Ibrance in Advanced HR-Positive HER2-Negative Breast Cancer.
by Dr. C.H. Weaver M.D. updated 6/2020
Positive results from two key clinical trials have changed the treatment of advanced breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a precision cancer medicine that work by blocking signals that tell breast cancer cells to divide. Trials have now demonstrated that combining the CDK 4/6 inhibitor Ibrance® (palbociclib) with standard anti-estrogen therapies improved outcomes in patients with stage IV hormone-positive, HER2-negative breast cancer.
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The PALOMA-1 clinical trial enrolled patients who had not received any prior treatment for stage IV breast cancer. Ibrance plus Femara® (letrozole) doubled the duration of cancer control when compared with Femara plus an inactive placebo.
In the PALOMA-3 trial, Ibrance plus Faslodex® (fulvestrant) more than doubled the duration of cancer control compared with Faslodex plus an inactive placebo. All patients on PALOMA-3 had progressed on a previous anti-estrogen therapy. A third had also received prior chemotherapy.
Ibrance was generally well tolerated in both studies. The most commonly reported side effect was low white blood cell count. Most patients were able to complete their prescribed treatment.
The United States Food and Drug Administration (FDA) has approved Ibrance to be used in women with hormone-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative, metastatic breast cancer.
The majority of breast cancers are HR-positive. These cancers are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of HR-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen.
Ibrance belongs to a class of drugs known as kinase inhibitors that work by blocking the action of enzymes called kinases. Kinases are involved in many cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells, and blocking them may help prevent cancer cells from growing. Specifically, Ibrance inhibits cyclin-dependent kinase (CDK) 4 and 6. These kinases are involved in the growth of HR-positive breast cancer.
Ibrance + Faslodex PALOMA3 – Second Line Treatment
PALOMA3 is a Phase III clinical trial that prompted the FDA approval for Ibrance. Ibrance was tested in combination with Faslodex for the treatment of patients with advanced HR-positive breast cancer. Faslodex is a type of hormonal therapy known as an estrogen receptor antagonist, which blocks the actions of estrogen.
Researchers enrolled 521 patients with metastatic HR-positive, HER2-negative breast cancer. In all of the patients, cancer had come back or progressed after previous hormonal therapy. Women were treated with Faslodex with or without Ibrance and directly compared. Women who were near menopause (pre- and perimenopausal) also received a drug called Zoladex® (goserelin). Zoladex is approved for the treatment of advanced breast cancer in pre- and perimenopausal women to reduce the production of estrogen.
Women treated with Ibrance plus Faslodex survived without cancer progression for 9.5 months, compared with 4.6 months for those treated with Faslodex alone.
In the Phase III clinical trial that prompted the FDA approval for Ibrance, known as the PALOMA3 trial, Ibrance was tested in combination with Faslodex for the treatment of patients with advanced HR-positive breast cancer. Faslodex is another type of hormonal therapy known as an estrogen receptor antagonist, which blocks the actions of estrogen. (1,2)
Researchers with the PALOMA3 study enrolled 521 patients with metastatic HR-positive, HER2-negative breast cancer. All of the patients, had cancer that had come back or progressed following previous hormonal therapy treatment. All patients were treated with Faslodex and half the patients were also treated with Ibrance. Women who were near menopause (pre- and perimenopausal) also received a drug called Zoladex® (goserelin). Zoladex is approved for the treatment of advanced breast cancer in pre- and perimenopausal women to reduce the production of estrogen.
Women who received the Ibrance-Faslodex combination survived on average 9.5 months without cancer progression compared with 4.6 months for those who received Faslodex without Ibrance.
The Ibrance/ Femara combination delays the time to cancer progression when used as first-line treatment for advanced breast cancer in postmenopausal women with ER-positive, HER2-negative cancer. In the PALOMA study, post-menopausal women with advanced ER-positive, HER2-negative breast cancer were enrolled in two sequential groups; one without, and one with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. All patients were treated with continuous Femara® with or without Ibrance® in 28-day cycles and their outcomes directly compared.
At 29 months from initiation of treatment 43% of women responded to treatment with the Femara®-Ibrance® combination compared to only 33% of those treated with Femara® alone. On average, individuals treated with the combination experienced a doubling in survival without evidence of cancer progression. The addition of Ibrance® improved the time to cancer progression to 20.2 months compared to only 10.2 months for those treated with Femara® alone. On average, women treated with Ibrance® survived 37. 5 months compared to 33.3 months for those treated with Femara® alone.
The study authors concluded that the addition of Ibrance® to Femara® significantly improved progression-free survival in women with advanced ER-positive, HER2-negative breast cancer. A phase 3 clinical study is currently underway with the goal of confirming these observations. (3)
Ibrance Side Effects
Few patients—less than 3%—had to stop treatment with Ibrance due to side effects. Common side effects included neutropenia (low number of immune cells called neutrophils), leukopenia (low number of white blood cells), anemia (low number of red blood cells), thrombocytopenia (low number of platelets), and fatigue.
PALLAS Adjuvant Trial Discontinued
The independent Data Monitoring Committee (IDMC) for the global Phase 3 early breast cancer PALbociclib CoLlaborative Adjuvant Study (PALLAS) trial determined that the study is unlikely to show a significant improvement in the primary endpoint of invasive disease-free survival (iDFS) following a preplanned interim analysis and the trial was discontinued.
The PALLAS trial was a Phase 3 study comparing the combination of at least five years of standard adjuvant endocrine therapy along with two years of Ibrance in pre- and postmenopausal women or men with HR+, HER2- early invasive (Stage 2 and Stage 3) breast cancer, including those at moderate to high risk of recurrence.
- United States Food and Drug Administration (FDA). Palbociclib (IBRANCE Capsules). Available here. Accessed March 15, 2016.
- Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. New England Journal of Medicine. June 1, 2015DOI: 10.1056/NEJMoa1505270.
- Finn R, Crown J, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet Oncology, Vol 16, No. 1, p25-35, January, 2015.
Sarah Schweber, MD is a board-certified medical oncologist at Memorial Sloan Kettering Commack whose practice focuses on caring for patients with breast and gynecologic cancers. She works as part of a team to provide state-of-the-art care to patients in a supportive environment, and feels privileged to be part of a dedicated group of medical oncologists, radiation oncologists, surgeons, radiologists, and nurses. In her practice, she follows evidence-based principles and works with patients to develop individualized treatment plans. Dr. Schweber earned her medical degree at University of New York Downstate College of Medicine.