FormalPara Key Points

CDK 4/6 inhibitors together with endocrine therapy significantly prolong progression-free survival (PFS) in pre- and/or postmenopausal women with HR+HER2- metastatic breast cancer. The PFS benefit is both statistically significant and clinically relevant with a hazard ratio around 0.5, independent of line of therapy and drug. Moreover, objective response rates and clinical benefit rates are also significantly increased.

In general, these drugs are well tolerated and side effects are manageable. Quality of life (QoL) data presented so far indicate that QoL is generally good and can be maintained on treatment. The patient-reported QoL was at least comparable to that under endocrine therapy alone in all QoL analyses.

Therefore, the addition of CDK 4/6 inhibitors to endocrine treatment was recommended by the international ABC4-panel. At the latest, CDK 4/6 inhibition is recommended in the second line of endocrine-based therapy.

1 Introduction

Despite considerable improvements in diagnosis and management of early breast cancer, about one-third of patients still progress to stage IV metastatic disease (MBC) [1]. Hormone receptor positive (HR +) and human epidermal growth factor receptor 2 negative (HER2 −) disease comprises 65–70% of all MBC patients. HR + HER2 − MBC is thus the most common subtype with a highly variable prognosis and a median overall survival of approximately 3 years [2]. Except for life-threatening metastatic disease, which needs a very prompt response, national and international guidelines endorse endocrine treatment as the first choice in HR + HER2 − MBC [3]. The variable prognosis of these patients depends on the responsiveness to endocrine agents. Improvements in response rates and prolongation of the duration of response together with prolongation of survival are therefore urgently needed in HR + HER2 − MBC. Next to treatment efficacy, maintenance or even improvement of quality of life (QoL), including symptom relief together with minimal treatment side effects, are highly relevant for patients with MBC.

As MBC is not a curable disease, both intrinsic and acquired resistance to endocrine treatment may be important mechanisms for disease progression. Recently, three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) that have the potential to overcome this endocrine resistance have been approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA): palbociclib, ribociclib and abemaciclib.

CDK4/6i are orally available small molecules that interfere with the phosphorylation of the retinoblastoma (Rb) protein. This reduction of phosphorylated Rb protein leads to a cell cycle arrest between the G1 and the S-phase of the cell cycle. As enhanced activity of the complex cyclin D1-CDK4/6 contributes to endocrine resistance, inhibition of this mechanism can help to enhance or re-induce the anti-proliferative effect of endocrine therapy [4]. Early in vitro and in vivo experiments showed that CDK4/6i preferentially inhibited luminal human breast cancer cell lines [5, 6] and promoted anti-tumor immunity with increased tumor immunogenicity in mice [7].

This review summarizes the clinical trial data of all three registered CDK4/6i that have led to their approval in HR + HER2 − MBC.

2 Palbociclib

2.1 Clinical Approval

The FDA and EMA approvals of palbociclib (IBRANCE®; PD 0332991) were mainly based on the three PALOMA studies (Palbociclib: Ongoing Trials in the Management of Breast Cancer; one phase II and two phase III), with > 1300 patients receiving palbociclib together with endocrine therapy until progression. Palbociclib has a broad label and is approved in pre- and postmenopausal patients for treatment of first-line or later MBC together with an aromatase inhibitor (AI) or fulvestrant.

2.2 Hormone Receptor (HR)-Positive Advanced Breast Cancer

2.2.1 Phase I

Preclinical data showed that palbociclib acts synergistically with tamoxifen in HR + breast cancer cell lines as well as in combination with trastuzumab in HER2 + cell lines [5, 6]. These findings led to implementation of the PALOMA clinical trial program with a focus on HR + HER2 − MBC.

The phase I study enrolled 12 patients and was designed to evaluate the safety of a dosing regimen consisting of oral palbociclib 125 mg taken daily on a 3-week-on/1-week-off schedule in combination with daily letrozole for postmenopausal women with advanced HR + breast cancer. The most common adverse events (AEs) were leukopenia, neutropenia, and fatigue. However, there was no neutropenic fever and no dose interactions between palbociclib and letrozole. All patients in this study experienced either stable disease (75%) or response to the treatment (25%) [8].

2.2.2 Phase II

PALOMA-1 (NCT00721409) was a randomized, open-label, multicenter phase II trial that randomized postmenopausal women with HR + HER2 − MBC in the first-line setting for advanced disease [9]. In total, 165 patients entered the study and were randomized to the experimental arm receiving palbociclib + letrozole or the control arm receiving letrozole alone as standard treatment. The study met its primary endpoint with an investigator-assessed progression-free survival (PFS) benefit of 10 months for the experimental arm compared with the control arm (20.2 vs 10.2 months) [9]. The study randomized two cohorts, one with ER + HER2 − disease and one that included only HR + HER2 − tumors with amplification of cyclin D1 (CCND1) and/or loss of p16 (INK4A or CDKN2A). After an amendment, the final analysis was done on both cohorts combined. In a subsequent subgroup analysis, no differential effect was found based on biomarker status [9]. After publication of the PALOMA-1 results, the FDA granted accelerated approval of palbociclib in combination with letrozole for treatment of postmenopausal women with ER + HER2 − advanced breast cancer as initial endocrine-based therapy in February 2015. This was an accelerated approval based on the PALOMA-1 PFS benefit. As a continued approval for this indication was contingent upon validation of the observed clinical benefit in a confirmatory trial, the results of the subsequent PALOMA-2 trial were highly anticipated [6]. Recently, the first results on overall survival (OS) for any of the CDK4/6i trials from PALOMA-2 were reported (n = 165, 106 with OS event). Median OS was 37.5 months in the palbociclib arm and 34.5 months in the control arm (hazard ratio [HR] 0.897; 95% CI 0.623–1.294; p = 0.281) [10].

Preclinical data suggest that adding palbociclib to endocrine therapy may reverse acquired endocrine resistance. The TREnd (To Reverse Endocrine Resistance) trial (n = 115) randomized women with HR + HER2 − MBC whose disease progressed on one or two prior endocrine therapy line(s). Median duration of clinical benefit was significantly longer for patients receiving the combination of palbociclib + endocrine therapy (11.5 vs 6 months; p = 0.0021). Although PFS was not significantly longer (10.8 vs 6.5 months), patients receiving palbociclib plus endocrine therapy due to secondary endocrine therapy resistance had significantly longer PFS (65.5 vs 11.5 months; p = 0.02) [11].

2.2.3 Phase III

PALOMA-2 (NCT01740427) was the confirmatory trial for PALOMA-1. It was a randomized, double-blinded, multicenter, placebo-controlled phase III trial that randomized 666 patients without prior treatment for advanced/metastatic breast cancer to either receive palbociclib + letrozole or placebo + letrozole (Table 1). The median PFS for patients treated with palbociclib + letrozole was 24.8 months compared with 14.5 months for patients treated with letrozole + placebo. Subgroup analyses of PFS according to stratification factors and other baseline characteristics confirmed a consistent benefit of palbociclib + letrozole across all subgroups. The PFS benefit of the combination was highly significant and the study reached its primary endpoint, thus supporting the previous results of PALOMA-1. Grade 3 or 4 neutropenia occurred in 66.4%, leukopenia in 24.8%, anemia in 5.4%, and thrombocytopenia in 1.6% of patients in the palbociclib + letrozole group [6].

Table 1 Overview of results of phase III studies for advanced breast cancer
Full size table

PALOMA-3 (NCT01942135) was a double-blinded, randomized, multicenter phase III trial that randomized for the first time pre- and postmenopausal women with HR + HER2 − MBC who had relapsed or progressed on/within 12 months of adjuvant endocrine treatment or on endocrine therapy for MBC and could have had up to one prior chemotherapy regimen for advanced breast cancer. All premenopausal patients received ovarian suppression with goserelin. A total of 521 patients were treated with fulvestrant plus palbociclib in the experimental arm or fulvestrant plus placebo in the control arm. The study showed a significant PFS benefit for patients receiving the experimental compared with standard treatment. Median PFS for premenopausal women in the palbociclib versus placebo arm was 9.5 versus 5.6 months, respectively (HR 0.50, 95% CI 0.29–0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women.

Grade 3 or 4 AEs occurred in 73% of patients in the fulvestrant plus palbociclib group and 22% of patients in the fulvestrant plus placebo group. The most common grade 3 or 4 AEs were neutropenia, anemia, and leucopenia [12, 13].

Quality of life (QoL) was maintained in the palbociclib arm and on-treatment global QoL scores significantly favored the experimental arm (p = 0.0313). Moreover, in the palbociclib arm, a significantly greater improvement in pain compared with baseline was observed (p = 0.0011) [14]. The treatment benefit derived from the addition of palbociclib is maintained even in the next line of therapy after progression, independent of therapeutic agents used [15]. Thus, there is no clinical evidence so far for a rebound effect after stopping CDK4/6i in MBC. Following PALOMA-3, the approval of palbociclib was extended to the combination with fulvestrant as a later line treatment for MBC and to include pre- and perimenopausal patients with sufficient ovarian suppression (e.g., goserelin) [12].

Recently, the first OS data for any of the phase III CDK4/6i trials was presented for PALOMA-3. With a crossover of 16%, median OS in palbociclib-treated patients was 34.9 months (95% CI 28.8–40.0) versus 28.0 months (95% CI 23.6–34.6) in the placebo group (HR 0.81; 0.64–1.03; p = 0.09). While not formally meeting statistical significance, the absolute OS difference of 6.9 months seems to maintain the final PFS benefit. In patients who had been sensitive to previous endocrine therapy, the absolute OS difference was 10 months (39.7 vs 29.7 months, HR 0.72; 0.55–0.94) [16] (Table 1).

2.3 Other Breast Cancer Subtypes

In PHER2 (NCT02530424), an exploratory phase II study in Italy, Patients with invasive unilateral nonmetastatic HER2 + HR + breast cancer and suitable for neoadjuvant therapy were treated with intravenous trastuzumab + pertuzumab in combination with oral palbociclib (125 mg once a day) and intramuscular fulvestrant (500 mg). The primary endpoint of this study is the effect on Ki67 and apoptosis before, during, and after treatment. The combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab had a significant effect on the expression of Ki67 at 2 weeks and at surgery in 36 enrolled patients. The trial is ongoing and two further cohorts are being enrolled [17].

3 Ribociclib

3.1 Clinical Approval

Ribociclib (KISQALI®; LEE011) is an orally bioavailable, small molecule and selective inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 for the combination with an AI in first-line treatment of post-menopausal patients with HR + HER2 − MBC [18, 19]. EMA approval followed in August 2017. There are several MONALEESA (Mammary ONcology Assessment of LEE011′s Efficacy and Safety) registration trials for ribociclib.

3.2 HR-Positive Advanced Breast Cancer

3.2.1 Phase I

A phase I study tested ribociclib as a single agent across a range of Rb-positive advanced solid tumors and lymphomas in US/European (n = 132) and Japanese patients (n = 17). Among the 132 patients, 20 patients had breast cancer. Pharmacokinetic data of the dose escalation study supported the 600 mg/day (3 weeks on/1 week off) dosing schedule with comparable efficacy and clinical activity and lower toxicity compared with higher doses and a daily intake. Dosing may be modified based on individual safety and tolerability. Interestingly, in Japanese patients the medication dose appeared higher on average than in non-Japanese patients. Notably, the overall exposure to a single oral dose of ribociclib 600 mg was not influenced by food intake or abstinence. Ribociclib is rapidly absorbed, with a time to maximum concentration (Tmax) of 1–5 h and a half-life (t½) of 33–42 h [20].

3.2.2 Phase II

MONALEESA-1 (NCT01919229), a pre-surgical pharmacodynamics study, randomized 14 postmenopausal women with resectable HR + HER2 − early breast cancer 1:1:1 to receive letrozole (2.5 mg/day, continuously) only or letrozole in combination with ribociclib (400 mg or 600 mg/day, continuously). The results revealed no drug–drug interaction between ribociclib and letrozole and showed that ribociclib + letrozole may reduce Ki67 expression in HR + HER2 − early breast cancer. Furthermore, the pharmacodynamic data provided evidence for an on-target inhibition by ribociclib [21, 22].

3.2.3 Phase III

The MONALEESA-2 (NCT01958021) study randomized 668 postmenopausal women with HR + HER2 − MBC 1:1 to receive either ribociclib (600 mg/day; 3 weeks on/1 week off) + letrozole (2.5 mg/day; continuously) or placebo + letrozole in the first-line setting. The primary endpoint was locally assessed PFS. The secondary endpoints included OS and safety. Tumor assessments were performed every 8 weeks for the first 18 months and every 12 weeks thereafter. The results showed that ribociclib + letrozole significantly increased PFS compared with placebo + letrozole (median PFS: not reached vs 14.7 months; HR 0.556; p = 0.00000329). The PFS rate at 12 months was 72.8% versus 60.9% in the ribociclib and placebo group, respectively. Treatment benefit was consistent across patient subgroups, including older patients (≥ 65 years) and those with visceral metastases, bone-only disease, or de novo MBC. In the ribociclib + letrozole arm, a decreased tumor size at the initial evaluation (∼ week 8) was observed in 76% of evaluable patients with measurable disease. In an additional follow-up of 11 months, a median PFS of 25.3 months for ribociclib + letrozole and 16 months for letrozole + placebo was seen. OS data is not yet mature and will be available in approximately 2–3 years [18].

In the safety analysis, neutropenia was the most common AE in the ribociclib + letrozole arm. Neutropenia is an expected CDK4/6i class effect and related to exposure. The median time to onset is described as 16 days from initiation of ribociclib treatment. Febrile neutropenia risk was low (ribociclib + letrozole arm: 1.5%) with no associated deaths. Neutropenia was the most common cause for dose reduction or dose interruption. However, the most common AEs leading to discontinuation of the medication were elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) or vomiting. QT prolongation is also related to exposure with a mean time to onset of 15 days. Mean increase is described as 22.9 ms. ECG monitoring and monitoring of serum electrolytes as well as review of prohibited concomitant medication is recommended. In MONALEESA 2, QT prolongation led to dose adjustments in < 1% of treated patients [23]. Based on these study findings, ECG monitoring is required at start of ribociclib therapy (Table 1).

Several additional trials (COMPLEEMENT-1, MONALEESA 3, MONALEESA-7) further assessed the effectiveness and safety of ribociclib in combination with antihormonal therapy in different patient populations.

The COMPLEEMENT-1 study (NCT02941926; currently active) is an open-label, multicenter, phase IIIb study to evaluate the safety and efficacy of ribociclib in combination with letrozole for the treatment of men and pre-/postmenopausal women with HR + HER2 − MBC with no prior hormonal therapy for advanced disease. The primary endpoint is defined as the number of participants with AEs as a measure of safety and tolerability [24].

MONALEESA-3 (NCT02422615) is a randomized, double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with HR + HER2 − MBC, who were treated with no or only one line of prior endocrine therapy [25]. In 726 patients, PFS was again significantly prolonged in the ribociclib-containing arm compared with fulvestrant alone (median 20.5 months [95% CI 18.5–23.5] vs 12.8 months [95% CI 10.9–16.3]; HR 0.593; 95% CI 0.480–0.732; p < 0.001). The magnitude of PFS benefit did not differ substantially between first- and second-line patients (HR 0.577 95% CI 0.415–0.802 vs HR 0.565; 95% CI 0.428–0.744). In patients with measurable disease, overall response rates (ORR) also favored the ribociclib arm (40.9% vs 28.7%). The only grade 3 AEs reported in ≥ 10% of patients were neutropenia (46.6% in the ribociclib vs 0% in the placebo arm) and leukopenia (13.5% vs 0%); again, the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% vs 0%) [22] (Table 1).

As the largest phase III trial in this setting, MONALEESA-7 (NCT02278120) assessed efficacy and safety of ribociclib solely in premenopausal women with HR + HER2 − MBC. It was a randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin. The study met the primary objective. PFS was significantly improved in the ribociclib arm (median PFS 23.8 months; 95% CI 19.2–not reached) vs the placebo arm (median PFS 13.0 months; 95% CI 11.0–16.4), with an HR of 0.553 (95% CI 0.441–0.694; p = 9.83 × 10–8). The overall response rate was significantly higher among patients with measurable disease at baseline in the ribociclib arm compared with the placebo arm (51% vs 36%). As expected, the most frequent AE was neutropenia, which was reported in 76% of patients in the ribociclib arm compared with 8% in the placebo arm. Grade 3/4 neutropenia was reported in 61% of patients in the ribociclib arm compared with 4% in the placebo arm, but it was asymptomatic in most patients [26, 27] (Table 1).

3.3 Other Breast Cancer Subtypes

In HER2 + MBC, ribociclib is currently being tested in combination with trastuzumab or TDM-1 (NCT02657343). For this phase I/II study, patients who previously received at least one regimen containing trastuzumab and a taxane but no more than four prior lines of therapy for MBC are enrolled [28].

In advanced androgen receptor (AR)-positive triple negative metastatic breast cancer (TNBC), there is also a multi-institutional, single arm, non-randomized phase II trial (NCT03090165) open for recruiting patients for therapy with ribociclib in combination with bicalutamide (AR-inhibitor) [29].

4 Abemaciclib

4.1 Clinical Approval

Abemaciclib (Verzenio®; LY2835219) is an orally available CDK4/6i that is registered for use in combination with fulvestrant in women with HR + HER2 − advanced breast cancer with disease progression following endocrine therapy. It is also approved as a monotherapy for patients with HR + HER2 − MBC who have previously received endocrine therapy and chemotherapy.

4.2 HR-Positive Advanced Breast Cancer

4.2.1 Phase I

Abemaciclib preferentially inhibits CDK4 with 14-fold specificity for CDK4/Cyclin D1 over CDK6/Cyclin D3 complexes. In cell line models, it led to cell cycle arrest in ER + breast cancer cells and was able to induce senescence and apoptosis when continuously administered [30]. In a preclinical rat model with brain tumors, abemaciclib crossed the blood–brain barrier and was as effective as temozolomide. In the same model, brain levels of abemaciclib were reached more efficiently and at lower doses than those of palbociclib, indicating that there may be a differential effect of the different CDK4/6i in brain [31]. Initial clinical results for abemaciclib were derived from a phase I study (NCT01394016) in HR + MBC, NSCLC, and melanoma [32, 33]. A phase Ib (NCT02057133) extension cohort presented data in 65 MBC patients with abemaciclib 200 mg twice daily together with endocrine therapy (AI or tamoxifen). Disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) with an AI (n = 36) was 67% with two confirmed PRs, and 75% with tamoxifen (n = 16).

There were no grade 4–5 toxicities; the most frequent grade 3 toxicities included diarrhea (31%), neutropenia (17%), fatigue (14%), nausea (6%), abdominal pain (3%), and vomiting (28%) [34].

4.2.2 Phase II

In MONARCH I (NCT02102490), a phase II single-arm monotherapy study, abemaciclib 200 mg was administered twice daily in 132 patients with HR + HER2 − MBC disease progression either on or after endocrine therapy or chemotherapy. At the 12-month final analysis, the overall response rate was 19.7% (95% CI 13.3–27.5) with a median duration of response of 8.6 months; the clinical benefit rate (CR, PR or SD > 6 months) was 42.4%, median PFS was 6.0 months, and median OS was 17.7 months in this cohort of heavily pretreated patients with a median of three lines of prior systemic therapy for MBC. Of these patients, 90.2% had visceral disease and 50.8% had three or more metastatic sites. Only 7.6% of patients discontinued treatment due to AEs [35]. These data led to the FDA approval of abemaciclib as monotherapy.

The neoMONARCH study (NCT02441946) is a randomized, multicenter, open-label phase II neoadjuvant study comparing the biological effects of abemaciclib (150 mg twice a day [BID]) plus anastrozole (A + Abema) versus abemaciclib monotherapy (Abema) versus anastrozole monotherapy (A) in postmenopausal women with HR + HER2 − early breast cancer [36]. Each regimen was given for 14 days and afterwards all patients received abemaciclib and anastrozole for an additional 14 days until surgery. The primary objective was the percent change from baseline in Ki67 protein expression after 2 weeks of therapy with the three initial regimens (n = 223 treated patients). The two abemaciclib arms had a substantially greater mean change in Ki67 than the anastrozole-alone arm (p < 0.001). Moreover, complete cell cycle arrest (Ki67 < 2.7%) was seen in only 14.8% of the A-arm tumors compared with 66.1% (A + Abema) and 58.8% (Abema).

4.2.3 Phase III

The first-line study, MONARCH 3 (NCT02246621), is a double-blind, randomized, phase III study of abemaciclib or placebo plus a nonsteroidal AI (letrozole or anastrozole) in 493 postmenopausal women with HR + HER2 − advanced breast cancer and no prior systemic therapy for advanced breast cancer (ABC). Patients received abemaciclib (150 mg BID continuously) or placebo plus an AI daily. The primary endpoint was investigator-assessed PFS; secondary objectives included response and safety. The study reached its primary endpoint at the planned interim analysis after 189 events. Median PFS was significantly longer in the abemaciclib arm (HR 0.54; 95% CI 0.41–0.72; p = 0.000021) with the median not yet reached compared with 14.7 months in the placebo arm. The PFS benefit was observed across all pre-specified and also across exploratory clinical subgroups. On the one hand, patients with adverse prognostic features such as a short treatment-free interval (< 36 months) before study start or patients with liver metastases benefitted substantially from abemaciclib. On the other hand, patients with bone-only disease and disease-free interval ≥ 36 months seemed to unveil a better prognosis when on endocrine monotherapy. In patients with measurable disease, the ORR was 59% versus 44% favoring the abemaciclib arm (p = 0.004). The most frequent grade 3 or 4 AEs were neutropenia (21.1% vs 1.2%), diarrhea (9.5% vs 1.2%), and leukopenia (7.6% vs 0.6%) [37]. Interestingly, there were 4.9% (n = 16) venous thromboembolic events in the abemaciclib arm compared with only one (0.9%) in the control arm. The majority of these patients were able to continue therapy.

The double-blind, phase III MONARCH 2 trial (NCT02107703) compared fulvestrant + abemaciclib (150 mg BID) with fulvestrant alone (2:1 randomization) in 669 patients with HR + HER2 − ABC with progression on or ≤ 12 months after (neo-)adjuvant endocrine therapy or on first-line endocrine therapy for MBC. The primary endpoint was again investigator-assessed PFS and secondary endpoints included OS, ORR, duration of response, clinical benefit rate, QoL, and safety. During the trial, the starting dose of abemaciclib was reduced from 200 mg BID to 150 mg BID and the sample size was increased accordingly in order to have the preplanned patient number (n = 450) treated with the lower dose. After a median follow-up of 19.5 months, PFS was significantly longer in patients with abemaciclib plus fulvestrant than in the control arm with a median of 16.4 versus 9.3 months (HR 0.553; 95% CI 0.449–0.681; p < 0.001). Also, ORR was significantly higher with abemaciclib than with fulvestrant alone (48.1% vs 23.1%). The most common AEs of any grade in the abemaciclib versus control arms were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). There was 13.4% grade 3 diarrhea in the abemaciclib arm. Diarrhea typically occurred in the first cycle with a median time to onset of 6 days. Even though most patients (70.1%) with a diarrhea event did not require therapy modifications, 2.9% of patients discontinued study drug due to diarrhea [38] (Table 1).

4.3 Other Breast Cancer Subtypes

The phase II monarcHER study (NCT02675231) is currently ongoing in patients with HR + , HER2 + locally advanced or metastatic breast cancer. It is a three-arm, open-label design comparing the efficacy of abemaciclib plus trastuzumab with or without fulvestrant to standard-of-care chemotherapy of physician’s choice plus trastuzumab.

5 Conclusion

In summary, CDK4/6i together with endocrine therapy significantly prolongs PFS in pre- and/or postmenopausal women with HR + HER2 − MBC. The PFS benefit is not just statistically significant but also clinically relevant with an HR around 0.5 independent of line of therapy and drug. Moreover, ORRs and clinical benefit rates are also significantly increased. In general, these drugs are well tolerated and side effects are manageable. QoL data presented so far indicate that is generally good and can be maintained on treatment. The patient-reported QoL was at least comparable to that under endocrine therapy alone in all QoL analyses. Therefore, addition of CDK4/6i to endocrine treatment was recommended by the international ABC4 panel. At the latest panel meeting, CDK4/6i was recommended in the second-line of endocrine-based therapy [14, 39].

There are three drugs registered at the moment, palbociclib, ribociclib, and abemaciclib. The clinical efficacy seen so far seems to be similar across the three compounds. Numerical differences in the PFS times are most likely due to slightly differing study entry criteria and patient characteristics in the phase III trials. Nevertheless, there are some differences regarding therapy management. Palbociclib and ribociclib seem to be rather similar with regard to drug intake (one dosing/day; 3 weeks on/1 week off) as well as side-effect profile with neutropenia as the major side effect. Monitoring at start of therapy differs slightly between these two agents but is fully detailed in the product information. Abemaciclib is taken twice daily in a continuous schedule. Its major side effect is diarrhea and neutropenia rates are lower than with the other two compounds. Abemaciclib is the only CDK4/6i with demonstrated substantial monotherapy activity and approval as a single agent. Moreover, it seems to cross the blood–brain barrier and have CNS activity.

Many open questions still exist for CDK4/6 inhibition in MBC. Considering all endocrine-based options in HR + HER2 − MBC and their sequential administration, patients have the chance for median therapy duration of about 3 years without any chemotherapy. Their definitive impact on survival may be best analyzed as a meta-analysis of all trials as post-progression survival is still long in MBC and none of the trials were sufficiently powered for assessment of OS benefit.

Given the clinical benefits seen in MBC, trials of CDK4/6i in the adjuvant setting have already been initiated for all three drugs. All CDK4/6i adjuvant trials focus on clinically high-risk populations with HR +/HER2 − breast cancer, even if the definitions of ‘high risk’ differ substantially (Fig. 1). The PALLAS trial (PALbociclib CoLlaborative Adjuvant Study) (NCT02513394) run by academic–industry cooperation between Pfizer and ABCSG/BIG and ALLIANCE evaluates patients with node-positive or node-negative disease and larger tumors (pT2–4) irrespective of their ‘biological’ risk (Table 2).

Fig. 1
figure 1

Adjuvant trials of palbociclib, ribociclib, and abemaciclib, illustrating the high-risk patient populations. ET endocrine therapy

Full size image
Table 2 Overview of ongoing adjuvant phase III studiesa
Full size table

Both later-initiated trials (MonarchE and NATALEE [New Adjuvant TriAl with LEE]) were planned to focus on patients with higher clinical–biological risk. MonarchE (NCT03155997) is evaluating impact of adjuvant abemaciclib in patients with more than four positive lymph nodes or one to three positive lymph nodes and additional risk factors (defined by T3 or G3 or Ki-67 > 20%). NATALEE (NCT03701334) will replace the two EarlLEE trials for adjuvant ribociclib. It will include Stage II–III patients with HR +/HER2 − early breast cancer. Two ribociclib adjuvant trials were discontinued before fully starting international accrual: EarLEE-1 had started to randomize patients with locally advanced breast cancer (stage III) or significant tumor rest after completion of neoadjuvant chemotherapy, but was stopped prematurely after inclusion of few patients. The second planned Novartis adjuvant study (EarlLEE-2) focusing on intermediate-risk patients was cancelled before starting.

Unfortunately, none of the trials have included genomic risk assessment or dynamic tests (e.g., course of Ki-67 expression during endocrine therapy) as inclusion criteria so far, despite promising data on excellent outcome in patients with higher clinical and/or biological risk by classical risk criteria and low genomic risk treated by endocrine therapy alone.