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CDK4/6 inhibitor selection in metastatic breast cancer

CDK4/6 inhibitor selection

Read time: 60 mins
Last updated:13th Apr 2022
Published:22nd Apr 2021

Abemaciclib, palbociclib and ribociclib are three CDK4/6 inhibitors approved for the treatment of HR+/HER2− locally advanced or metastatic breast cancer, but how do they compare and how will you decide on which CDK4/6 inhibitor to select for your breast cancer patient?

Overview

Abemaciclib, palbociclib and ribociclib are three cyclin dependent kinase (CDK)4/6 inhibitors that are US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for the treatment of hormone receptor positive/human epidermal growth factor 2 negative (HR+/HER2−) locally advanced or metastatic breast cancer1–6. Abemaciclib is also FDA approved as a monotherapy for HR+/HER2− advanced breast cancer in patients who have progressed following endocrine therapy and prior chemotherapy treatment3. Both the FDA and EMA have also extended the indication for abemaciclib to include adjuvant therapy for high-risk early breast cancer3,4.

Abemaciclib, palbociclib and ribociclib are orally active CDK4/6 inhibitors that have been investigated in landmark Phase III clinical trials for treatment of advanced breast cancer (MONARCH, PALOMA and MONALEESA, respectively) either in combination with a nonsteroidal aromatase inhibitor, or with fulvestrant in endocrine-resistant patients. These trials consistently show that all three CDK4/6 inhibitors significantly increase progression free survival (PFS) when compared with endocrine therapy (ET) alone7–14. More recently, both abemaciclib and ribociclib were additionally shown to improve overall survival15–17. Abemaciclib has also been shown to improve invasive disease-free survival in patients with HR+/HER2− early breast cancer at high risk of recurrence18,19.

Studies that directly compare the CDK4/6 inhibitors are currently lacking. Available clinical trial data should not be directly cross-compared, given the differences in study design and patient populations assessed. Whilst there are ongoing investigations into the differences between the CDK4/6 inhibitors, treatment selection may be influenced by notable differences in the toxicity profiles for the individual CDK4/6 inhibitors, schedule of administration, need for monitoring and the level and quality of evidence available for specific patient groups or disease characteristics20,21. Other potential differentiating features currently under active investigation include central nervous system penetration, activity as a monotherapy, efficacy in heavily pre-treated and elderly patients, and differences in biomarkers for treatment response20,21.

Dr Laura Spring from the Massachusetts General Hospital Cancer Centre also points out that patient preference and financial toxicity are also key considerations when selecting a CDK4/6 inhibitor for her advanced breast cancer patients.

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Patient and disease characteristics

Differences in patient populations include menopausal status, endocrine therapy sensitivity, prior treatments received and degree and location of metastatic spread (Table 1).

Table 1: Patient and disease characteristics included in the landmark clinical trials for CDK4/6 inhibitors. Subgroup analysis is available for the patient and disease characteristics highlighted in green (adapted from Dickler et al.10; Sledge et al.22; Goetz et al.23; Finn et al.24; Cristofanilli et al.14; Hortobagyi et al.7; Slamon et al.8; Tripathy et al.9).

Lil_CDK46_Pt2_Table1.png

To learn more about the efficacy and safety for the overall populations assessed in the landmark clinical trials, visit our section on CDK4/6 inhibitors in metastatic breast cancer.

Postmenopausal women

All three CDK4/6 inhibitors, abemaciclib, palbociclib and ribociclib, show efficacy in endocrine-sensitive and endocrine-resistant postmenopausal women20

There have been single-population focused clinical trials for all three CDK4/6 inhibitors in the sensitive setting (MONARCH 3, PALOMA-2 and MONALEESA-2), whereas only ribociclib has been assessed in this manner in the resistant setting (MONALEESA-3)13,23,25,26. For palbociclib and abemaciclib, subgroup analysis data are available for clinical trials that included both pre- and postmenopausal women in the resistant setting (MONARCH 2, PALOMA-3)14,22,27.

Endocrine sensitive population

Abemaciclib, palbociclib and ribociclib were all assessed in a postmenopausal and sensitive population in the first-line setting in the MONARCH 3, PALOMA-2 and MONALEESA-2 clinical trials (Table 2)13,23,25. All three trials were Phase III, randomised and placebo controlled, and the CDK4/6 inhibitors were assessed in combination with a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI. In all studies, the endocrine partner assessed was letrozole; however, the MONARCH 3 study also included patients who received anastrozole (20.9% of patients included in the trial). In this setting, abemaciclib, palbociclib and ribociclib all achieved a significant improvement in median progression-free survival (mPFS) with hazard ratios (HR) of 0.54, 0.58 and 0.57, respectively13,23,25. Overall survival with ribociclib plus letrazone was more than 12 months longer than with ribociclib plus placebo (HR for death, 0.76; 95 confidence intervals 0.63-0.93; P=0.008)28. However, the overall survival data for the MONARCH-3 and PALOMA-2 trials are yet to be published.

Endocrine resistant population

The MONALEESA-3 clinical trial on ribociclib is the only trial that solely assessed postmenopausal women who were treatment-naive, or who received up to one line of prior endocrine therapy in the advanced setting26. This trial highlighted improved median progression-free survival for ribociclib plus fulvestrant (20.5 months; n = 484), compared with placebo plus fulvestrant (12.8 months; n = 242) (HR 0.593; P<0.001) in postmenopausal women26. This improvement was consistent for patients who were treatment-naive (HR 0.577), and those who previously received endocrine therapy for advanced disease (HR 0.565)26.

Subgroup analysis in the MONARCH 2 and PALOMA-3 clinical trials also highlighted improved mPFS in postmenopausal women with resistant disease who were treated with fulvestrant plus abemaciclib or palbociclib, respectively14,22,27. In MONARCH 2, 83.2% (371/446) of patients in the abemaciclib arm and 80.7% (180/223) of patients in the placebo arm were postmenopausal women22. Sub-group analysis based on menopausal state indicated that postmenopausal women benefited from abemaciclib with an overall survival hazard ratio of 0.773 (95% CI, 0.609–0.980)28. This study also found that all assessed patients with primary endocrine resistance benefited more from abemaciclib treatment than those with secondary resistance (HR 0.686 and 0.787, respectively)27.

In the PALOMA-3 trial, postmenopausal women made up 79% (275/347) of patients in the palbociclib plus fulvestrant arm and 138/174 (79%) of patients in the placebo plus fulvestrant arm14. Median PFS was 9.9 months in the palbociclib arm, compared with 3.9 months in the placebo arm (HR 0.45; 95% CI, 0.34–0.59)14. This was in line with the mPFS findings for all patients assessed in PALOMA-3 (HR 0.46; 95% CI, 0.36–0.59)14.

Dr Alistair Ring, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust discusses the benefit of CDK4/6 inhibitors in the endocrine therapy resistant metastatic breast cancer population.

Pre-/perimenopausal women

Ribociclib is the only CDK4/6 inhibitor investigated solely in pre-/perimenopausal women in the endocrine sensitive setting9,16

Of the landmark CDK4/6 clinical trials, only the MONALEESA-7 trial focused solely on the pre-/perimenopausal patient group. In the MONALEESA-7 study, ribociclib was compared to placebo, both given in combination with endocrine therapy (NSAI or tamoxifen) and goserelin in patients who had not received prior endocrine therapy in the advanced setting9. In this setting, the ribociclib arm demonstrated a median progression-free survival of 23.8 months compared to 13.0 months in the placebo arm (HR 0.55; 95% CI, 0.44–0.69; P<0.0001)9. The estimated overall survival at 42 months was 70.2% for the ribociclib arm and 46.0% for the placebo arm (HR for death 0.71; 95% CI, 0.54–0.95; P=0.00973)16.

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Pharmacological features

There are notable differences in the pharmacokinetics and drug-drug interactions for the available CDK4/6 inhibitors.

Pharmacokinetics

Abemaciclib is more potent against CDK4 and CDK6 compared with palbociclib and ribociclib, and has additional potency against CDK920

Abemaciclib, palbociclib and ribociclib also differ in their potency and affinity for CDKs. All three are orally active agents that bind to the ATP clefts of CDK4 and CDK620. Palbociclib and ribociclib potencies are similar; however, palbociclib has greater affinity for CDK6, compared with ribociclib20. Abemaciclib is the most potent of all three inhibitors for both CDK4 and CDK6 (Table 2). Abemaciclib also has significant affinity for CDK9 and is therefore considered to be less specific than palbociclib or ribociclib42. It is thought that this affinity to CDK9 may partly explain the clinical efficacy of abemaciclib as a monotherapy, and the higher levels of gastrointestinal toxicity observed for abemaciclib, compared with ribociclib and palbociclib10,20. Further, it may partially explain why some patients who progressed on palbociclib responded to subsequent abemaciclib treatment43,44. Whilst this requires further investigation, the findings suggest that resistance mechanisms may at least partly differ between abemaciclib and palbociclib.

Table 2: IC50 of the three CDK4/6 inhibitors for CDK4 and CDK6 (adapted from Marra et al.20).

Lil_CDK46_Pt2_Table2.png

Drug-drug interactions

Ribociclib is unique in that it can prolong the QT interval and co-administration with other QT-prolonging drugs should be avoided20

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Toxicity, safety and tolerability

Abemaciclib, palbociclib and ribociclib are generally well tolerated, with some notable differences in side effects of the three CDK4/6 inhibitors20

Abemaciclib, palbociclib and ribociclib are now considered standard of care for HR+/HER2− metastatic breast cancer (mBC), with overall increases in quality of life. They are all generally well tolerated; however, there are notable differences in the side effects caused by each CDK4/6 inhibitor, and in the level and type of monitoring required. These differences provide an opportunity to select a CDK4/6 inhibitor that is optimal for a patient based on the presence of comorbidities. Here, we discuss differences in adverse events and monitoring for each of the CDK4/6 inhibitors.

Some of the noteworthy side effects of any frequency that may help to differentiate the available CDK4/6 inhibitors are neutropenia, diarrhoea, prolongation of QT intervals, venous thromboembolism, hepatotoxicity and creatinine levels (Figure 1)20,21. More recently, reports of pneumonitis for all three CDK4/6 inhibitors indicate that this may be a rare but serious adverse event; however, details on how frequently this occurs for each CDK4/6 inhibitor is currently lacking47.

Lil_CDK46_Part2_Fig1.png

Figure 1. Common grade 3–4 adverse events reported in the pivotal trials for the three CDK4/6 inhibitors (adapted from Marra et al.20).

Most of the side effects of CDK4/6 inhibitors can be managed with dose reduction or supportive care measures, which have been shown to help restrict treatment discontinuation20,21.

In the following clip, Dr Gregory Vidal from the West Cancer Centre and Research Institute discusses how he manages breast cancer patients who experience high levels of diarrhoea and neutropenia in response to CDK4/6 treatment.

To learn more about the frequency of side effects for the overall populations assessed in the landmark clinical trials, visit our section on CDK4/6 inhibitors in metastatic breast cancer.

Neutropenias

Neutropenia is a common side effect for all three CDK4/6 inhibitors; however it is less common for abemaciclib, compared with ribociclib and palbociclib48

CDK4/6 inhibitors can cause neutropenia, leucopenia and, less frequently, anaemia and thrombocytopenia48. This is probably due to the central role of CDK6 in the proliferation of haematological precursors21. Notably, neutropenia appears to be roughly twice as common with palbociclib and ribociclib, compared with abemaciclib (Figure 1)9,10,12–14,22,25,26,49. Despite high rates of neutropenia, febrile neutropenia is not common, with ≤2% of patients affected in the palbociclib and ribociclib trials, and ≤0.9% in the abemaciclib trials9,10,12–14,22,25,26.

Unlike neutropenia caused by chemotherapy (apoptosis-mediated), neutropenia caused by CDK4/6 inhibitors arises because of cell cycle arrest and can be effectively reversed within days through dose modification48. This was highlighted in the PALOMA-2 and PALOMA-3 clinical trials, where neutropenia accounted for ≤1.6% of discontinuations, despite 66.5% and 62.0% of patients experiencing grade 3 or 4 neutropenia, respectively13,14. For palbociclib, dose reduction in patients with persistent neutropenia is common; however, dose modification did not appear to negatively impact on progression-free survival6,50.

Neutropenia occurs early on, within 4 weeks for ribociclib treatment and a median onset of 16 days for palbociclib25,50. Indeed, palbociclib and ribociclib are given over 3 weeks followed by 1 week off in order to mitigate the severity of neutropenia2,6,21. Given the lesser effect of abemaciclib on the occurrence of grade 3 or 4 neutropenia, compared with palbociclib and ribociclib, abemaciclib can be dosed continuously21,45. Abemaciclib may therefore be considered for patients who present with baseline neutropenia, or for patients who find it difficult or confusing to adhere to treatment cycles.

Diarrhoea

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CDK4/6 inhibitor cross-resistance

Clinical trials have not yet identified any predictive markers for CDK4/6 inhibitor response in patients with HR+/HER2− metastatic breast cancer; however, it is an active area of research and interest. An understanding of predictive markers for CDK4/6 inhibitor response may one day enable better patient selection for treatment. A biomarker specific to any one CDK4/6 inhibitor may additionally inform on choosing the best CDK4/6 inhibitors for a patient.

Dr Laura Spring also highlights that an understanding of the mechanisms of resistance to CDK4/6 inhibitors may one day help to guide the sequencing of treatment for metastatic breast cancer.

Possible markers of CDK4/6 inhibitor response

Recent clinical and laboratory research indicate that the molecular landscape of resistance to CDK4/6 inhibitors is diverse. Investigative markers of interest include factors involved in the cell cycle and oncogenic signal transduction pathways22. The RB1 tumour suppressor that plays a signalling role downstream of CDK4/6 is a key marker of interest (Figure 2)56. Two separate studies identified RB1 gene alterations in 2.6% and 4.7% of patients receiving CDK4/6 treatments57,58. Despite the low prevalence, a small study found that RB1 gene alterations were acquired in 3 patients who ultimately progressed on either ribociclib or palbociclib treatment59. More recently, analysis of serial biopsies from 5 patients treated with ribociclib and letrozole further revealed that loss of RB and PTEN of the PI3K signalling pathway coincided with the onset of treatment resistance60.

Lil_CDK46_Part2_Fig2.png

Figure 2. Retinoblastoma (RB) lies downstream of CDK4/6 signalling (adapted from Portman et al.56). AKT, protein kinase B; CDK4/6, cyclin dependent kinase 4/6; E2F, E2 transcription factor; ER, oestrogen receptor; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases.

Cell cycle regulation factors other than RB1 are also being explored as resistance markers. These include alterations in the FAT1 gene and the overexpression of specific micro-RNAs that regulate the levels of CDK6, overexpression of which promotes in vitro resistance to CDK4/6 inhibitors57,61,62. Further, amplification of cyclin E1 was associated with shorter time to progression in the PALOMA-3 study on palbociclib, whilst aurora kinase A (AURKA) amplification was associated with CDK4/6 inhibitor resistance in tumour biopsies63,64.

Other than cell cycle regulators, factors such as PTEN, AKT and PDK1 of the PI3K oncogenic signalling pathway have also been implicated in CDK4/6 inhibitor resistance60,64,65. Further, analysis of patient samples and translational models highlight an involvement of the ERBB2 (HER2) and FGFR signalling pathways66–68. Altogether, multiple cellular factors may impact on CDK4/6 inhibitor resistance, with no clear dominant alteration.

Cross-resistance

Dr Laura Spring of the Massachusetts General Hospital Cancer Centre shares her analysis of a retrospective study by Wander and colleagues which looked at the utility of abemaciclib following progression on palbociclib44.

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