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CDK4/6 inhibitors in breast cancer

CDK4/6 inhibitor trials in breast cancer

Read time: 60 mins
Last updated:24th May 2022
Published:22nd Apr 2021

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors now represent standard of care for advanced breast cancer. Could they also be beneficial in early breast cancer?

  • Find out the results of clinical trials for CDK4/6 inhibitors in early and advanced breast cancer
  • Learn the latest CDK4/6 inhibitor survival data from our breast cancer experts
  • Optimally manage CDK4/6 inhibitor safety in your patients

CDK4/6 inhibitor clinical trials in early breast cancer

The CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib are approved in the US and Europe for treatment of HR+/HER2− advanced breast cancer (ABC) in combination with endocrine therapy (ET)1. Indeed, combined therapy is now considered standard of care for patients with ABC at high risk of recurrence1.

Investigation to determine whether CDK4/6 inhibition would be beneficial in early disease led to FDA and EMA approval of abemaciclib for high-risk HR+/HER2− early breast cancer based on the outcome for the monarchE trial2–5

CDK4/6 inhibitor treatment in early breast cancer

In October 2021, the US Food and Drug Administration (FDA) extended the indication for abemaciclib to include adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score of ≥20%2. The FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay as a companion diagnostic test for selecting patients for this indication2. In April 2022, the European Medicines Agency also approved the use of abemaciclib as adjuvant treatment of adults with HR+/HER2−, node-positive, early breast cancer (EBC) at high risk of recurrence3.

Soon after the FDA approved the extended indication for abemaciclib, the American Society for Clinical Oncology (ASCO) updated their guidelines to include abemaciclib for 2 years plus ET for ≥5 years as a treatment option for patients with high-risk HR+/HER2− EBC6. The updated guidelines also define high risk of recurrence according to the monarchE criteria of ≥4 positive axial lymph nodes (ALN) or 1–3 positive ALN and one or more of6:

  • histological grade 3 disease
  • tumour size ≥5cm
  • Ki-67 score ≥20%

Evidence for CDK4/6 inhibitors in early breast cancer

Following the success of CDK4/6 inhibition in the treatment of ABC, four phase 3 clinical trials were initiated to evaluate efficacy of CDK4/6 inhibitors in combination with ET for treatment of high-risk HR+/HER2− EBC. These trials include the monarchE4,5 trial for abemaciclib, the NATALEE8 trial for ribociclib, and the PALLAS9 and PENELOPE-B10 trials for palbociclib. The trials differed in their definition of high-risk EBC, but nodal involvement was an inclusion criterion in all trials except the PALLAS trial, which recruited a small number of node-negative patients. None of the trials used biomarkers to define high-risk, although the monarchE and NATALEE trials included patients with Ki-67 scores of ≥20. The primary endpoint for each trial was invasive disease-free survival (Table 1).

Table 1. Clinical trials for CDK4/6 inhibitors in HR+/HER2− early breast cancer4,5,8–10. ALN, axial lymph node; bid, twice daily; CPS-EG, clinical-pathological state oestrogen receptor grade; ET, endocrine therapy; HR, hormone receptor; HER2, human epidermal growth factor 2; IDFS, invasive disease-free survival; NACT, neoadjuvant chemotherapy; od, once daily; RT, radiotherapy

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CDK4/6 inhibitor clinical trials in advanced breast cancer

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) abemaciclib, palbociclib and ribociclib have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer (ABC)13–18.

In this video, Dr Gregory Vidal from the West Cancer Centre and Research Institute (University of Tennessee, USA) shares his view on the landmark clinical trials for CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer (mBC).

The patient populations assessed, treatment arms and the key outcomes for the landmark clinical trials for abemaciclib (MONARCH series19–24), palbociclib (PALOMA series25,26) and ribociclib (MONALEESA series27–32) are summarised in Table 2. Note that cross-study comparisons should be avoided because of differences in patient populations assessed, treatment partners used, and study design.

Table 2. Summary of CDK4/6 inhibitor clinical trials in advanced breast cancer.

Lil_CDK46_Pt1_Table3.png

The efficacy and safety of the CDK4/6 inhibitors in the landmark trials are discussed in detail below.

It is important to note that there are several ongoing clinical trials for CDK4/6 inhibitors that aim to understand their utility in different clinical settings and patient subgroups, such as those with central nervous system involvement or heavily pre-treated disease.

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Abemaciclib in advanced breast cancer

In the clinical trial MONARCH 1, abemaciclib showed benefit as monotherapy in heavily pre-treated patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC)19,20. In the MONARCH 2 and 3 trials, adding abemaciclib to endocrine therapy (ET) demonstrated significant and clinically meaningful improvement in median progression-free survival in first- and second-line therapy for HR+/HER2-21–24. Diarrhoea emerged as the predominant abemaciclib-related adverse event, and was managed with conventional anti-diarrhoeal agents or dose reduction19–24.

Exploratory analysis of MONARCH 2 and 3 indicated that adding abemaciclib to ET shows greatest benefit to patient subgroups with high proliferative disease, progesterone receptor-negative status, or liver metastases22,34.

Efficacy

MONARCH 1

The Phase II MONARCH 1 trial evaluated the efficacy of abemaciclib monotherapy in 132 women with refractory HR+/ HER2− mBC19. Patients had received a median of 3 (range 1–8) lines of prior systemic therapy in the metastatic setting, including a median of 1 (range 1–3) line of chemotherapy (ChT) and 2 (range of 1–6) lines of ET. This heavily pre-treated patient group all had measurable disease at study entry and 90.2% had visceral disease, while 50.8% had 3 or more metastatic sites19.

Treatment with abemaciclib monotherapy benefited some patients with a poor prognosis, showing a confirmed objective response rate (ORR) of 19.7% (95% CI, 13.3–27.5)19. Of these responders, 46.2% received at least 2 prior chemotherapies in the advanced setting. 92.3% had visceral disease, and 46.2% had three or more metastatic sites19.

MONARCH 2

MONARCH 2 was a Phase III study involving 669 women with HR+/HER2− advanced breast cancer (ABC) who had progressed while receiving neoadjuvant or adjuvant ET ≤12 months from the end of adjuvant ET, or while receiving first-line ET for mBC21.

Study participants were initially given a 200 mg twice-daily dose of abemaciclib; however, a review of safety data and dose reduction rates led to the protocol being amended and the dose reduced to 150 mg for all new and enrolled patients.

Administration of abemaciclib (150 mg, twice daily) on a continuous schedule plus fulvestrant (500 mg) significantly extended progression-free survival versus placebo plus fulvestrant with 16.4 months in the abemaciclib arm and 9.3 months in the placebo arm (P<0.001) (Figure 3)21.

Lil_CDK46_Fig6.png

Figure 3. Investigator-assessed progression-free survival following treatment with abemaciclib plus fulvestrant or placebo plus fulvestrant (Adapted from Sledge et al.21). CI, confidence interval; HR, hazard ratio.

Among patients with measurable disease, the overall response rate was 48.1% in patients receiving abemaciclib and 21.3% in the placebo group (P<0.001). Meanwhile, the clinical benefit rates were 72.2% and 56.1%, respectively (P<0.001)21.

Investigators in the MONARCH 2 study also included an exploratory analysis of change in tumour size over time. After 12, 28-day treatment cycles, the mean change in tumour size was −62.5% in the abemaciclib group and −32.8% in the placebo group21.

In a recent updated analysis of the MONARCH 2 cohorts, overall survival (OS) was found to be significantly improved in the abemaciclib plus fulvestrant group, with OS of 46.7 months compared with 37.3 months in the placebo plus fulvestrant group (P=0.01) (Figure 4)22.

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Palbociclib in advanced breast cancer

In 2015, the PALOMA-1 trial defined for the first time the efficacy and activity of palbociclib in metastatic breast cancer (mBC)38. PALOMA-1, 2 and 3 achieved their primary endpoint of improvement in progression-free survival (PFS)25,26,38. Most common grade 3–4 adverse events in the combination arms were neutropenia, leucopenia, fatigue (PALOMA-1)38, including anaemia and febrile neutropenia (PALOMA-2)25, and thrombocytopenia (PALOMA-3)26. No cases of febrile neutropenia or neutropenia-related infections were reported in PALOMA-138. Febrile neutropenia was reported in 0.6% of patients in the experimental arm in PALOMA-326. In PALOMA-2, there was a significantly greater improvement in pain in palbociclib plus letrozole25. Patients in PALOMA-3 who received palbociclib showed significant improvement in pain and in time-to-deterioration questionnaire scores26.

Post-hoc analyses were conducted on the PALOMA-2 and PALOMA-3 trials to evaluate time to chemotherapy for the patients enrolled in both trials. Results indicate that palbociclib plus letrozole prolonged time to chemotherapy, compared with placebo plus letrozole, across all subgroups. In addition, there was a longer time to subsequent chemotherapy for patients in PALOMA-2 (palbociclib plus letrozole in the first-line), compared with those in PALOMA-3 (palbociclib plus endocrine after progressing on prior endocrine therapy)39.

Efficacy

PALOMA-2

The PALOMA-2 trial randomised 666 postmenopausal women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (mBC), who had received no prior treatment for their disease25,26.

The primary endpoint was median mPFS26,40. The combination of palbociclib and letrozole produced an mPFS of 24.8 months (95% CI, 22.1 months, non-estimable) versus 14.5 months (95% CI, 12.9–17.1 months) with placebo plus letrozole (Figure 6)25,26.

Lil_CDK46_Fig9.png

Figure 6. Primary endpoint (mPFS) results in the PALOMA-2 trial (Adapted from Finn et al.26). CI, confidence interval; HR, hazard ratio; LET, letrozole; NE, non-estimable; PFS, progression-free survival; PLA, placebo.

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Ribociclib in advanced breast cancer

The MONALEESA clinical trials demonstrate the treatment benefit and manageable safety profile of ribociclib in combination with aromatase inhibitors or fulvestrant, compared with placebo, in hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC)27–32. Many adverse events reported were consistent across all trials27–32. The most common adverse events of any grade that occurred in ≥25% of patients were neutropenia, leukopenia and nausea.

The MONALEESA clinical programme for ribociclib includes diverse patient populations in different treatment settings27–32. In addition to the data provided by this programme, ongoing clinical investigations are evaluating other applications and characteristics of ribociclib with different combination drugs, in different patient populations and in other treatment settings. Overall survival data with ribociclib for the treatment of HR+/HER2− ABC in a Phase III setting have not been published. Combining ribociclib with other therapeutic agents has become an option to improve PFS and overcome endocrine therapy (ET) resistance52.

At the European Society for Medical Oncology (ESMO) Congress in 2021, the results of a phase 3b, multicentre, open-label study of ribociclib plus letrozole were revealed. In this study, the patient settings were broader than those explored in the MONALEESA studies. This study recruited patients of any menopausal status with HR+/HER2– ABC who were not responsive to curative treatment. The secondary endpoints that were reported confirmed the previous findings of MONALEESA in a wider population53.

Efficacy

MONALEESA-2

The MONALEESA-2 trial included 668 postmenopausal women with HR+/HER2- metastatic or recurrent BC who had received no prior treatment for their advanced disease27,28.

The trial met its primary endpoint (median progression free-survival [mPFS]) and demonstrated superiority of ribociclib plus letrozole versus placebo plus letrozole. At the point of analysis, the ribociclib group had not reached the median duration of PFS (95% CI, 19.3–not reached) compared with 14.7 months (95% CI, 13.0–16.5) in the placebo group (Figure 7)27,28.

Lil_CDK46_Fig10.png

Figure 7. Median progression-free survival following treatment with ribociclib plus letrozole or placebo plus letrozole (Adapted from Hortobagyi et al.28). CI, confidence interval; HR, hazard ratio; PFS, progression free survival.

At the time of the second interim analysis (median 26.4 months of follow-up), mPFS rates for ribociclib plus letrozole were 25.3 months vs. 16.0 months for the placebo plus letrozole group (HR 0.568; 95% CI, 0.457–0.704; log-rank P=9.63 x 10-8)27.

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Dalpiciclib in advanced breast cancer

The DAWNA-1 trial was a randomised, double-blind, phase 3 trial of the investigational CDK4/6 inhibitor dalpiciclib (SHR6390) as monotherapy for pre-treated HR+/HER2− advanced breast cancer (ABC) or metastatic breast cancer (mBC) patients who had relapsed or progressed on previous endocrine therapy (ET)56,57.

361 patients were randomised (2:1) to receive the investigational drug dalpiciclib plus fulvestrant (n = 241) or placebo plus fulvestrant (n = 120). At baseline, approximately 60% of patients had visceral metastases and 45% were premenopausal or perimenopausal. The primary endpoint was investigator assessed progression-free survival (PFS) and as of November 2020, 71.4% of the total projected PFS events had occurred, and a pre-planned interim analysis was carried out56.

Efficacy

DAWNA-1

The investigator-assessed PFS was 15.7 months in the dalpiciclib-fulvestrant arm and 7.2 months in the placebo-fulvestrant arm (P<0.0001). The median PFS based on an independent review committee (IRC) assessment (Table 7) was 13.6 months and 7.7 months, respectively (P<0.0001)56.

In all prespecified subgroups, PFS favoured dalpiciclib plus fulvestrant, with a hazard ration (HR) of <1 irrespective of menopausal status, presence of visceral metastasis, or prior ET. Investigator and IRC assessed overall response rate (ORR) and clinical benefit rate (CBR) were observed to be higher in the dalpiciclib-fulvestrant group, compared with the placebo-fulvestrant group (Table 7)56

Table 7. PFS based on independent review committee and investigator assessment (adapted56). CI, 95% confidence interval; CMH P, Cochran–Mantel–Haenszel p-value; Dalp, dalpiciclib; fulv, fulvestrant; HR, hazard ratio; IRC, independent review committee; INV, investigator; Mo, months; PBO, placebo; PFS, progression-free survival; ORR, overall response rate; NR, not reported; TFSCT, time to first subsequent chemotherapy.

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CDK4/6 inhibitor side-effect management

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) abemaciclib, palbociclib and ribociclib, show similar side effects, though with some differences13–15. Similar side effects associated with CDK4/6 inhibitor-based combination treatments include neutropenia or gastrointestinal events13–15.

Abemaciclib is structurally distinct from palbociclib and ribociclib, and is more selective for CDK4 than CDK615. CDK4 is important for breast tumorigenesis, while CDK6 is important in haematopoietic stem cell differentiation. CDK4 is associated with higher rates of diarrhoea and fatigue than CDK6, but lower rates of haematological side effects, including neutropenia13–15. In contrast to palbociclib, ribociclib has a higher incidence of QT interval prolongation13,14. The most common side effect for palbociclib and ribociclib is neutropenia13,14.

CDK4/6 inhibitor-associated toxicity can be managed by dose reductions or dose modifications13–15,52. Early monitoring with regular clinical assessments and management of side effects is important12–14,51. Accurate communication between the patient and clinician can avert treatment-related misunderstandings13–15,52.

Dr Laura Spring, a clinical/translational investigator and breast medical oncologist at the Massachusetts General Hospital Cancer Center and Harvard Medical School, summarises the CDK4/6 inhibitor toxicities as reported in pivotal clinical trials.


Not all CDK4/6 inhibitor-related side-effects observed in the clinical management of breast cancer have been reported in clinical trials. In our next videos, Dr Veronique Dieras and Professor Nadia Harbeck explain what additional CDK4/6 inhibitor-related side-effects clinicians could observe in clinical practice.

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References

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