Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment

Abstract

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Keywords

Abemaciclib cyclin-dependent kinase 4/6 inhibitors palbociclib ribociclib trilaciclib

Introduction

Cell cycle dysregulation is induced by such complex mechanisms as the functional imbalance of oncogenes and tumor suppressor genes, thus contributing to uncontrolled cell proliferation and subsequent cancer development.¹ Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors represent novel effective therapies developed over recent decades, particularly in the setting of metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, a disease state for which prior treatment options commonly included anthracycline- or taxoid-based chemotherapy, aromatase inhibitors, tamoxifen, and other anti-estrogens, such as fulvestrant.² Palbociclib and ribociclib are currently Food and Drug Administration (FDA) approved for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer (MBC), to be used in combination with an aromatase inhibitor in postmenopausal women.^3,4 Palbociclib is also FDA-approved for use in combination with fulvestrant in HR-positive, HER2-negative breast cancer progressing despite endocrine therapy.^5,6 Abemaciclib was newly FDA-approved as monotherapy for HR-positive, HER2-negative advanced breast cancer previously treated with chemotherapy and endocrine therapy, as well as in combination with fulvestrant in HR-positive, HER2-negative breast cancer after progression on endocrine therapy.⁷ In this review, we will discuss the current data supporting the FDA-approved indications, as well as current research and future directions of treatment with CDK 4/6 inhibitors.

Mechanism of action

The normal cell cycle consists of four phases: the first growth phase (G1), DNA synthesis phase (S), the second growth phase (G2), and cell division in mitosis (M). Various checkpoints regulate progression from one cell cycle phase to the next. These checkpoints may also initiate apoptosis if cellular damage is detected.¹ Cyclin D1-cyclin dependent kinase/6 retinoblastoma 1 signaling pathway (cycD1-CDK4/6-Rb1) regulates progression from G1 to S phase of the cell cycle.⁸ This is the “restriction point”, irreversibly committing the cell to mitosis regardless of external signals.⁹

During G1, the Rb protein is found in an inactive complex with E2 transcription factor (E2F), which prevents the gene expression necessary for entry into S phase. At the G1-S checkpoint, mitogenic signaling pathways drive the expression of cyclin D, which associates with and activates CDK4 and CDK6. The active complex of cyclin D-CDK4/6 phosphorylates the Rb protein, which is unable to interact with E2F. Thus, E2F is rendered active and able to drive the gene expression necessary for entry into the S phase.^10–12 In addition, the active combination of CDK 4/6 and cyclin D is involved in the phosphorylation of the cell proliferation-specific forkhead box M1 (FOXM1), which suppresses cellular senescence and induces expression of genes necessary for cell division.¹³ Amplification of CDK4 CCND1 (encoding cyclin D1) and overexpression of cyclin D protein are frequent in human cancers, although specific abnormalities vary depending on cancer types.^14,15

Palbociclib, ribociclib, abemaciclib, and trilaciclib are potent CDK4 and CDK6 inhibitors that prevent the retinoblastoma protein from being phosphorylated further downstream in the cell cycle,¹⁶ thus suppressing progression from G1 to S phase and preventing the cell from being irreversibly committed to mitosis and proliferating regardless of external signals. Preventing further unchecked proliferation characteristic of malignancies is the rationale for using CDK 4/6 inhibitors in oncologic applications.

CDK 4/6 inhibitors are used in combination with endocrine therapy in metastatic HR-positive breast cancer in order to further build upon the effects of endocrine therapy, which antagonizes the estrogen receptors breast cancer cells use to proliferate. Unfortunately, all patients do not respond to endocrine therapy alone, and some patients who initially respond to endocrine therapy become resistant and experience disease progression at a later date. Many potential mechanisms to explain endocrine therapy resistance have been proposed, including dysregulation of the CDK 4/6 retinoblastoma pathway. Simultaneously blocking the HRs used by cancers to facilitate proliferation and preventing dysregulation of the CDK 4/6 retinoblastoma pathway, which would lead to uncontrolled cell proliferation, is the rationale for using CDK 4/6 inhibitors in combination with endocrine therapy.¹⁷

The most well-studied CDK 4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, all inhibit CDK 4 and 6 with a high degree of selectivity, although their half maximal inhibitory concentrations (IC50) against other cellular CDKs do vary.¹⁸ In addition, abemaciclib has been found to have greater selectivity for CDK4 than for CDK6, as opposed to palbociclib and ribociclib, who have more equal selectivities for CDK4 and CDK6.¹⁹ These individual factors may contribute to the approval of abemaciclib alone as single-agent treatment. They may also contribute to each drug’s dosing regimen and adverse effects profile, which will be further discussed.

See Figure 1 for a detailed illustration of the mechanism of action of CDK 4/6 inhibitors.

Palbociclib

Palbociclib (PD 0332991) is the most well-studied of the CDK 4/6 inhibitors. It is currently FDA-approved for use with letrozole in postmenopausal women with metastatic, HR-positive, HER2-negative breast cancer in the first line setting, based on the results of the PALOMA-1 and PALOMA-2 trials, with a recommended dosing regimen of 125 mg once daily for 21 days, followed by 7 days off.^3,4,20. PALOMA-1 compared palbociclib and letrozole to letrozole alone. The findings of median progression-free survival (PFS) of 10.2 months in the letrozole group and 20.2 months in the palbociclib and letrozole group led to accelerated FDA-approval for the previously mentioned indication.³ These findings were confirmed with the PALOMA-2 trial, which further assessed the safety and efficacy of palbociclib plus letrozole as first-line therapy for postmenopausal women with ER-positive, HER2-negative advanced breast cancer. The median PFS in the palbociclib and letrozole group when compared to the letrozole group was 24.8 months vs. 14.5 months.⁴

Based on the results of the PALOMA-3 trial, palbociclib became approved in combination with fulvestrant for HR-positive, HER2-negative breast cancer that had progressed after endocrine therapy. The median PFS in the palbociclib and fulvestrant group when compared to the fulvestrant and placebo group was 9.5 months vs. 4.6 months.⁶

Together, the results of the PALOMA-1, PALOMA-2, and PALOMA-3 trials indicate significant PFS benefit of palbociclib in combination with endocrine therapy, the previous standard of care for most patients presenting with de novo or prior localized metastatic HR-positive, HER2-negative breast cancer.²¹ Although long-term follow-up is still needed in order to measure overall survival and long-term treatment effect, palbociclib nonetheless represents another viable treatment option for a progressive and incurable disease state.

Given the successful use of palbociclib in HR-positive, HER2-negative MBC, and the fact that the HER2 signal converges onto the cycD1-CDK4/6-Rb1 pathway, there is the question of using palbociclib in combination with trastuzumab and other targeted therapies in HER2-positive breast cancer. Although trastuzumab and other HER2-targeting therapies represent major advancements in breast cancer treatment, 40–70% of HER2-positive tumors become resistant to treatment within the first year, sometimes as soon as one to two months after treatment initiation.²²

CDK 4/6 inhibitors are an especially compelling potential therapy in HER2-positive breast cancer. HER2 is a protein overexpressed in HER2-positive breast cancers that activates various types of epidermal growth factor receptors to induce cell proliferation and promote survival. Although there are many pathways that can lead to resistance to HER2-targeted therapies, CDK 4/6 inhibition has been shown in animal models to block the inappropriate cyclin D1 activation present in acquired HER2 resistance. Dysregulation of CDK 4/6 activity has been found to induce murine mammary tumors. Conversely, in murine models, CDK 4/6 inhibitors have been shown to antagonize HER2-driven growth of mammary tumors. The majority of information regarding CDK 4/6 inhibitors in HER2-positive breast cancer comes from laboratory data.^23,24 There are currently no published results of clinical trials assessing the use of CDK 4/6 inhibitors in HER2-positive breast cancer or with HER2-targeted therapies, although this remains a valuable question for further research. Prior studies reveal a ten percent incidence of HER2 overexpression in estrogen receptor-positive tumors,²⁵ indicating a significant treatment population for which palbociclib is not approved.

Metastatic germ cell tumors represent an interesting possibility for the use of palbociclib. Currently, limited treatment options exist for refractory germ cell tumors, particularly teratoma with malignant transformation and unresectable growing teratoma. Upregulation of CDK4 and cyclin D2 is present in germ cell tumors, and teratomas and well-differentiated nonseminoma germ cell tumors have strong retinoblastoma protein expression, although it is decreased or absent in poorly differentiated germ cell tumors. In a non-randomized open-label study of 29 patients, Vaughn et al. demonstrate that 8 out of 29 patients experienced 24 weeks of PFS with generally well-tolerated treatment and no treatment-related deaths.²⁶ Although intriguing, considerable more research is needed in order to determine whether palbociclib has any role in the treatment of metastatic germ cell tumors.

Dickson et al. describe the use of palbociclib in patients with advanced well-differentiated or dedifferentiated liposarcoma, a disease for which surgery, rather than chemotherapy, is the cornerstone of treatment. However, in locally advanced or metastatic disease not amendable to surgical resection, there are limited other treatment options. CDK4 is amplified in more than 90% of well-differentiated and dedifferentiated liposarcoma, making palbociclib an attractive treatment option.^16,27 Dickson et al. found that in 29 patients with confirmed CDK4 amplification and retinoblastoma protein expression who experienced disease progression while on systemic therapy, palbociclib resulted in a median PFS of 18 weeks, including one partial response (PR).¹⁶ Although these results represent a promising area for further research in non-resectable disease, non-surgical treatment options continue to be very limited.

Palbociclib also offers promise in the treatment of hematologic malignancies. Marzec et al. and Leonard et al. describe the potential use of palbociclib in mantle cell lymphoma, which has a poor prognosis, with a median survival time of 3.5 years. The characteristic chromosomal translocation t(11;14) causes ectopic cyclin D1 expression, which subsequently activates CDK4 and CDK6 to ultimately promote inactivation of Rb protein. Low nanomolar doses of palbociclib have been found to completely inhibit mantle cell lymphoma cell lines,^28,29 especially significant since the breast, colon, and non-small cell lung cell lines used by Fry et al. required 10–20 times higher concentrations of palbociclib for efficacy.³⁰ Thus, palbociclib represents a drug of considerable promise and area of active research. Indeed, several studies of palbociclib in relapsed/previously treated mantle cell lymphoma are ongoing, representing an area of promise in what is currently a devastating diagnosis.³¹

Baughn et al. discuss how activation of CDK4 and CDK6 precedes proliferation of bone marrow cells in multiple myeloma. Palbociclib was found to prevent myeloma growth in human xenografts when used in combination with dexamethasone, although the mechanism of dexamethasone cytotoxicity in not entirely defined.³² Niesvizky et al. also studied palbociclib in multiple myeloma, specifically in relapsed or refractory disease in combination with bortezomib and dexamethasone. Of the 21 patients enrolled in phase 1, 2 patients had very good PR, and 7 had stable disease (SD). In phase 2, which evaluated efficacy and safety, 5 patients had objective responses, and 11 patients had SD.³³ These studies indicate that palbociclib has promising implications in the field of multiple myeloma research.

In phase I trials, dose-limiting toxicities of palbociclib included neutropenia and thrombocytopenia, fatigue, nausea, diarrhea, and constipation.⁵ Specific treatment protocols for palbociclib-induced neutropenia recommend regular monitoring of complete blood count (CBC), treatment of concomitant fever and infection, and potential treatment interruption and/or dose reduction depending on severity.³⁴ Palbociclib-induced neutropenia is different than neutropenia induced by cytotoxic chemotherapy in that it is more rapidly reversible, thus the rationale for giving palbociclib 21 days in a row followed by 7 days off.³⁵ However, multivariate analysis of PALOMA-3 trial data indicate that incidence of infection had no statistically significant relationship to the presence of grade 3 or grade 4 neutropenia.³⁶ Grade 3 or 4 gastrointestinal side effects of palbociclib are rare, and symptomatic management is recommended.³⁴

When combined with the potential benefits to the wide variety of malignancies described above, with new research coming out frequently, palbociclib remains a viable option for further research and patient care. Since MBC is not curable, the goals of treatment include prolongation of survival, control of pain and other disease-related symptoms, and quality of life maintenance or improvement. Harbeck et al. performed a quality of life assessment based on validated questionnaires regarding symptoms and physical function given to patients participating in the PALOMA-3 trial (QLQ-C30 used for cancer patients in general and QLQ-BR23 used for breast cancer patients specifically) and concluded that the combination of palbociclib and fulvestrant allowed for good quality of life while also delaying disease progression.³⁷

Table 1 summarizes various clinical studies of palbociclib. Table 4 summaries the adverse effects of palbociclib and other CDK 4/6 inhibitors.

Table 1.

Palbociclib studies.

Study name and author	Trial phase	Patients	Drugs and dosage	n	Clinical efficacy	Adverse effects
PALOMA-1: The CDK 4/6 inhibitor palbociclib in combination with letrozole alone as first-line treatment of estrogen receptor-positive, HER2-negative, advanced breast cancer Finn et al.³	II	Post-menopausal women with MBC who did not receive prior systemic treatment	Palbociclib 125 mg once daily plus letrozole 2.5 mg daily vs. letrozole 2.5 mg daily	165	Median PFS of 5.7 months in letrozole group and 26.1 months in palbociclib group	Neutropenia, leukopenia, pulmonary embolism
PALOMA-2: Palbociclib and letrozole in advanced breast cancer Finn et al.⁴	III	ER⁺ MBC with no prior treatment	Letrozole 2.5 mg daily with or without palbociclib Palbociclib 125 mg daily on days 1-21 of a 28-day cycle	666	Median PFS 24.8 months vs. 14.5 months for letrozole monotherapy	Neutropenia, leukopenia
PALOMA-3: Palbociclib in HR positive advanced breast cancer Cristofanilli et al.⁶	III	HR⁺ MBC after progression on one line of endocrine therapy for MBC	Palbociclib (125 mg per day for 3 weeks followed by 1 week off) with standard dose fulvestrant	521	Median PFS 9.2 months vs. 3.8 months for fulvestrant monotherapy	Neutropenia, leukopenia
CDK4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment DeMichele et al.³⁸	II	Metastatic Rb⁺ breast cancer	Palbociclib 125 mg daily for 21 days, followed by 7 days off	37	Overall: 5% PR, 38% SD <6 months, 14% SD ≥6 months, 19% CBR HR⁺ patients: 6% PR, 39% SD <6 months, 16% SD ≥6 months, 21% CBR	Neutropenia, leukopenia, lymphopenia, thrombocytopenia
Phase I, dose-escalation trial of the oral CDK 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer Flaherty et al.³⁹	Ib	Rb⁺ advanced solid tumors	75 mg, 125 mg, 150 mg once daily dosages	41	27% SD for ≥4 cycles, 16% SD for ≥10 cycles	Neutropenia, leukopenia
A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in NSCLC patients with inactivated CDKN2A Gopalan et al.⁴⁰	II	Previously treated, advanced Rb⁺, CDKN2A inactivated NSCLC	Palbociclib125 mg daily for 21 days followed by a 7-day break	19	50% SD, 12.5 weeks median PFS	Neutropenia
Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib Dickson et al.¹⁶	II	18 years of age or older with advanced well differentiated or dedifferentiated liposarcoma	Palbociclib 125 mg daily for 21 days followed by a 7-day break	60	17.9 weeks median PFS	Neutropenia
Phase 2 trial of the CDK 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors Vaughn et al.²⁶	II	Patients with incurable, refractory germ cell tumors with pRB expression by immunohistochemistry	Palbociclib 125 mg daily for 21 days followed by a 7-day break	30	28% 24-week PFS rate	Neutropenia, neutropenic fever, leukopenia, thrombocytopenia, anemia, anorexia, mucositis, fatigue, and weight loss
Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma Leonard et al.²⁹	Ib	18 years of age or older with mantle cell lymphoma and ≥1 prior therapy completed	Palbociclib 125 mg daily for 21 days followed by a 7-day break	17	6% CR, 12% PR, 15% ORR 4 months, 4 months median PFS	Neutropenia, thrombocytopenia, fatigue and diarrhea
Phase 1/2 study of CDK 4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma Niesvizky et al.³³	II/III	18 years of age or older with a diagnosis of symptomatic MM and relapsed and/or refractory MM after ≥1 previous treatment. Rb-positive tumors	Phase 2 dose: palbociclib 100 mg once daily on days 1–12 of a 21-day cycle with bortezomib and dexameth-asone on days 8, 11, 15, and 18	21 in phase I, 32 in phase II	Median duration of objective response of 2.8 months. 44% SD with median duration of 3.9 months	Anemia, thrombocytopenia, rash, and neutropenia

MBC: metastatic breast cancer; PFS: progression-free survival; PR: partial response; SD: stable disease, CBR: clinical benefit rate; ORR: overall response rate.

Table 4.

Adverse effects of CDK4/6 inhibitors.⁷³

	Hematologic side effects	Gastrointestinal toxicity	Liver enzyme elevation	Pulmonary embolism	QT prolongation
Symptoms	Fatigue, SOB, increased tendency to bleed/bruise	Nausea, vomiting, diarrhea	Weight loss, Jaundice, dark urine, itching, abdominal swelling	SOB, chest pain, cough, tachypnea, tachycardia	Palpitations, syncopal episodes
Clinical assessment	Complete blood counts	Electrolyte levels	Liver function tests	Monitor patient symptoms	ECG
Crucial time window	2 weeks after drug administration in treatment Cycles 1 and 2 (palbociclib and ribociclib)	1 week after drug administration (abemaciclib)	Throughout treatment	Throughout treatment	First 4 weeks of treatment
Frequency of monitoring	Start of each treatment cycle. additional assessments during Cycles 1 and 2.	Throughout treatment	Throughout treatment	Throughout treatment	Throughout treatment
Additional risk factors	Infections, fever, Asian ethnicity, low baseline neutrophil count	Fever, dizziness, abdominal pain	Concomitant medication	Deep-vein thrombosis	Diarrhea, vomiting, concomitant medication

Ribociclib

Ribociclib (LEE011) was originally studied in patients with lymphomas and advanced solid tumors. In a phase I study, 125 of 132 patients received ribociclib in a schedule of 21 days on, 7 days off, and 7 patients received continuous dosing. Of those 132 patients, 3 patients had PR, and 43 patients achieved best response of SD. Eight patients, who had various tumor types, such as squamous cell carcinomas of the head and neck, teratomas, and liposarcomas, had PFS for greater than 6 months.⁴¹

Curigliano et al. assessed the biological activity of ribociclib with letrozole compared to letrozole alone as neoadjuvant therapy in surgically resectable HR-positive, HER2-negative breast cancer. Fourteen women were randomized to receive letrozole alone, letrozole with 400 mg of ribociclib, or letrozole with 600 mg of ribocicilib. Patients who took ribociclib were noted to have significantly reduced expression of Ki67, which is a protein indicating cell proliferation in HR-positive, HER2-negative breast cancer. The total decrease in the percentage of Ki67 positive cells was 69% in the letrozole-alone arm, 96% in the letrozole and 400 mg ribociclib arm, and 92% in the letrozole and 600 mg ribociclib arm. There were no grade 3 or 4 adverse events noted throughout the 9-month treatment course.⁴²

Based on the results of the MONALEESA-2 study, ribociclib has been approved by the FDA as first-line treatment for use in combination with aromatase inhibitors in post-menopausal women with HR-positive, HER2-negative advanced or MBC in a dosing regimen of 600 mg once daily for 21 days, followed by 7 days off. The MONALEESA-2 study included 668 postmenopausal women with untreated HR-positive, HER2-negative recurrent or MBC. All patients received letrozole and were randomized to receive either ribociclib or placebo in addition. Patients who received ribociclib were given 600 mg daily for 21 consecutive days, followed by 7 days off. The overall response rates (ORR) in the ribociclib group and the placebo group were 52.7% and 37.1%, respectively. The PFS at 18 months in the ribociclib and placebo groups was 63% and 42.2%, respectively. However, participants who received ribociclib experienced significantly more neutropenia, leukopenia, nausea, diarrhea, alopecia, and vomiting.^19,43

The ongoing MONALEESA-3 trial is investigating the addition of ribociclib to fulvestrant in HR-positive advanced breast cancer who have never received endocrine therapy or who received only one prior type of endocrine therapy.⁴⁴ The MONALEESA-7 trial is investigating the combination of ribociclib with either tamoxifen or nonsteroidal aromatase inhibitors plus goserelin in premenopausal or perimenopausal women with HR-positive advanced breast cancer. To date, MONALEESA-7 is the only clinical trial dedicated to investigating CDK4/6 inhibitors specifically in the premenopausal and perimenopausal setting,⁴⁵ which has potential exciting new clinical applications in MBC patients who have not yet completed menopause. The earliest results of MONALEESA-7 were presented at the 2017 San Antonio Breast Cancer Symposium. The median PFS in the ribociclib arm compared to the placebo arm was 23.8 months and 13 months, respectively. Although the results of all secondary endpoints are not yet available, the overall response rate was also significantly higher in the ribociclib arm when compared to the placebo arm, at 51 vs. 36%.⁴⁶ Even though more long-term follow-up is needed, ribociclib shows great clinical promise when compared to the standard of care in premenopausal or perimenopausal HR-positive breast cancer patients.

Although ribociclib has been most researched in breast cancer, it has also been studied in other malignancies. For example, ribociclib is being studied in pediatric neuroblastoma and malignant rhabdoid tumor (MRT). In one study, 32 pediatric patients aged 1–21 years received 1 of 3 possible doses of ribociclib. Out of these 32 patients, 3 patients experienced dose-limiting fatigue or thrombocytopenia. In addition, 7 neuroblastoma patients and 2 patients with primary CNS MRT experienced SD for between 6 and 13 cycles of ribociclib,⁴⁷ indicating ribociclib as an area of promise for further research.

The combinations of ribociclib plus binimetinib or encorafenib have been evaluated in phase Ib/II studies of advanced melanoma with NRAS and BRAF mutations. Metastatic melanoma continues to be a devastating diagnosis with a dismal prognosis, with 5-year survival rates ranging from approximately 5 to 19%, depending on the location and number of metastatic sites.⁴⁸ In patients with the NRAS mutation, the combination of ribociclib with binimetinib was associated with encouraging preliminary activity, although patients did experience creatinine phosphokinase elevation, creatinine elevation, acneiform rashes, nausea, edema, leukopenia, and neutropenia.^49,50 In patients with the BRAF mutation, the combination of ribociclib and encorafenib also showed promising preliminary activity, although it was associated with nausea, pruritus, rash, myalgia, and hand-foot syndrome.^50,51 Although preliminary, these responses hold significant potential for advancement in the treatment with patients with extremely poor prognoses.

Common adverse effects (AEs) of ribociclib are similar to palbociclib and have included neutropenia, leukopenia, fatigue, and nausea.^41,52–55 Overall, cytopenias were common reasons for dose reduction or interruption. As with palbociclib, it is recommended to manage ribocicilb-induced neutropenia with regular CBC monitoring, treatment of any accompanying fevers or infections, and dose reduction and/or treatment interruption depending on severity.³⁴ Ribociclib-induced neutropenia is also more rapidly reversible than neutropenia associated with cytotoxic chemotherapy, which is why ribociclib is given in a standard 21 days on and 7 days off regimen.³⁵ Similar to palbociclib, grade 3 or 4 gastrointestinal side effects are rare, and symptomatic management is the treatment of choice.³⁴ However, since previous trials have reported corrected Q-T interval (QTc) prolongation with ribociclib use,^42,47 caution must be used when prescribing antiemetics in order to avoid potentiating torsades de pointes.³⁴ This acceptable safety profile supports the use of ribociclib in further investigations.⁴¹ Table 4 summarizes the adverse effects of ribociclib and other CDK 4/6 inhibitors.

Table 2 summarizes various clinical studies of ribociclib.

Table 2.

Ribociclib studies.

Study name and author	Trial phase	Patients	Drugs and dosage	n	Clinical efficacy	Adverse effects
Hortobagyi et al.⁴³	III	Postmenopausal women with HR-positive, HER2-negative recurrent or MBC who had not received previous systemic therapy for advanced disease	Ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole	668	18 months PFS 63.0% in the ribociclib group and 42.2% in the placebo group 52.7% ORR for ribociclib and letrozole and 37.1% for letrozole and placebo	Neutropenia, nausea, fatigue, diarrhea, arthralgia, and rash
Geoerger et al.⁴⁷	I	Pediatric patients with neuroblastoma, malignant rhabdoid tumors, or other CDK4/6-altered tumors	Ribociclib 280, 350, or 470 mg	32	9 patients with SD, 7 with neuroblastoma, 2 with primary CNS malignant rhabdoid tumor	Fatigue, thrombocytopenia, neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, nausea, vomiting, and QTc prolongation
Bardia et al.⁵²	Ib/II	Postmenopausal women with ER+, HER2− advanced breast cancer previously treated with letrozole or anastrozole	Ribociclib: 600 mg/day in 3 weeks on/1 week off schedule, combined with exemestane 25 mg/day	14	2 patients with unconfirmed PR, 4 patients with SD	Neutropenia, leukopenia, lymphopenia, ALT and AST elevation, anemia
Munster et al.⁵³	Ib	Pretreated and treatment-naive postmenopausal women with ER+, HER2− advanced breast cancer	Ribociclib: 600 mg/day in 3 weeks on/1 week off schedule combined with letrozole 2.5 mg/day	47	Treatment naive: 2 CR, 11 PR, 3 unconfirmed PR, 5 SD, 46% ORR, 89% DCR 79% CBR, 25.3 months median PFS Previously treated: 5.5 months median PFS	Neutropenia, ALT and AST elevation, asthenia, fatigue, urinary tract infection, constipation, nausea
Tolaney et al.⁵⁴	Ib	Postmenopausal women with HR+, HER2− advanced breast cancer	Ribociclib: 600 mg/day on 3 weeks on/1 week off schedule or continuous 400 mg/day Fulvestrant: 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent cycles	28	Ribociclib 3 weeks on/1 week of schedule; 3 PR, 9 SD Ribociclib 400 mg/day, continuous: 2 PR, 7 SD	Ribociclib 3 weeks on/1 week off schedule: neutropenia, fatigue, ALT and AST elevation Ribociclib 400 mg/day: neutropenia, reduced leukocyte count, ALT and AST elevation
Bardia et al.⁵⁵	Ib/II	Postmenopausal women with ER+, HER2− advanced breast cancer previously treated with letrozole or anastrozole	Ribociclib: 300 mg/day on 3 weeks on/1 week off schedule Everolimus: 2.5 mg/day Exemestane: 25 mg/day	77	9% ORR, 73% DCR, 26% CBR	Neutropenia, leukopenia, lymphopenia, anemia, thrombocyto-penia, ALT and AST elevation
Curigliano et al.⁴²	II	Postmenopausal women with HR+, HER2- Grade II/III, invasive, early breast cancer who have received no prior treatment	Ribociclib: 400 mg/day or 600 mg/day Letrozole: 2.5 mg/day	14	Ribociclib 400 mg/day + letrozole: 96% decrease in Ki67 Ribociclib 600 mg/day + letrozole: 92% decrease in Ki67 Letrozole only: 69% decrease in Ki67	No grade 3 or 4 adverse events. Reported abdominal pain, nausea, diarrhea, vomiting, asthenia, stomatitis, fatigue, decreased appetite, hypomagnesemia, QTc prolongation, dyspnea, hot flushes
Sosman et al.⁴⁹	Ib/II	Patients with advanced NRAS-mutant melanoma	Ribociclib: 200 mg/day on 3 weeks on/1 week off schedule Binimetinib45 mg BID	22	7 PR, 11 SD, 33% had 20%–30% tumor shrinkage	Creatine kinase elevation, neutropenia, acneiform, dermatitis, rash
Taylor et al.⁵¹	Ib/II	Patients with advanced BRAFV600-mutant melanoma	Encorafenib + ribociclib	18	2 confirmed PRs, 3 unconfirmed PRs, 10 SD, 1 SD >9 cycles	Hand–foot syndrome, rash, myalgia
Tripathy⁴⁶	III	Premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer without prior endocrine therapy for advanced breast cancer	Ribociclib 600 mg once daily, 3 weeks on, 1 week off, in combination with tamoxifen, letrozole, or anastrazole and goserelin implant vs. placebo in combination with tamoxifen letrozole, or anastrazole and goserelin implant	672	Median PFS of 23.8 months in ribociclib arm and 13 months in placebo arm	Neutropenia, hot flashes, nausea, leukopenia, and joint pain/stiffness

ALT: alanine aminotransferase; AST: aspartate aminotransferase; MBC: metastatic breast cancer; PFS: progression-free survival; PR: partial response; SD: stable disease, CBR: clinical benefit rate; ORR: overall response rate.

Abemaciclib

Similarly to palbociclib and ribociclib, abemaciclib has shown promising results in breast cancer and has been FDA-approved for use in combination with fulvestrant in HR-positive, HER2-negative breast cancer progressing after endocrine therapy and also as monotherapy for HR-positive HER2-negative MBC previously treated with endocrine therapy and chemotherapy. Support for the use of abemaciclib as monotherapy comes from the MONARCH 1 study, a phase 2 trial, and support for the use in combination with fulvestrant comes from the MONARCH 2 study, a phase 3 trial. The FDA-approved dosing regimen of abemaciclib is 150 mg twice daily when given in combination with fulvestrant and 200 mg twice daily when given as monotherapy. Unlike palbociclib and ribociclib, abemaciclib is dosed continuously.⁷

MONARCH 1 is a phase 2 of single agent abemaciclib in HR-positive, HER2-negative MBC progressing during or following endocrine therapy. Out of 132 patients in the study, 19.7% had a confirmed objective response in the 12-month final analysis, with a median PFS of 6 months and a mean OS of 17.7 months. The most common AEs included diarrhea, fatigue, and nausea.⁵⁶

The MONARCH 2 study further expands upon the promising results of MONARCH 1. Patients with HR-positive and HER2-negative breast cancer who progressed on neoadjuvant or adjuvant endocrine therapy within 12 months after adjuvant endocrine therapy or during first line endocrine therapy secondary to metastatic disease were given either fulvestrant alone or fulvestrant and abemaciclib. Study results indicated that median PFS in the fulvestrant group and the fulvestrant and abemaciclib group was 9.3 months and 16.4 months. ORR for fulvestrant alone and fulvestrant and abemaciclib was 21.3% and 48.1%. The most common AEs included diarrhea, neutropenia, nausea, and fatigue.⁵⁷

The MONARCH 3 study, a randomized phase 3 trial, compared abemaciclib with the nonsteroidal aromatase inhibitors letrozole or anastrazole as first line treatment for post-menopausal women with HR-positive and HER2-negative breast cancer with metastasis or locoregional recurrence. The trial included 493 patients, who were randomized to receive either abemaciclib or placebo with daily letrozole or anastrazole until disease progression or unacceptable treatment toxicity.⁵⁸ Median PFS was prolonged significantly in the abemaciclib arm (not yet reached in abemaciclib arm and 14.7 months in placebo arm). ORR in the abemaciclib and placebo arms was 48.2% and 34.5%, respectively. The most common AEs were diarrhea, neutropenia, and leukopenia.⁵⁸

The neoMONARCH phase 2 study evaluated abemaciclib alone or abemaciclib combined with anastrazole vs. anastrazole alone in the neoadjuvant setting in previously untreated postmenopausal women with early stage HR-positive, HER2-negative breast cancer. Patients taking abemaciclib, whether alone or in combination with anastrazole, were noted to have significantly reduced expression of Ki67. The percentages of patients with reduced Ki67 expression in the abemaciclib and anastrazole combination group, the abemaciclib alone group, and the anastrazole alone group were 66%, 59%, and 15%, respectively.^59,60 However, as discussed previously with ribociclib,⁴² the question of whether measured Ki67 reduction directly translates to long-term clinical benefit requires further exploration.

Abemaciclib has largely been studied in breast cancer. However, the ongoing JUNIPER study is comparing abemaciclib and best supportive care with erlotinib and best supportive care in patients with KRAS positive stage 4 non-small cell lung cancer (NSCLC) progressing after or ineligible for platinum-based chemotherapy. CDK4 is required for tumor progression in KRAS-induced adenocarcinoma of the lung. Ablation of CDK4 subsequently induces KRAS-expressing cells to become senescent. If significant difference in PFS and OS is achieved with abemaciclib, abemaciclib may ultimately become a favored treatment for KRAS-positive NSCLC.⁶¹

Similar to palbociclib, abemaciclib has also shown promising results in multiple myeloma. Iriyama et al. found that abemaciclib inhibited myeloma cell growth and showed apparent cytocidal activity and autophagy in a dose-dependent manner.⁶² Although there are no current active clinical trials specifically investigating abemaciclib in multiple myeloma patients, this nonetheless represents a significant finding in the field of multiple myeloma research.

The efficacy and approval of abemaciclib for use as monotherapy contrasts with palbociclib and ribociclib, which have only been approved in combination with other therapies. Although the specific reason for increased efficacy of abemaciclib as monotherapy has not been defined, it may be related to greater selectivity for CDK4 than CDK6 or to the continuous dosing of abemaciclib, which is recommended as 150 mg twice daily when used in combination with fulvestrant or 200 mg twice daily when used as monotherapy. Unlike palbociclib and ribociclib, which have an established dosing schedule of 21 days on and 7 days off, the most common dosing regimen for abemaciclib does not include scheduled time off.¹⁹ Interestingly, abemaciclib has demonstrated a lower rate of neutropenia when compared to palbociclib and ribociclib, despite a continuous dosing schedule. Notably, other side effects, such as fatigue and diarrhea, are still common.^{4,43,56,63–65} The most common adverse effects of abemaciclib are gastrointestinal in origin, which are largely grade 1 or grade 2 in severity and often managed symptomatically.⁶³ However, patients should be instructed to notify their healthcare providers at the start of loose stools and to immediately increase fluid intake and begin antidiarrheal medications, such as loperamide. For grade 3 or grade 4 diarrhea, abemaciclib should be discontinued until the diarrhea is grade 1 or less, after which it should be resumed at the next lowest dose.⁶⁶

In the MONARCH 1 trial, grade 3 diarrhea occurred in 20% of patients receiving abemaciclib alone. In the MONARCH 2 trial, grade 3 diarrhea occurred in 13% of patients receiving the combination abemaciclib and fulvestrant. In the MONARCH 3 trial, grade 3 diarrhea occurred in 9% of patients receiving abemaciclib with aromatase inhibitors. The incidence of diarrhea was found to be most frequent during the first month of abemaciclib treatment. In the MONARCH 2 and 3 trials, the median duration of grade 3 diarrhea was 9 days and 8 days, respectively. The frequency of dose omissions and dose reductions secondary to diarrhea in the MONARCH 2 trial was 22% and 22%, respectively. The frequency of dose omissions and dose reductions in the MONARCH 3 trial was 19% and 13%, respectively.^56–58,67

A review of ongoing clinical trials reveals considerable overlap between palbociclib, ribociclib, and abemaciclib, revealing that further studies of abemaciclib are underway in patients with breast cancer, glioblastoma, liposarcoma, mantle cell lymphoma, squamous cell carcinoma of the head and neck, squamous cell esophageal carcinoma, and pancreatic adenocarcinoma.⁶⁸

Table 3 summarizes various clinical studies of abemaciclib. Table 4 summarizes the adverse effects of abemaciclib, as well as those of other CDK 4/6 inhibitors.

Table 3.

Abemaciclib studies.

Study name and authors	Phase	Patients	Drugs and dosage	N	Clinical efficacy	Adverse effects
MONARCH 1: A phase II study of abemaciclib, a CDK4/6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer (MBC) Dickler et al.⁵⁶	II	Women ≥18 years of age with refractory HR+, HER2− MBC.	Abemaciclib 200 mg on continuous schedule every 12 h	132	Median PFS 6.0 months, and median OS 17.7 months	Diarrhea, fatigue, and nausea
MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2− MBC who had progressed while receiving endocrine therapy Sledge et al.⁵⁷	III	Women with MBC of any menopausal status who progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), 12 months after adjuvant ET, or while receiving ET for MBC. No more than one prior ET for MBC.	Abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label)	669	16.4 months median PFS abemaciclib plus fulvestrant, 9.3 months median PFS fulvestrant alone	Diarrhea, neutropenia, nausea, decreased appetite, and fatigue
Efficacy and safety of abemaciclib, for patients with breast cancer, NSCLC, and other solid tumors Patnaik et al.⁶³	Ib	Advanced solid tumors	Abemaciclib 200 mg every 12 h	225 33 in dose escalation phase and 192 in tumor- specific cohorts	All solid tumors: 23% PR, 47% SD, 70% DCR, 5.8 months median PFS Breast cancer (n = 47): 23% PR, 47% SD, 23% ORR, 49% clinical benefit rate (CBR), 70% DCR, 5.8 months median PFS	Leukopenia, neutropenia, abdominal pain, anemia
Efficacy and safety of abemaciclib, for patients with breast cancer, NSCLC, and other solid tumors Patnaik et al.⁶³	Ib	HR⁺ ABC	Combination abemaciclib and fulvestrant	19	21% PR, 21% ORR, 79% DCR, 63% CBR
Efficacy and safety of abemaciclib, for patients with breast cancer, NSCLC, and other solid tumors Patnaik et al.⁶³	Ib	NSCLC	Abemaciclib	68	All NSCLC: 3% PR, 46% SD, 49% DCR, 2 months median PFS KRAS-mutant NSCLC: 3% PR, 31% SD ≥24 weeks, 55% DCR, 2.8 months median PFS KRAS wild-type NSCLC: 3% PR, 12% SD ≥24 weeks, 39% DCR, 1.9 months median PFS
Phase 1 study of abemaciclib, as a single agent for Japanese patients with advanced cancer Fujiwara et al.⁶⁴	Ib	Japanese patients with advanced cancer (N = 12)	Escalating doses of 100 mg, 150 mg, or 200 mg BID	12	>30% tumor shrinkage in 2 patients (HR⁻, HER2⁺ breast cancer and small intestine neuro-endocrine carcinoma)	Leukopenia, diarrhea, neutropenia
A phase 1 b study of abemaciclib in combination with endocrine and HER2-targeted therapies for patients with metastatic breast cancer Beeram et al.⁶⁵	Ib	HR⁺ metastatic breast cancer	Abemaciclib with endocrine and HER2-targeted therapies	110 (total) 20 16 16 15 15 4 18 6 5 HR + 1 HR-	Combined with letrozole: 76% 6-month PFS Combined with anastrozole: 87% 6-month PFS Combined with tamoxifen: 73% 6-month PFS Combined with exemestane: 75% 6-month PFS Combined with exemestane + everolimus (150 mg BID dose): 89% 6-month PFS Combined with exemestane + everolimus (200 mg BID dose): 100% 6-month PFS Combined with trastuzumab (150 mg BID dose): 29% 6-month PFS in HR⁺ breast cancer (n = 11), 38% in HR⁻ breast cancer (n = 7) Combined with trastuzumab (200 mg BID dose): 50% 6-month PFS	Combination with letrozole: diarrhea, fatigue, neutropenia, nausea, vomiting Combination with anastrozole: diarrhea, leukopenia, neutropenia, lymphopenia, fatigue Combination with tamoxifen: diarrhea, fatigue, reduced lymphocyte count, reduced leukocyte count Combination with exemestane: diarrhea, abdominal pain, neutropenia Combination with exemestane + everolimus (150 mg BID dose): neutropenia, leukopenia, lymphopenia, diarrhea, anemia, fatigue, stomatitis Combination with exemestane + everolimus (200 mg BID dose): neutropenia, thrombocytopenia, and leukopenia Combination with trastuzumab (150 mg BID dose): fatigue, abdominal pain, thrombocytopenia, diarrhea, and anemia Combination with trastuzumab (200 mg BID dose): diarrhea, anemia, reduced neutrophil and leukocyte counts, lymphopenia, thrombocytopenia, fatigue, abdominal pain
MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer Goetz et al.⁶⁷	III	Postmenopausal women with HR+, HER2− advanced breast cancer with no prior systemic therapy	Abemaciclib 150 mg twice daily or placebo plus 1 mg anastrazole once daily or 2.5 mg letrozole once daily	493	Median PFS not reached in abemaciclib arm vs. median PFS 14.7 months in placebo arm. Objective response rate (in patients with measurable disease) of 59% in abemaciclib arm and 44% in placebo arm	Neutropenia, diarrhea, leukopenia
neoMONARCH: A neoadjuvant phase II study of abemaciclib in postmenopausal women with HR+/HER2– breast cancer Hurwitz et al.⁶⁰	II	Postmenopausal women with HR+, HER2– breast cancer, with tumors ≥1 centimeter (cm) in diameter	Abemaciclib 150 mg twice daily or abemaciclib 150 mg twice daily with anastrazole 1 mg daily or anastrazole 1 mg daily monotherapy	224	Baseline reduction in mean Ki67 percent of 93.5% in abemaciclib and anastrazole, 93.1% in abemacicli, 71% in anastrazole alone	Diarrhea, constipation, increased creatinine, neutropenia

Trilaciclib

Trilaciclib (G1T28) is the newest CDK 4/6 inhibitor, which is being studied in the prevention of chemotherapy-induced myelosuppression in small cell lung cancer and triple negative breast cancer. Chemotherapy-induced myelosuppression often causes serious issues, such as febrile neutropenia, dose reductions, and treatment delays. Long-term hematopoietic stem cell damage can lead to myelodysplastic syndrome and acute leukemia.⁶⁹ The transient arrest of these hematopoietic stem and progenitor cells has been shown to protect cell counts and prolong survival in murine models with chemotherapy or radiation exposure.^70,71 Chemotherapy-induced myelosuppression is currently managed with transfusions of red blood cells, platelets, granulocyte colony-stimulating factor (GCSF), and erythropoietin (EPO). However, these treatments are not without risk. Red blood cells and platelets are associated with transfusion reactions and transmission of infectious diseases, despite careful screening to minimize this risk. GCSF is associated with such adverse effects as fevers and bone pain, which may ultimately lead to treatment discontinuation. EPO has alarmingly been associated with increased risk of thrombosis and overall mortality.⁶⁹

Prior research has demonstrated that bone marrow hematopoietic stem and progenitor cells have a high dependence on CDK 4/6 in order to proliferate.⁶⁹ The previously mentioned adverse effects of red blood cells, platelets, GCSF, and EPO contributed to the rationale to study CDK 4/6 inhibitors as prophylaxis of chemotherapy-induced myelosuppression. Palbociclib was previously studied in combination with carboplatin and compared to carboplatin alone in two murine breast cancer models with compromised G1 checkpoints. The mice treated with carboplatin alone were noted to have increased apoptosis of hematopoietic stem and progenitor cells when compared to carboplatin administered with palbociclib. Coadministration of palbociclib and carboplatin was noted to produce increased hematocrit levels, platelet counts, myeloid cells, and lymphocytes when compared to carboplatin alone.⁷¹ However, palbociclib is administered orally, with a mean half-life of 25.9 h,³⁹ making it impractical for administration with shorter-acting intravenous chemotherapy. Trilaciclib represents a more attractive CDK 4/6 inhibitor for the purpose of preventing chemotherapy-induced myelosuppression secondary to its intravenous administration and half-life of approximately 5 h.⁷² While encouraging, significantly more research is needed to determine whether trilaciclib should become part of the standard of care for prophylaxis with cytotoxic chemotherapy.

It is important to note that the described adverse effects of CDK 4/6 inhibitors must be interpreted in clinical context. As CDK 4/6 inhibitors continue to be used in research and clinical practice and postmarketing surveillance continues to be done, new information may become available regarding rare and/or long-term adverse effects. In addition, as mentioned previously, other treatment options for metastatic HR-positive, HER2-negative breast cancer include anthracycline- or taxoid-based chemotherapy, aromatase inhibitors, tamoxifen, and fulvestrant,² all of which have documented adverse effects. Notably, anthracycline-based chemotherapy has a well-documented association with the development of congestive heart failure and cardiomyopathy. Taxane-based chemotherapy has been associated with bradycardia and myocardial ischemia, although the association with congestive heart failure and cardiomyopathy is not as well-defined as that of anthracycline-based chemotherapy. Adverse effects of tamoxifen are similar to those occurring at menopause onset, including hot flashes, depression, mood instability, libido loss, and vaginal dryness. Tamoxifen is also associated with an increased risk of thromboembolic events, including deep venous thrombosis, pulmonary embolism, and cerebral vascular accidents, as well as with an increased risk of endometrial cancer. Aromatase inhibitors share similar menopausal symptoms as tamoxifen and also have a controversial association with increased risk of cardiovascular disease. In addition, osteopenia and osteoporosis are well-known adverse effects of aromatase inhibitors.⁷⁴ Trial adverse effects of fulvestrant include hot flashes, joint pain, fatigue, headache, nausea, diarrhea, and constipation.⁷⁵ As CDK 4/6 inhibitors continue to be used and postmarketing surveillance continues to be done, new postmarketing surveillance data about safety and efficacy will become available and further advancements may be made. The question of which specific treatment to use for metastatic HR-positive, HER2-negative breast cancer widely differs depending on patient comorbidities, risk factors, and preferences, as well as provider experience and comfort. Although some choices are intuitive, such as choosing not to use anthracycline-based chemotherapy in a patient with severe congestive heart failure, the question of which specific patients would or would not benefit from CDK 4/6 inhibitors has no clear-cut answer.

Drug costs and pharmacoeconomics

Palbociclib and ribociclib have undergone various pharmacoeconomic analyses with differing conclusions. In February 2015, the initial wholesale acquisition price of palbociclib was $469 (all prices in United States currency), only to increase to $552 per capsule by January 2017.⁷⁶ Mamiya et al. concluded that the addition of palbociclib to letrozole in previously untreated patients with advanced breast cancer resulted in an annual $768,498 cost for every additional quality-adjusted life-year gained, compared to an additional $918,166 per additional quality-adjusted life-year in patients who had received prior endocrine therapy, thus concluding that palbociclib is not likely to be cost effective in the United States.⁷⁷ Likewise, Bhattacharya and Yang concluded that palbociclib and anastrazole were less cost effective than letrozole alone or anastrazole alone.⁷⁸ Matter-Walstra, Schwenkglenks, and Dedes originally analyzed the combination of palbociclib and letrozole in the context of the Swiss healthcare system and determined that the combination could not be considered cost effective first-line treatment for HR-positive, HER2-negative advanced breast cancer.⁷⁹ However, they reanalyzed the data a year later, found that the Swiss price of palbociclib was lower than originally assumed and came to the new conclusion that palbociclib and letrozole had a 19% probability of being cost effective.⁸⁰

Li et al. found that palbociclib is not cost effective secondary to dose reductions or treatment interruptions, subsequently resulting in wasted medication and elevated pharmacy costs.⁸¹ The initial dose of palbociclib is 125 mg once daily. This is subsequently changed to 100 mg once daily at the first dose reduction, and 75 mg once daily at the second dose reduction.⁸²

Ribociclib has slightly more positive views in terms of cost effectiveness. As of March 2017, the wholesale acquisition cost of a 28-day supply of ribociclib was approximately $10,950 for 600 mg once daily (given as 3 200 mg tablets), $8,760 for 400 mg once daily (given as 2200 mg tablets), and $4380 for 200 mg once daily (1 tablet).⁷⁶ Mistry et al. analyzed the cost of ribociclib and letrozole as first-line treatment for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer and concluded that it was a cost-effective option.⁸³ In contrast to the analysis by Li et al., ribociclib’s dosing regimen allows for dosing changes without wasted medication. Hettle et al. compared the regimen of palbociclib and letrozole to that of ribociclib and letrozole and concluded that ribociclib is more likely than palbociclib to be effective.⁸⁴

Despite the high costs and mixed reports of cost effectiveness, palbociclib and ribociclib have demonstrated significant clinical effectiveness, as previously discussed. In addition, practitioners are unlikely to tell patients that they may not use FDA-approved treatments secondary to high costs to the United States healthcare system as a whole. A detailed analysis of drug costs and healthcare in the United States is beyond the scope of this paper. However, it is nonetheless important for providers to be aware of the economic impact of the medications they prescribe.

Conclusion and future directions

The CDK 4/6 inhibitors of palbociclib, ribociclib, and abemaciclib represent a significant advancement in the treatment of metastatic, post-menopausal, HR-positive, HER2-negative breast cancer. While the use of trilaciclib remains largely experimental at this time, all four CDK 4/6 inhibitors represent exciting new treatment options and research opportunities in a wide variety of hematologic malignancies and solid tumors. As previously discussed, factors such as different dosing regimens (21 days of palbociclib and ribociclib, followed by 7 days off vs. twice daily dosing of abemaciclib) and adverse effect profiles (largely hematologic with palbociclib and ribociclib vs. gastrointestinal with abemaciclib) for reasons that are not yet completely and thoroughly defined may further impact clinical decisions regarding the use of individual CDK 4/6 inhibitors in individual patient care. It is possible that with time, these medications may become part of the accepted standard of care for a variety of malignancies.

A review of ongoing clinical trials reveals that further studies of ribociclib in melanoma are underway, along with various phase I-III trials for many of the same indications as palbociclib, including liposarcoma, glioblastoma, NSCLC, teratoma, pancreatic adenocarcinoma, HCC, prostate cancer, myelofibrosis, estrogen receptor (ER) positive gynecologic cancers, and squamous cell carcinoma of the head and neck.⁵⁰

Palbociclib also has many potential future clinical indications. Preliminary in vitro or animal studies have demonstrated potential benefit in such diverse malignancies as melanoma,⁸⁵ pancreatic ductal adenocarcinoma,⁸⁶ esophageal adenocarcinoma,⁸⁷ KRAS-positive metastatic colon cancer,⁸⁸ KRAS-mutant NSCLC,⁸⁹ renal cell carcinoma,⁹⁰ acute myeloid leukemia,⁹¹ and hepatocellular carcinoma.⁹² Such devastating diagnoses could benefit from additional treatment options.

Other questions currently remain to be explored. The only clearly defined indication to use one CDK 4/6 inhibitor over another would be ribociclib in premenopausal or perimenopausal women, although practitioners may certainly use clinical judgment with regard to dosing and adverse effects. In our practice, we prefer to use palbociclib in combination with letrozole, secondary to this combination being the most well-studied. In addition, ribociclib has the inherent adverse effect of QTc prolongation, which is especially concerning if patients are already taking QTc-prolonging medications. However, we also consider insurance coverage and individual preferences with regard to potential adverse effects.

The utility of switching from one CDK 4/6 inhibitor to another is not known, and there is currently no consensus about changing one CDK 4/6 inhibitor to another in the event of disease progression. Preclinical data of ER-positive breast cancer cell lines demonstrated that clonal cells resistant to palbociclib and ribociclb had incomplete abemaciclib cross resistance,⁹³ suggesting the possibility of trying a different CDK 4/6 inhibitor upon resistance to one CDK 4/6 inhibitor. Hurwitz et al. presented phase I results of a phase I/II study of ribociclib, everolimus, and exemestane in 17 patients with endocrine-resistant advanced breast cancer. Phase II of the study will evaluate the combination of ribociclib, everolimus, and exemestane following progression on a CDK 4/6 inhibitor,⁹⁴ thus helping to further explore the validity of the preclinical data. As previously mentioned, CDK 4/6 inhibitors also remain an area for further research and potential benefit in a wide variety of hematologic malignancies and solid tumors, including HER2-positive breast cancer, liposarcoma, multiple myeloma, mantle cell lymphoma, melanoma, and pancreatic adenocarcinoma, to name a few.

In addition, there is also the question of combining CDK 4/6 inhibitors with checkpoint inhibitors. Checkpoint inhibitors act as modulators of immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), two T-cell receptors that maintain tolerance of self-antigens while acting to downregulate T-cell signaling and prevent uncontrolled T-cell proliferation. Currently FDA-approved checkpoint inhibitors include the CTLA-4 inhibitor ipilimumab, the PD-1 inhibitors nivolumab and pembrolizumab, and the PD-L1 inhibitors, which block the ligand for the PD-1 receptor and include atezolizumab, avelumab, and durvalumab. Ipilimumab is used to treat metastatic or unresectable melanoma, and the remaining PD-1 inhibitors and PD-L1 inhibitors are widely used to treat NSCLC progressing despite platinum-based chemotherapy.^95–97 Several recruiting phase I/II clinical trials aim to answer the question of whether the combination of checkpoint inhibitors with CDK 4/6 inhibitors could work together to inhibit uncontrolled cellular proliferation and ultimately benefit patients with metastatic HR-positive, HER2-negative breast cancer (NCT02778685, NCT03147287, NCT02779751, NCT03280563), stage IV NSCLC (NCT02779751), or advanced small cell lung cancer (NCT03041311).

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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