CDK4/6 inhibitor selection in metastatic breast cancer

Declaration of sponsorship Lilly

CDK4/6 inhibitor selection

Declaration of sponsorship Lilly

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 cancer^1–6. 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 cancer^3,4.

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) alone^7–14. More recently, both abemaciclib and ribociclib were additionally shown to improve overall survival^15–17. Abemaciclib has also been shown to improve invasive disease-free survival in patients with HR+/HER2− early breast cancer at high risk of recurrence^18,19.

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 characteristics^20,21. 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 response^20,21.

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.

Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines

Personalised dashboard providing updates and recommendations for content within your areas of interest

Click here to register now

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).

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, respectively^13,23,25. 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, respectively^14,22,27. 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 setting^9,16

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.

Why sign up with Medthority?

Click here to register now

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 palbociclib^10,20. Further, it may partially explain why some patients who progressed on palbociclib responded to subsequent abemaciclib treatment^43,44. 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).

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

Why sign up with Medthority?

Click here to register now

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.

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 discontinuation^20,21.

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 trials^{9,10,12–14,22,25,26}.

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, respectively^13,14. For palbociclib, dose reduction in patients with persistent neutropenia is common; however, dose modification did not appear to negatively impact on progression-free survival^6,50.

Neutropenia occurs early on, within 4 weeks for ribociclib treatment and a median onset of 16 days for palbociclib^25,50. Indeed, palbociclib and ribociclib are given over 3 weeks followed by 1 week off in order to mitigate the severity of neutropenia^2,6,21. Given the lesser effect of abemaciclib on the occurrence of grade 3 or 4 neutropenia, compared with palbociclib and ribociclib, abemaciclib can be dosed continuously^21,45. 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

Why sign up with Medthority?

Click here to register now

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 treatments^57,58. 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.

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 inhibitors^57,61,62. 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 biopsies^63,64.

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 resistance^60,64,65. Further, analysis of patient samples and translational models highlight an involvement of the ERBB2 (HER2) and FGFR signalling pathways^66–68. 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.

Why sign up with Medthority?

Click here to register now

References

Ribociclib, Kisqali® Highlights of Prescribing Information (FDA, CDER). 2020.
Ribociclib, Kisqali® Summary of Product Characteristics (SmPC) - (EMC). 2020. https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf. Accessed 12 May 2020.
Abemaciclib, Verzenios® Summary of Product Characteristics (SmPC) - (EMC). https://www.medicines.org.uk/emc/product/9532/smpc. Accessed 15 May 2020.
Abemaciclib, VERZENIO^TM Highlights of Prescribing Information (FDA, CDER). .
Palbociclib, IBRANCE® Highlights of Prescribing Information (FDA, CDER). 2019 www.fda.gov/medwatch. Accessed 15 May 2020.
Palbociclib, IBRANCE® Summary of Product Characteristics (SmPC) - (EMC). 2020. https://www.ema.europa.eu/en/documents/product-information/ibrance-epar-product-information_en.pdf. Accessed 12 May 2020.
FDA. Verzenio: Highlights of prescribing information. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208716s006s007s008lbl.pdf. Accessed 23 March 2022.
Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. New England Journal of Medicine. 2016;375(18):1738–1748.
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. Journal of Clinical Oncology. 2018;36(24):2465–2472.
Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. The Lancet Oncology. 2018;19(7):904–915.
Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, n patients with refractory HR+/HER2- metastatic breast cancer. Clinical Cancer Research. 2017;23(17):5218–5224.
Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. Journal of Clinical Oncology. 2017;35(25):2875–2884.
Goetz MP, Toi M, Campone M, Trédan O, Bourayou N, Sohn J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology. 2017;35(32):3638–3646.
Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. New England Journal of Medicine. 2016;375(20):1925–1936.
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. The Lancet Oncology. 2016;17(4):425–439.
Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Medical Oncology. 2019. doi:10.1093/annonc/mdz394.
Im S-A, Lu Y-S, Bardia A, Harbeck N, Colleoni M, Franke F, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. New England Journal of Medicine. 2019;381(4):307–316.
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. New England Journal of Medicine. 2020;382(6):514–524.
Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR1, HER22, node-positive, high-risk, early breast cancer (monarchE). Journal of Clinical Oncology. 2020;38(34):3987–3998.
Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Annals of Oncology. 2021;32(12):1571–1581.
Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? npj Breast Cancer. 2019;5(1). doi:10.1038/s41523-019-0121-y.
Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions. Current Oncology Reports. 2019;21(3). doi:10.1007/s11912-019-0769-3.
Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. Journal of Clinical Oncology. 2017;35(25):2875–2884.
Goetz MP, Toi M, Campone M, Trédan O, Bourayou N, Sohn J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology. 2017;35(32):3638–3646.
Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. New England Journal of Medicine. 2016;375(20):1925–1936.
Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. New England Journal of Medicine. 2016;375(18):1738–1748.
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. Journal of Clinical Oncology. 2018;36(24):2465–2472.
Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy - MONARCH 2: A Randomized Clinical Trial. JAMA Oncology. 2020;6(1):116–124.
Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Hart L, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. https://doi.org/101056/NEJMoa2114663. 2022;386(10):942–950.
Battisti NML, De Glas N, Sedrak MS, Loh KP, Liposits G, Soto-Perez-de-Celis E, et al. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. Therapeutic Advances in Medical Oncology. 2018;10. doi:10.1177/1758835918809610.
Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Research and Treatment. 2019;174(3):719–729.
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Annals of Oncology. 2018;(April):1541–1547.
Nguyen L V., Searle K, Jerzak KJ. Central nervous system-specific efficacy of CDK4/6 inhibitors in randomized controlled trials for metastatic breast cancer. Oncotarget. 2019;10(59):6317–6322.
Sahebjam S, Le Rhun E, Kulanthaivel P, Turner PK, Klise S, Wang HT, et al. Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer. Journal of Clinical Oncology. 2016;34(15_suppl):526–526.
Anders CK, Le Rhun E, Bachelot TD, Yardley DA, Awada A, Conte PF, et al. A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019;37(15_suppl):1017–1017.
Barroso-Sousa R, Shapiro GI, Tolaney SM. Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Breast Care. 2016;11(3):167–173.
DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment. Clinical Cancer Research. 2015;21(5):995–1001.
Hoste G, Punie K, Wildiers H, Beuselinck B, Lefever I, Van Nieuwenhuysen E, et al. Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer. Breast Cancer Research and Treatment. 2018;171(1):131–141.
Battisti NML, Kingston B, King J, Denton A, Waters S, Sita-Lumsden A, et al. Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience. Breast Cancer Research and Treatment. 2019;174(3):731–740.
Ban M, Miše BP, Majić A, Dražić I, Vrdoljak E. Efficacy and safety of palbociclib in heavily pretreated patients with HR+/HER2- metastatic breast cancer. Future Oncology. 2018;14(6):537–544.
Demirci U, Gokmen E, Eralp Y, Gunduz S, Goksu SS, Korkmaz T, et al. Abstract P5-11-19: Ribociclib for the treatment of hormone receptor-positive refractory advanced breast cancer: Managed access programme in Turkey. In: Cancer Research. 2020. American Association for Cancer Research (AACR): P5-11-19-P5-11–19.
Chen P, Lee N V., Hu W, Xu M, Ferre RA, Lam H, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Molecular Cancer Therapeutics. 2016;15(10):2273–2281.
Mariotti V, Khong HT, Soliman HH, Costa RL, Fisher S, Boulware D, et al. Efficacy of abemaciclib (abema) after palbociclib (palbo) in patients (pts) with metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019;37(15_suppl):e12521–e12521.
Wander SA, Zangardi M, Niemierko A, Kambadakone A, Kim LS, Xi J, et al. A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019;37(15_suppl):1057–1057.
Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients | OncologyPRO. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/drug-drug-interactions-between-palbociclib-and-proton-pump-inhibitors-may-significantly-affect-clinical-outcome-of-metastatic-breast-cancer-patients. Accessed 29 September 2021.
FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer | FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung-inflammation-ibrance-kisqali-and-verzenio-breast-cancer. Accessed 4 March 2020.
Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Therapeutic Advances in Medical Oncology. 2018;10. doi:10.1177/1758835918793326.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. The Lancet Oncology. 2015;16(1):25–35.
Verma S, Bartlett CH, Schnell P, DeMichele AM, Loi S, Ro J, et al. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor‐Positive/HER2‐Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo‐Controlled, Phase III Study (PALOMA‐3). The Oncologist. 2016;21(10):1165–1175.
McCartney A, Moretti E, Sanna G, Pestrin M, Risi E, Malorni L, et al. The role of abemaciclib in treatment of advanced breast cancer. Therapeutic Advances in Medical Oncology. 2018;10. doi:10.1177/1758835918776925.
Masuda H, Tanabe Y, Matsumoto K, Shimomura A, Doi M, Miyoshi Y, et al. Phase II randomized study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with HR-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B. Presented at European Society for Medical Oncology (ESMO) Congress 2021, 16–21 September 2021. Virtual. 277P.
Olson SR, Deloughery TG, Shatzel JJ. Cyclin-Dependent Kinase Inhibitor-Associated Thromboembolism. JAMA Oncology. 2019;5(2):141–142.
Tamoxifen Summary of Product Characteristics (SmPC) - (EMC). https://www.medicines.org.uk/emc/product/2248/smpc. Accessed 15 May 2020.
Olson SR, Deloughery TG, Shatzel JJ. Cyclin-Dependent Kinase Inhibitor-Associated Thromboembolism. JAMA Oncology. 2019;5(2):141–142.
Chappell JC, Turner PK, Pak YA, Bacon J, Chiang AY, Royalty J, et al. Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate. Clinical Pharmacology and Therapeutics. 2019;105(5):1187–1195.
Portman N, Alexandrou S, Carson E, Wang S, Lim E, Caldon CE. Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. Endocrine-Related Cancer. 2019;26(1):R15–R30.
Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C, et al. Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway. Cancer Cell. 2018;34(6):893-905.e8.
O’leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discovery. 2018;8(11):1390–1403.
Condorelli R, Spring L, Lacroix L, Bailleux C, Scott V, Dubois J, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Annals of Oncology. 2018;29(3):640–645.
Costa C, Ye W, Ly A, Hosono Y, Murchi E, Walmsley CS, et al. Pten loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discovery. 2020;10(1):72–85.
Yang C, Li Z, Bhatt T, Dickler M, Giri D, Scaltriti M, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene. 2017;36(16):2255–2264.
Cornell L, Wander SA, Visal T, Wagle N, Shapiro Correspondence GI, Shapiro GI. MicroRNA-Mediated Suppression of the TGF-b Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance Article MicroRNA-Mediated Suppression of the TGF-b Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance. Cell Reports. 2019;26. doi:10.1016/j.celrep.2019.02.023.
Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, et al. Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019;37(14):1169–1178.
Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia J, Lloyd MR, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer. bioRxiv. 2019;857839.
Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE, et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Research. 2017;77(9):2488–2499.
Nayar U, Cohen O, Kapstad C, Cuoco MS, Waks AG, Wander SA, et al. Acquired HER2 mutations in ER + metastatic breast cancer confer resistance to estrogen receptor–directed therapies. Nature Genetics. 2019;51(2):207–216.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nature Communications. 2019;10(1):1–14.
Drago JZ, Formisano L, Juric D, Niemierko A, Servetto A, Wander SA, et al. FGFR1 amplification mediates endocrine resistance but retains torc sensitivity in metastatic hormone receptor-positive (HR+) breast cancer. Clinical Cancer Research. 2019;25(21):6443–6451.

Why sign up with Medthority?

Click here to register now

Welcome:

Updates in your area
of interest

Articles your peers
are looking at

Bookmarks
saved

Days to your
next event

CDK4/6 inhibitor selection

In this Section

Overview

Why sign up with Medthority?

Patient and disease characteristics

Postmenopausal women

Endocrine sensitive population

Endocrine resistant population

Pre-/perimenopausal women

Why sign up with Medthority?

Pharmacological features

Pharmacokinetics

Drug-drug interactions

Why sign up with Medthority?

Toxicity, safety and tolerability

Neutropenias

Diarrhoea

Why sign up with Medthority?

CDK4/6 inhibitor cross-resistance

Possible markers of CDK4/6 inhibitor response

Cross-resistance

Why sign up with Medthority?

References

Why sign up with Medthority?