Approximately 1 in 8 women in the United States will have invasive breast cancer during their lifetime, making breast cancer one of the most common cancer diagnoses in women.1 Breast cancer is not one disease; several subtypes have been identified based on distinctions in molecular profiling and tumor biology, as well as clinical presentation and behavior.2,3
During each patient’s laboratory work-up, oncology specialists rely on findings related to the tumor’s estrogen receptor (ER) and progesterone receptor status, as well as the amplification and overexpression of the human epidermal growth factor receptor 2 (HER2), to direct treatment planning.2,3
Approximately 75% of breast cancers rely on ER signaling to grow and survive.2 Endocrine therapy, which blocks the growth-promoting activity of estrogen, represents the primary intervention for early- and advanced-stage ER-positive breast cancer.3 However, some patients do not respond to endocrine therapy (ie, de novo resistance), and some patients who initially respond to therapy have disease that progresses during therapy (ie, acquired resistance).3
Overview of the CDK4/CDK6 Pathway in Breast Cancer
Multiple mechanisms for endocrine resistance have been hypothesized, including the disruption of the ER pathway components and cell signaling, as well as the activation of escape pathways to facilitate cancer-cell survival.3 Among these mechanisms, the dysregulation of the cyclin D–cyclin-dependent kinase (CDK)4/CDK6-INK4-retinoblastoma (Rb) pathway has been shown to correlate with poor response to endocrine therapy.4 The cyclin D–CDK4/CDK6-INK4-Rb pathway regulates the progression of the cell cycle from the G1 (pre-DNA synthesis) phase to the S (DNA synthesis) phase.
Overall, CDK4/CDK6 in complex with cyclin D promotes the activity of Rb tumor-suppressor protein and related proteins that are important in DNA replication, and facilitates cell proliferation (Figure 1).5 Because alterations in the CDK4/CDK6 pathway are frequent in ER-positive breast cancer, the suppression of cyclin D–supported CDK4/CDK6 activity is a viable therapeutic option for women with breast cancer who do not respond to hormone-based therapies.4,6
The first agents developed to target CDK activity were pan-CDK inhibitors, such as flavopiridol. Pan-CDK inhibitors had modest activity and challenging side effects, including diarrhea and a proinflammatory syndrome associated with hypotension.7,8 The subsequent development of targeted CDK agents focused on more selective inhibitors of CDK4 and CDK6 kinases. These agents have demonstrated dose-dependent cell-cycle arrest in human breast cancer and an improved overall safety profile.9
Today, 2 CDK4/CDK6 inhibitors are approved by the US Food and Drug Administration (FDA) for the treatment of women with advanced or metastatic breast cancer—palbociclib (Ibrance) and ribociclib (Kisqali).9,10
Palbociclib is approved by the FDA for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer in 2 clinical settings—in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or in combination with fulvestrant (Faslodex) at disease progression after endocrine therapy.9
Ribociclib is approved by the FDA, in combination with an aromatase inhibitor such as letrozole (Femara), as initial, endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.10
One additional CDK4/CDK6 inhibitor–abemaciclib (LY2835219)–is currently in clinical development.7
Clinical Development of Palbociclib for Advanced Breast Cancer
Palbociclib, an orally administered drug, inhibits CDK4 at nanomolar concentrations and is highly selective.11,12 Preclinical data have demonstrated that palbociclib has antiproliferative effects in multiple cell lines in CDK4-amplified tumors, such as liposarcoma, as well as in tumors in which the downstream target of CDK4 (Rb) is intact, including mantle-cell lymphoma, multiple myeloma, and breast, ovarian, and colon cancers.7
Phase 1 studies established a dosing regimen of 125 mg once daily for 3 of 4 weeks.13,14 Because neutropenia was the dose-limiting toxicity, a 1-week break was recommended for neutrophil recovery. The most common nonhematologic adverse events related to the use of palbociclib in early-phase clinical trials included fatigue, nausea, diarrhea, dyspnea, arthralgia, constipation, and rash.13,14
The first phase 2 study of palbociclib assessed the drug as monotherapy in patients with endocrine therapy–resistant, Rb-positive breast cancer and showed a clinical benefit rate (defined as the rate of complete response, partial response, and stable disease) of 19%, with acceptable tolerability and safety.15
The second phase 2 clinical trial, PALOMA-1, was an open-label, randomized study that compared the combination of palbociclib plus letrozole with letrozole monotherapy in 165 patients with newly diagnosed ER-positive, HER2-negative advanced breast cancer.16 Patients who received palbociclib plus letrozole had significantly longer progression-free survival (PFS) than those who received letrozole monotherapy: the median PFS was 20.2 months (95% confidence interval [CI], 13.8-27.5) with palbociclib plus letrozole versus 10.2 months (95% CI, 5.7-12.6) with letrozole monotherapy (hazard ratio, 0.49; 95% CI, 0.32-0.75; one-sided P value, .0004).16
This study served as the basis for the initial FDA approval of palbociclib in February 2015.17 Because the FDA used its accelerated process for its initial approval of palbociclib, combined with letrozole, its benefits are subject to verification with additional clinical trial data.17 The PALOMA-2 study has been conducted for this purpose, and its data have recently been incorporated into the drug’s prescribing information.9,18
In PALOMA-2, 666 postmenopausal women with ER-positive, HER2-negative breast cancer received palbociclib plus letrozole or placebo plus letrozole.18 Women who received palbociclib plus letrozole had a significantly longer PFS than women who received placebo plus letrozole; the median PFS was 24.8 months (95% CI, 22.1-not estimable) with the active combination compared with 14.5 months (95% CI, 12.9-17.1) with letrozole monotherapy (hazard ratio, 0.58; 95% CI, 0.46-0.72; P <.001).18 The confirmed overall response rate (ORR) in patients with measurable disease was 55% for the palbociclib plus letrozole arm compared with 44% for the letrozole plus placebo arm.18 The rates of myelosuppression were higher with palbociclib plus letrozole than with letrozole monotherapy.18
In February 2016, the FDA approved an expanded indication for palbociclib on the basis of PALOMA-3, a phase 3 clinical trial that assessed the safety and efficacy of the combination of palbociclib plus fulvestrant in premenopausal women whose disease progressed after endocrine therapy.19,20
In PALOMA-3, 521 women received palbociclib plus fulvestrant or placebo plus fulvestrant.20 Women in the palbociclib plus fulvestrant arm had a significantly longer median PFS than women in the placebo plus fulvestrant arm: the median PFS was 9.2 months (95% CI, 7.5-not estimable) versus 3.8 months (95% CI, 3.2-5.5; P <.001), respectively (hazard ratio, 42; 95% CI, 0.32-0.56; P <.001; Figure 2).20
The most common grade 3 or 4 adverse events reported in the palbociclib plus fulvestrant arm were neutropenia (62.0%), leukopenia (25.2%), anemia (2.6%), thrombocytopenia (2.3%), and fatigue (2.0%).20 The rate of discontinuation because of adverse events was 2.6% with palbociclib plus fulvestrant versus 1.7% with fulvestrant plus placebo.20
Clinical Development of Ribociclib for Advanced Breast Cancer
Like palbociclib, ribociclib is an oral, bioavailable small molecule that inhibits CDK4/CDK6 at nanomolar concentrations.21 In preclinical evaluations, ribociclib caused cell-cycle arrest at the G1 phase, as well as antitumor activity in several cancer models, including melanoma with BRAF or NRAS mutations and breast cancer.21
In a phase 1 clinical trial of ribociclib that included 132 patients with Rb-positive advanced solid tumors or lymphomas, the recommended dose of ribociclib for expansion was 600 mg once daily for 21 days of the 28-day dosing schedule.22 Neutropenia was the primary toxicity associated with the recommended dosage of ribociclib, but it resolved within 14 days after treatment interruption and rarely required growth factor support.22 The most common nonhematologic, treatment-related adverse events were fatigue, nausea, and vomiting. Grade 3 or 4 asymptomatic corrected QT prolongation was observed only at doses ≥600 mg once daily. No clinically significant arrhythmias were observed. Encouraging clinical responses were noted in patients with breast cancer, head and neck carcinoma, or melanoma in this phase 1 clinical trial.22
In a subsequent, phase 1b clinical trial involving 47 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, ribociclib plus letrozole demonstrated an acceptable safety profile and clinical activity, particularly in patients who had not received previous systemic treatment for advanced disease.23
The ORR was 5% in patients with previously treated disease versus 39% in treatment-naïve patients.23 The clinical benefit rate (defined as stable complete response plus partial response and stable disease lasting at least 24 weeks) was 32% for 19 evaluable patients with previously treated disease versus 73% for 22 evaluable patients with treatment-naïve disease.23 Grade 3 or 4 adverse events that were suspected to be drug-related included neutropenia (43%), lymphopenia (4%), and leukopenia (2%).23
MONALEESA-2 Design and Methods: Phase 3 Study of Ribociclib
Based on the early-phase clinical trials suggesting activity and safety of ribociclib in postmenopausal women with ER-positive, HER2-negative advanced breast cancer, a large phase 3 clinical trial was initiated.24 MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety-2) is a randomized, double-blind, placebo-controlled study that compares ribociclib (600 mg once daily for 21 days of a 28-day cycle) plus letrozole (2.5 mg once daily) versus placebo plus letrozole (2.5 mg once daily) in women with treatment-naïve ER-positive, HER2-negative advanced breast cancer.24
Patients were eligible for enrollment if they had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, or at least 1 predominantly lytic bone lesion.24 In addition, patients’ Eastern Cooperative Oncology Group performance status had to be 0 or 1, and patients had to demonstrate adequate bone marrow and organ function.24
Patients were excluded from the study if they received a CDK4/CDK6 inhibitor or any previous systemic chemotherapy or endocrine therapy for advanced disease.24 Patients with inflammatory breast cancer, central nervous system metastases, a history of cardiac disease or dysfunction, or impaired gastrointestinal function that altered drug absorption were also excluded. Previous neoadjuvant or adjuvant use of a nonsteroidal aromatase inhibitor was permitted only if the disease-free interval was more than 12 months. The concomitant use of medications known to prolong the QT interval or induce torsades de pointes was also not permitted.24
Patients were stratified based on the presence or absence of liver or lung metastases.24 They received treatment with ribociclib until disease progression, unacceptable toxicity, or death. Dose reductions of ribociclib (ie, from 600 mg to 400 mg to 200 mg once daily) were permitted if treatment-related adverse events were noted. Dose reductions were not permitted for letrozole. Patients who discontinued ribociclib or placebo could continue receiving letrozole, but treatment crossover was not permitted.24
The primary end point of MONALEESA-2 was locally assessed PFS, according to RECIST criteria, version 1.1.24 The secondary end points were overall survival (OS), ORR (complete or partial response), clinical benefit rate (ORR plus stable disease lasting at least 24 weeks), safety, and quality-of-life assessments. Pharmacokinetics and biomarkers of response or resistance were exploratory end points. Tumor assessments were performed during screening, every 8 weeks during the first 18 months, every 12 weeks thereafter until disease progression, and at the end of treatment. All imaging data were reviewed by a blinded independent review committee.24
For the primary efficacy analysis, PFS was compared in the 2 groups using a log-rank test that was stratified according to the presence or absence of liver or lung metastases. The investigators determined that 302 adverse events (ie, disease progression or death) were required to detect a hazard ratio of 0.67 with a power of 93.5% at a one-sided alpha level of 0.025.24
A stratified Cox regression analysis was performed to estimate the hazard ratio and the 95% CIs for PFS.24 A prespecified interim analysis was planned after disease progression or death was reported in 211 of the 302 (70%) patients. The superiority of ribociclib plus letrozole over letrozole plus placebo would be demonstrated if the hazard ratio would be ≤0.56, with a P <1.29 × 10–5.24
Efficacy analyses were performed for the intention-to-treat (ITT) population. The safety database included all patients who received at least 1 dose of the study medication and had at least 1 safety assessment after baseline.24
MONALEESA-2 Study Findings
From January 2014 to March 2015, 668 patients were randomized in MONALEESA-2: 334 patients were assigned to receive ribociclib plus letrozole (ribociclib arm), and 334 patients were assigned to receive placebo plus letrozole (placebo arm).24 Patient characteristics at baseline were well-balanced between the 2 groups. All patients (median age, 62 years) had HR-positive disease. Overall, 34% of patients had newly diagnosed advanced or metastatic breast cancer. Visceral disease was present in 59% of women, whereas 22% had bone-only disease.24
At the data cutoff date in January 2016, treatment was still being administered to 195 patients in the ribociclib arm and to 154 patients in the placebo arm. The median duration of treatment exposure from the first to the last dose of ribociclib or placebo was 13.0 months and 12.4 months, respectively.24
The median relative dose intensity was 100% for letrozole in both groups, 100% for placebo, and 87.5% for ribociclib.24 Ribociclib was interrupted in 76.9% of patients, and letrozole was interrupted in 39.5% of patients in the ribociclib-containing arm. The most common adverse event leading to a dose reduction of ribociclib was neutropenia (31.1%). Treatment discontinuation was most often attributed to progressive disease (26% of patients in the ribociclib arm vs 44.7% in the placebo arm), decision by patient or physician (6.6% vs 7.8%, respectively), or adverse events (7.5% vs 2.1%, respectively).24
Progression-free survival. The prespecified interim analysis of data in MONALEESA-2 was triggered after disease progression or death in at least 211 patients. Because of a delay in reporting from local clinical trial centers, at the time of the data cutoff, 243 patients had disease progression or died and were included in the interim analysis.24
This clinical trial met its primary end point. After a median follow-up of 15.3 months, the median PFS was not reached in the ribociclib arm (95% CI, 19.3-not reached) compared with 14.7 months (95% CI, 13.0-16.5) in the placebo arm (hazard ratio, 0.56; 95% CI, 0.43-0.72; P <3.29 × 10–6; Figure 3).24 At a subsequent analysis with an additional 11-month follow-up, the median PFS was 25.3 months in the ribociclib plus letrozole arm versus 16 months in the placebo plus letrozole arm.25
Based on local assessments, the rate of PFS was significantly higher in patients who received ribociclib plus letrozole compared with those who received placebo plus letrozole.24 At 12 months, the PFS rate was 72.8% (95% CI, 67.3-77.6) in the ribociclib arm and 60.9% (95% CI, 55.1-66.2) in the placebo arm; at 18 months, the PFS rates were 63.0% (95% CI, 54.6-70.3) and 42.2% (95% CI, 34.8-49.5), respectively (Table 1).24 The investigator-assessed PFS benefit in patients in the ribociclib arm was observed in all the predefined subgroups.24
Overall response rate and clinical benefit rate. The ORR and clinical benefit rate were significantly higher in patients who received ribociclib plus letrozole than in those receiving placebo plus letrozole.24 The ORR in the ITT population was 40.7% in the ribociclib arm versus 27.5% in the placebo arm; these rates were 52.7% versus 37.1%, respectively, in patients with measurable disease (P <.001 for both comparisons). The clinical benefit rate in the ITT population was 79.6% in the ribociclib arm versus 72.8% in the placebo arm; these rates were 80.1% versus 71.8%, respectively, in patients with measurable disease (P = .02 for both comparisons; Table 2).24
Overall survival. At the time of the interim analysis, OS results were not mature.24 Overall, 43 deaths occurred at the data cutoff–23 deaths in the ribociclib arm versus 20 deaths in the placebo arm. The study remains blinded for OS assessment.24
The safety population comprised 334 patients in the ribociclib arm and 330 patients in the placebo arm.24 Adverse events of any grade occurring in at least 35% of the patients in the ribociclib arm or the placebo arm included neutropenia (74.3% vs 5.2%, respectively), nausea (51.5% vs 28.5%, respectively), infections (50.3% vs 42.4%, respectively), fatigue (36.5% vs 30.0%, respectively), and diarrhea (35.0% vs 22.1%, respectively; Table 3).24 The majority of these adverse events were grade 1 or 2.24
Grade 3 or 4 adverse events occurring in at least 5% of patients in the ribociclib arm or the placebo arm included neutropenia (59.3% vs 0.9%, respectively), leukopenia (21.0% vs 0.6%, respectively), hypertension (9.9% vs 10.9%, respectively), increased alanine aminotransferase levels (9.3% vs 1.2%, respectively), lymphopenia (6.9% vs 0.9%, respectively), and increased aspartate aminotransferase levels (5.7% vs 1.2%, respectively).24 Overall, 5 (1.5%) patients in the ribociclib group and none in the placebo group had febrile neutropenia.24
Furthermore, 4 (1.2%) patients in the ribociclib group reported concomitant increases in aminotransferase levels and bilirubin levels in the absence of cholestasis, which is the biochemical definition of Hy’s law.24 The investigators suspected that 3 of these 4 cases were treatment-related, and none resulted in death. In all 4 patients, aminotransferase and bilirubin levels returned to normal after ribociclib was discontinued.24
Infections were reported in 50.3% of patients in the ribociclib arm compared with 42.4% of patients in the placebo group.24 The most common infections in the ribociclib group and in the placebo group were urinary tract infections (10.8% vs 8.2%, respectively) and upper respiratory tract infections (10.5% vs 10.6%, respectively), the majority of which were grade 1 or 2. Grade 3 infections were reported only in the ribociclib group, including urinary tract infection in 2 patients. No grade 4 infections occurred in either group.24
Prolongation of the QT interval corrected for heart rate, according to Fridericia’s formula (QTcF) to more than 480 milliseconds, occurred in 2.7% of patients who received 600 mg of ribociclib.24 These changes typically occurred within the first 4 weeks of treatment. In routine practice, electrocardiograms (ECGs) should be assessed before starting ribociclib therapy in patients with QTcF values of less than 450 milliseconds.10 The ECG should be repeated at approximately day 14 of the first cycle, the beginning of the second cycle, and as clinically indicated.10
Serious adverse events were reported in 21.3% of patients in the ribociclib group versus 12% in the placebo group.24 Of these events, 7.5% in the ribociclib group and 1.5% in the placebo group were believed to be related to the study drugs. Overall, 4 deaths occurred during treatment: 3 deaths in the ribociclib group and 1 death in the placebo group. One patient in each group died from breast cancer progression. The remaining 2 deaths in the ribociclib group were attributed to sudden death (from grade 3 hypokalemia and grade 2 prolongation in the QTcF interval on day 1 of cycle 2) and death from an unknown cause. The sudden death was thought to be related to ribociclib.24
Implication. Based on findings from the phase 3 MONALEESA-2 clinical trial, Hortobagyi and colleagues concluded that the addition of ribociclib to letrozole significantly prolonged PFS and resulted in higher rates of overall response compared with letrozole plus placebo in the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. The longer PFS was associated with an increased rate of myelosuppression with ribociclib than with letrozole alone.24
Commenting on these findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology in Milan, Italy, stated, “I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development). The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib.”26
Subgroup Analyses of MONALEESA-2
During the 2016 San Antonio Breast Cancer Symposium, Burris and colleagues presented efficacy and safety results from the prospective subgroup analysis of the MONALEESA-2 study in patients with advanced breast cancer and visceral metastases, including liver, lung, and/or other metastatic sites and those with bone-only disease.27
This subgroup analysis showed that PFS was prolonged in patients with visceral metastases who received ribociclib plus letrozole compared with those who received placebo plus letrozole (hazard ratio, 0.54; 95% CI, 0.39-0.74). The median PFS was not reached in the ribociclib arm versus 13.0 months (95% CI, 12.6-16.5) in the placebo arm.27
In the 147 patients with bone-only disease, the number of PFS events was relatively low at the data cut-off: 18 events were reported in the ribociclib arm versus 32 events in the placebo arm. The median PFS was not reached (95% CI, not reached) in the ribociclib arm compared with 15.3 months (95% CI, 13.8-not reached) in the placebo arm (hazard ratio, 0.69; 95% CI, 0.38-1.25).27
Burris and colleagues concluded that the treatment benefit of ribociclib plus letrozole compared with letrozole plus placebo was maintained across all the preplanned patient subgroups, including those with visceral metastases or with bone-only disease.27 The treatment benefit of ribociclib plus letrozole was observed in the total patient population, regardless of the number of metastatic sites. Ribociclib plus letrozole was generally well-tolerated in both patient subgroups, with a similar safety profile to that observed in the total patient population.27
De Novo Disease
Also at the meeting, O’Shaugnessy and colleagues presented the safety and efficacy data from a planned subgroup analysis of the MONALEESA-2 study in patients with de novo advanced breast cancer.28 This analysis showed that PFS was prolonged in patients with de novo advanced breast cancer who received ribociclib plus letrozole versus those who received placebo plus letrozole (hazard ratio, 0.45; 95% CI, 0.27-0.75). The median PFS was not reached in the ribociclib arm compared with 16.4 months (95% CI, 13.4-not reached) in the placebo arm. The 12-month PFS rate was 81.6% with ribociclib versus 65.7% with placebo.28
O’Shaugnessy and colleagues concluded that the treatment benefit associated with ribociclib plus letrozole was maintained in patients with de novo advanced breast cancer who may have a different disease biology from those with previously treated disease. The combination of ribociclib plus letrozole was generally well-tolerated in patients with de novo disease, with a similar safety profile observed in the total patient population.28
At the 2017 European Cancer Congress, Sonke and colleagues presented the safety and efficacy data of ribociclib plus letrozole in a subset analysis of older patients (aged ≥65 years) with HR-positive, HER2-negative advanced breast cancer who participated in the MONALESSA-2 clinical trial.29
This subgroup analysis showed safety and efficacy similar to the general patient population. The median PFS was not reached (95% CI, 19.3-not reached) in the ribociclib plus letrozole group versus 18.4 months (95% CI, 15.0-not reached) in the placebo plus letrozole group (hazard ratio, 0.608; 95% CI, 0.394-0.937). The ORR was 37% in patients who received ribociclib plus letrozole versus 31% in patients who received placebo plus letrozole.29
Adverse events that occurred 10% more frequently in the ribociclib plus letrozole group than in the placebo plus letrozole group included neutropenia (74% vs 5%, respectively), leukopenia (31% vs 4%, respectively), fatigue (37% vs 24%, respectively), alopecia (33% vs 17%, respectively), diarrhea (41% vs 26%, respectively), and vomiting (35% vs 19%, respectively). Overall, the efficacy and safety of ribociclib in the elderly patient population were comparable to what was reported in younger patient populations.29
Future Development of Ribociclib
In addition to evaluations in ER-positive breast cancer, ribociclib is currently being studied in other tumor types, including prostate cancer, non–small-cell lung cancer, BRAF mutation–positive melanoma, high-grade glioma, and liposarcoma.30
Some of the ongoing studies of ribociclib in advanced breast cancer include30:
- MONALEESA-7, a phase 3 clinical trial involving premenopausal patients with advanced breast cancer; all patients receive goserelin, a gonadotropin-releasing hormone agonist, in combination with a nonsteroidal aromatase inhibitor (eg, letrozole or anastrozole) or tamoxifen, with or without ribociclib
- MONALEESA-3, a phase 3 clinical trial in which postmenopausal patients with ER-positive, HER2-negative advanced breast cancer are randomized to fulvestrant with or without ribociclib in the first- or second-line setting
- A phase 1b/2 study in which ribociclib is combined with letrozole and buparlisib (BKM120), an inhibitor of phosphatidylinositol 3-kinase
- A phase 1b/2 study in which ribociclib is combined with exemestane and everolimus in ER-positive, HER2-negative advanced breast cancer. Patients must have had no more than 1 previous line of therapy in the metastatic or locally advanced setting.
Author Disclosure Statement
Dr Hart reported no conflicts of interest.
- National Cancer Institute. Breast cancer risk in American women. www.cancer.gov/types/breast/risk-fact-sheet. Accessed February 17, 2016.
- Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR. Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers. Am J Clin Pathol. 2005;123:21-27.
- Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-247.
- Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18:333-345.
- Coleman ML, Marshall CJ, Olson MF. RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol. 2004;5:355-366.
- Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.
- Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res. 2014;20:3379-3383.
- Senderowicz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs. 1999;17:313-320.
- Ibrance (palbociclib) capsules [prescribing information]. New York, NY: Pfizer; March 2017.
- Kisqali (ribociclib) tablets [prescribing information]. East Hanover, NJ: Novartis; March 2017.
- 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. Mol Cancer Ther. 2004;3:1427-1438.
- Toogood PL, Harvey PJ, Repine JT, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem. 2005;48:2388-2406.
- Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011;104:1862-1868.
- Flaherty KT, Lorusso PM, Demichele A, et al. Phase 1, 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. Clin Cancer Res. 2012;18:568-576.
- DeMichele A, Clark AS, Tan KS, et al. CDK 4/6 inhibitor palbociclib (PD 0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21:995-1001.
- 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;16:25-35.
- US Food and Drug Administration. FDA approves Ibrance for postmenopausal women with advanced breast cancer. Press release. February 3, 2015. www.fda.gov/newsevents/newsroom/pressannouncements/ucm432871.htm. Accessed December 14, 2016.
- Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925-1936.
- US Food and Drug Administration. Palbociclib (Ibrance capsules). www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm487080.htm. Accessed February 21, 2017.
- Turner NC, Ro J, André F, et al; for the PALOMA3 Study Group. Palbociclib in hormone-receptor–positive advanced breast cancer. N Engl J Med. 2015;373:209-219.
- Kim S, Loo A, Chopra R, et al. LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6—reactivating Rb in cancer. Mol Cancer Ther. 2013;12(11 suppl):Abstract PR02.
- 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;22:5696-5705.
- 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 Ib safety, preliminary efficacy and molecular analysis. Poster presented at the American Society of Clinical Oncology annual meeting; June 3-7, 2016; Chicago, IL.
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738-1748.
- Novartis Pharmaceuticals Corporation. Novartis Kisqali (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor. Press release. March 13, 2017. www.novartis.com/news/media-releases/novartis-kisqalir-ribociclib-lee011-receives-fda-approval-first-line-treatment. Accessed May 15, 2017.
- European Society for Medical Oncology. ESMO 2016 press release: ribociclib improves progression-free survival in advanced breast cancer. October 8, 2016. www.esmo.org/Conferences/ESMO-2016-Congress/Press-Media/Ribociclib-Improves-Progression-free-Survival-in-Advanced-Breast-Cancer. Accessed December 15, 2016.
- Burris HA, Chan A, Campone M, et al. First-line ribociclib + letrozole in patients with HR+, HER2– advanced breast cancer presenting with visceral metastases or bone-only disease: a subgroup analysis of the MONALEESA-2 trial. Presented at the San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.
- O’Shaughnessy J, Petrakova K, Sonke GS, et al. First-line ribociclib + letrozole in patients with de novo HR+, HER2– advanced breast cancer: a subgroup analysis of the MONALEESA-2 trial. Poster presented at the San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.
- Sonke GS, Hart LL, Campone M, et al. Efficacy and safety of ribociclib + letrozole in elderly patients with HR+, HER2– advanced breast cancer in MONALEESA-2 trial. Presented at the European Cancer Congress; January 27-30, 2017; Amsterdam, The Netherlands.
- ClinicalTrials.gov. Ribociclib. Search results. https://clinicaltrials.gov/ct2/results?term=Ribociclib&Search=Search. Accessed December 15, 2016.