et al. 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 [abstract 215TiP]. Ann Oncol. 2017;28(suppl_5):66. doi: 10.1093/annonc/mdx362.064.
- Rastogi P, Toi M, Harbeck N, Bourayou N, Frenzel M, Johnston S. MonarchE: A randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, HR+, HER2- breast cancer. [abstract OT3-05-05]. Cancer Research. 2018;78(suppl_4). doi: 10.1158/1538-7445.SABCS17-OT3-05-05.
- Endocrine therapy with or without abemaciclib (LY2835219) following surgery in participants with breast cancer (monarchE). clinicaltrials.gov/ct2/show/NCT03155997. Accessed October 23, 2018.