CDK4/6 Inhibitors for Metastatic Breast Cancer

Recruiting at 62 trial locations

Overseen By Cindy MacInnis, MBA

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: American Society of Clinical Oncology

Must be taking: CDK4/6 inhibitors

Must not be taking: QT-prolonging drugs

Disqualifiers: Previous CDK4/6, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 48 months

500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether starting with a lower dose of CDK4/6 inhibitors, medications for metastatic breast cancer, can help patients better tolerate side effects and remain on treatment longer. It focuses on patients 65 and older with hormone receptor-positive (HR+) and HER2-negative breast cancer. Participants will choose between two dosing strategies and combine the medication with a hormone therapy of their choice. Those who have never used these inhibitors for their metastatic cancer and have the appropriate type of breast cancer might be suitable candidates. The goal is to find a more personalized treatment approach that balances effectiveness with fewer side effects. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering patients a chance to contribute to a potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you cannot use drugs that prolong the QT interval (a heart rhythm measure) or other investigational agents. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that palbociclib and ribociclib are generally well-tolerated treatments for advanced breast cancer. Studies have found that neutropenia, a low count of a certain type of white blood cell, is the most common side effect of palbociclib. In one study, 66% of patients experienced this. In real-world settings, other side effects like low white blood cell counts and low platelet counts have also been observed.

Ribociclib has a similar safety profile. Common side effects include reduced levels of different types of white blood cells. These effects occur in many patients but are usually manageable.

Both drugs have FDA approval for treating breast cancer, indicating they have passed thorough safety checks. This trial aims to determine if starting at lower doses and adjusting the dose can further reduce side effects for older patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CDK4/6 inhibitors like palbociclib and ribociclib for metastatic breast cancer because they offer a more targeted approach to treatment. Unlike traditional chemotherapy, which affects both cancerous and healthy cells, these drugs specifically inhibit proteins that are crucial for cancer cell division and growth. This targeted action can potentially lead to fewer side effects and improved effectiveness. Additionally, the trial explores different dosing strategies, including titrated doses that adjust based on patient tolerance, which may enhance the safety and personalization of treatment.

What evidence suggests that this trial's treatments could be effective for Metastatic Breast Cancer?

This trial will compare different dosing regimens of CDK4/6 inhibitors, such as palbociclib and ribociclib, for advanced breast cancer. Studies have shown that these inhibitors are effective treatments. Participants in one arm of this trial will receive the indicated dose of either palbociclib or ribociclib, as provided in the FDA-approved drug label. In another arm, participants will receive a titrated dose, starting with a lower dose and escalating based on treatment tolerance. Research indicates that combining palbociclib with hormone therapy can reduce the risk of cancer progression by 30%. Additionally, real-world evidence supports its ability to help patients with hormone receptor-positive, HER2-negative breast cancer live longer. Ribociclib has also been proven to extend the lives of patients with this type of breast cancer. Clinical results show a significant improvement in overall survival when ribociclib is used with hormone therapy. Both treatments are well-regarded in the medical community for their effectiveness in managing advanced breast cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Julie Gralow, MD

Principal Investigator

American Society of Clinical Oncology

Are You a Good Fit for This Trial?

This trial is for people aged 65 or older with a specific type of advanced breast cancer (HR+ HER2- metastatic). They must have normal liver and kidney function, adequate blood cell counts, and be starting CDK4/6 inhibitor therapy with endocrine therapy for the first time.

Inclusion Criteria

My breast cancer is hormone receptor positive and HER2 negative.

I am eligible to start treatment with CDK4/6 inhibitors and hormone therapy for my cancer.

My liver tests are within acceptable limits for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CDK4/6 inhibitors (palbociclib or ribociclib) with endocrine therapy, randomized to either indicated or titrated dosing regimen

48 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Palbociclib
• Ribociclib

Trial Overview The study tests different dosing strategies of two drugs, Ribociclib and Palbociclib, used in treating advanced breast cancer. Patients will either receive the standard dose or start at a lower dose that increases if tolerated well, alongside chosen endocrine therapy.

How Is the Trial Designed?

Group I: Arm 2: Titrated Dose Experimental Treatment 2 Interventions

Arm 2 is the titrated dosing regimen: participants will start cycle 1 with either 100 mg or 75 mg dose of palbociclib or 400 mg or 200 mg dose of ribociclib, in combination with endocrine therapy (AI or fulvestrant). For cycle 2 and for subsequent cycles, escalation to the indicated dose will be based on treatment tolerance.

Group II: Arm 1: Indicated Dose Experimental Treatment 4 Interventions

Arm 1 of the study is the indicated dosing regimen, provided in the FDA approved drug label: participants will start cycle 1 with either 125mg dose of palbociclib or 600mg dose of ribociclib, in combination with endocrine therapy (AI or fulvestrant).

Palbociclib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

American Society of Clinical Oncology

Lead Sponsor

Trials

40

Recruited

148,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Published Research Related to This Trial

CDK4/6 inhibitors have nearly doubled the progression-free survival (PFS) for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer when used in combination with endocrine therapy, highlighting their efficacy in treatment.

Three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are FDA and EMA approved for treating this type of breast cancer, indicating their established safety and effectiveness in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer. Wu, Y., Zhang, Y., Pi, H., et al.[2020]

In a study of 396 female patients with hormone receptor positive, HER2-negative metastatic breast cancer receiving CDK4 and 6 inhibitors, the most common adverse events were neutropenia, diarrhea, and fatigue, with varying frequencies depending on the specific drug used.

The study found that while the overall incidence of adverse events was lower than in clinical trials, the rates of dose reductions and treatment holds due to these events were higher, suggesting that clinicians may be actively managing side effects to help patients continue their therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. Price, GL., Sudharshan, L., Ryan, P., et al.[2022]

In a study of 144 patients with hormone-positive metastatic breast cancer treated with CDK4/6 inhibitors (palbociclib or ribociclib), the median progression-free survival was 16.5 months and median overall survival was 29.7 months, indicating significant efficacy of these treatments.

The CDK4/6 inhibitors were well tolerated, with only 2.1% of patients discontinuing treatment, and factors like liver metastases and low progesterone receptor positivity were identified as poor prognostic indicators for survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of cyclin-dependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: a single institutional study from India. Ganguly, S., Mukherjee, N., Mandal, S., et al.[2022]

Cyclin-dependent kinase 4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, are important advancements in the treatment of both metastatic and early-stage breast cancer, showing promise in improving patient outcomes.

The round-table discussion highlighted the need for further research to address key questions regarding the optimal use and long-term effects of these inhibitors in breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. Preusser, M., De Mattos-Arruda, L., Thill, M., et al.[2021]

All three FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are equally effective for treating HR-positive, HER2-negative metastatic breast cancer, highlighting the need for strategies to choose and sequence these treatments.

Ongoing research is focused on identifying biomarkers to predict which patients will benefit most from CDK4/6 inhibitors, exploring whether to continue treatment after disease progression, and investigating new combinations and uses beyond HR+/HER2- metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future perspectives and challenges with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer. Bayraktar, S., Batoo, S., Al-Hattab, E., et al.[2021]

CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) significantly improve progression-free survival in patients with hormone receptor-positive HER2-negative metastatic breast cancer when used alongside endocrine therapy, with a consistent hazard ratio of around 0.5 across phase III trials.

These treatments are generally well tolerated, with manageable side effects; however, abemaciclib is associated with a higher incidence of diarrhea, while palbociclib and ribociclib are more likely to cause hematological toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. Eggersmann, TK., Degenhardt, T., Gluz, O., et al.[2019]

The addition of CDK4 and 6 inhibitors (like abemaciclib, palbociclib, or ribociclib) to endocrine therapy significantly improves progression-free survival and response rates in patients with HR+ and HER2- metastatic breast cancer, establishing these inhibitors as a new standard of care.

Exploratory analyses suggest that abemaciclib may be particularly beneficial for women with poor prognosis indicators, although further confirmation is needed for these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Martin, M., Garcia-Saenz, JA., Manso, L., et al.[2021]

In a phase II trial involving 162 patients with early HR+/HER2- breast cancer, adjuvant palbociclib combined with endocrine therapy was found to be feasible, with 63% of patients completing the full 2-year treatment course.

The safety profile of palbociclib in this early treatment setting was consistent with its use in metastatic cases, showing manageable toxicity and no cases of febrile neutropenia, although about 56% of patients required dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma. Mayer, EL., DeMichele, A., Rugo, HS., et al.[2023]

CDK 4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been established as standard treatment for hormone receptor-positive, HER2-negative metastatic breast cancer, significantly doubling the efficacy of endocrine therapies.

Common side effects of CDK 4/6 inhibitors include neutropenia and other non-hematological toxicities like liver impairment and diarrhea, highlighting the importance of clinical monitoring for patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors. Ettl, J.[2020]

A total of 1611 individual case safety reports were analyzed, revealing that palbociclib and ribociclib were associated with serious adverse drug reactions (ADRs) like leukopenia and thrombocytopenia, although most patients recovered from these conditions.

In contrast, abemaciclib was linked to mostly non-serious ADRs, indicating a potentially better safety profile, especially when combined with treatments like fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. Martins, V., Jesus, M., Pereira, L., et al.[2023]

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have significantly improved treatment outcomes for hormone receptor-positive and HER2-negative breast cancer, establishing themselves as key options in both first- and second-line therapies.

While these inhibitors effectively prolong overall survival and progression-free survival in patients, they are also associated with notable adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials. Stanciu, IM., Parosanu, AI., Nitipir, C.[2023]

CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, significantly improve progression-free survival in patients with hormone-receptor-positive, HER2-negative advanced breast cancer when used in combination with endocrine therapy, as shown in multiple clinical trials.

Effective management of adverse events, such as neutropenia and diarrhea, is essential for patient safety and treatment success, highlighting the importance of monitoring and adjusting doses as needed during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Thill, M., Schmidt, M.[2020]

Palbociclib, a CDK 4/6 inhibitor, has been shown to improve progression-free survival in patients with HR+/HER2- metastatic breast cancer when used in combination with aromatase inhibitors or fulvestrant, indicating its efficacy in this specific cancer subtype.

Emerging research suggests that palbociclib may also be effective in treating HER2-positive and triple-negative breast cancers, with ongoing trials exploring its potential as a replacement for chemotherapy in neoadjuvant settings and its synergy with immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of palbociclib as a breast cancer treatment option: a current update. Gallanis, GT., Pericas, RI., Riegel, AT., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9553912/

Real-world study of overall survival with palbociclib plus ... The 5-year survival rate for de novo MBC is only 29.0%. The majority (68%) of breast cancer cases have a hormone receptor–positive (HR+)/human ...

2. nature.com nature.com/articles/s41523-025-00786-z

Real-world effectiveness of palbociclib plus an aromatase ... In a large (n = 2888), heterogeneous population in the United States, palbociclib plus ET was associated with a 30% reduction in risk of disease ...

3. onclive.com onclive.com/view/real-world-outcomes-support-use-of-first-line-palbociclib-plus-et-in-hr-her2-advanced-breast-cancer

Real-World Outcomes Support Use of First-Line Palbociclib ... Real-world data from the UK, Spain, and Germany support palbociclib plus endocrine therapy as effective for HR-positive/HER2-negative advanced ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0960977625004655

metastatic breast cancer: A Flatiron Health database analysis The median time from palbociclib start to a first dose adjustment was 85 days; 25 % of patients experienced a first dose adjustment at a median time of 52 days ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00137

Overall Survival With Palbociclib Plus Letrozole in ... The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance

Palbociclib (IBRANCE) Safety data was evaluated in 444 patients who received palbociclib plus letrozole. Neutropenia was the most frequently reported adverse reaction ...

7. ibrance.com ibrance.com/about-ibrance

About IBRANCE® (palbociclib) For mBC | Safety Info IBRANCE® WAS THE FIRST FDA-APPROVED MEDICATION in its class. IBRANCE is a targeted therapy known as a CDK 4/6 inhibitor . It is not a traditional ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8676999/

Effectiveness and Safety of Palbociclib plus Endocrine ... In this observational retrospective multicentre study, we evaluated data for all women with metastatic breast cancer who were treated with palbociclib. The ...

9. ibrance.pfizerpro.com ibrance.pfizerpro.com/additional-data/select-publications

Real-World Evidence Introduction| IBRANCE® (palbociclib) The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), ...

10. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-021-07790-z

Real-world safety of palbociclib in breast cancer patients in ... This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia.