CDK4/6 Inhibitors for Metastatic Breast Cancer

Recruiting at 50 trial locations

Overseen By Jacqueline Perez, MPH

Age: 65+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

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

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to generate evidence on an alternative dosing strategy for CDK4/6 inhibitors to help more patients with Metastatic Breast Cancer (MBC) (age ≥ 65 years) tolerate side effects and stay on treatment longer, to derive the most clinical benefit from these drugs. The primary objective of the CDK Study is to compare time to treatment discontinuation (TTD) on the approved dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle) or ribociclib (600 mg orally daily on days 1-21 of 28-day cycle) vs. TTD using titrated dosing approach with the same schedule but starting at a lower dose of palbociclib (100 mg or 75 mg) or ribociclib (400 mg or 200 mg) and escalating the dose if well-tolerated in combination with provider/patient choice endocrine therapy (aromatase inhibitor (AI) or fulvestrant) in patients age 65 or older with HR+/HER2- MBC. The secondary and exploratory objectives will generate evidence needed to personalize treatment decisions by comparing patient-centric secondary outcomes and evaluating baseline factors. Together with their treating physician, participants will choose the CDK4/6 inhibitor (palbociclib or ribociclib) and which endocrine therapy (aromatase inhibitor or fulvestrant) of their choice but will be randomized to either Arm 1 (indicated dosing) or Arm 2 (titrated dosing).

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.

What data supports the effectiveness of the drug Palbociclib for metastatic breast cancer?

Research shows that Palbociclib, when combined with endocrine therapy, significantly improves progression-free survival in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. This means patients live longer without their cancer getting worse compared to using endocrine therapy alone. ^{1 2 3 4 5}

What is the safety profile of CDK4/6 inhibitors like Palbociclib, Ribociclib, and Abemaciclib for metastatic breast cancer?

CDK4/6 inhibitors, including Palbociclib, Ribociclib, and Abemaciclib, are generally safe but can cause side effects like low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), liver issues, heart rhythm changes, and diarrhea. Most side effects are manageable and often resolve with proper monitoring and treatment adjustments. ^{6 7 8 9 10}

How do CDK4/6 inhibitors like Palbociclib and Ribociclib differ from other drugs for metastatic breast cancer?

CDK4/6 inhibitors like Palbociclib and Ribociclib are unique because they specifically target proteins (CDK4 and CDK6) that help cancer cells grow, and they are used in combination with hormone therapy to significantly extend the time patients live without their cancer getting worse. This combination approach is different from traditional chemotherapy and is particularly effective for hormone receptor-positive, HER2-negative metastatic breast cancer. ^{2 4 11 12 13}

Research Team

Julie Gralow, MD

Principal Investigator

American Society of Clinical Oncology

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Palbociclib (CDK4/6 Inhibitor)
• Ribociclib (CDK4/6 Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Future perspectives and challenges with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer. [2021]

3. England 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. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. [2019]

5. England pubmed.ncbi.nlm.nih.gov

An evaluation of palbociclib as a breast cancer treatment option: a current update. [2022]

6. England 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. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. [2023]

9. Switzerland 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. [2023]

10. England pubmed.ncbi.nlm.nih.gov

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

11. New Zealand pubmed.ncbi.nlm.nih.gov

Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer. [2020]

12. England 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. [2022]

13. England pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. [2021]