by Dr. C.H. Weaver M.D. updated 6/2019
The US Food and Drug Administration (FDA) approved the the precision cancer medicine Kisqali® (ribociclib, LEE011) for first line treatment of estrogen hormone receptor positive (ER+), HER 2 negative (HER2-Neg) metastatic breast cancer because when combined with other hormonal therapy the combination benefits all such women and leads to improved survival without cancer recurrence.
Advanced or metastatic breast cancer refers to cancer that originated in the breast, but has spread to several and/or distant sites in the body. The goals of treatment for metastatic breast cancer are to improve duration of survival while maintaining quality of life.
The majority of breast cancers are referred to as HR+, meaning their cancer is stimulated to grow from exposure to the female hormones estrogen and/or progesterone. These patients are treated with endocrine therapy (sometimes referred to as hormone, or anti-estrogen therapy), which reduces the cancer cells’ exposure to estrogen through varying mechanisms. Endocrine therapy has proven extremely effective in reducing HR-positive cancer growth and spread for extended periods of time.
Mature results from the MONALEESA trials evaluating Kisqali® continue to show that Kisqali improves outcomes in women with ER+ Her2-Neg breast cancer.
The trials determined that adding Kisqali to standard endocrine therapy significantly improved overall survival for premenopausal women with advanced HR-positive/HER2-negative breast cancer compared with endocrine therapy alone. This is the first study to show improved survival for combining a precision cancer medicine with endocrine therapy as a first-line treatment for advanced breast cancer.
Kisqali is a selective cyclin-dependent kinase inhibitor-this class of drugs helps slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. In July 2018, the U.S. Food and Drug Administration approved an expanded indication for Kisqali to be used in combination with an aromatase inhibitor to include pre- and peri-menopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.(3)
Monaleesa-3 clinical trial evaluated 726 postmenopausal patients with ER+, HER2-Neg advanced breast cancer who were treated with Kisqali® + Faslodex (fulvestrant) and compared to treatment with Faslodex alone. (1,2) The study demonstrated that the addition of Kisqali delayed cancer progression and prolonged survival. The initial trial results showed significantly longer overall survival in women treated with Kisqali. Longer follow up results were released in the NEJM and at The San Antonio Breast Cancer Symposia in Dec. 2019. (9)
- At 42 months, the estimated survival among patients treated in the first line setting was 67% for women treated with Kisqali plus Faslodex compared to 56% for treatment with Faslodex alone.
- For women treated at the time of early-relapse or in the second-line setting the average survival duration was 40 months with Kisqali plus Faslodex compared to 32 months with Faslodex alone.
MONALEESA-2 clinical trial directly compared Kisqali plus Femara to Femara alone as initial treatment of 668 postmenopausal women with ER+, HER2-Neg advanced breast cancer. (3)
Among patients with measurable disease the overall response rate was 52.7% with Kisqali and Femara compared to only 37.1% with Femara alone. After a median follow-up of 15.3 months, Kisqali was also associated with a significant improvement in time to cancer progression.
Breast cancer experts at the meeting believe that CDK4/6 inhibition with Kisqali and other cyclin-dependent kinase inhibitors will be a game changer in the treatment of advanced breast cancer. The key question is whether doctors should use them in all patients or whether some biomarker could be identified to use them more selectively. Doctors do not know whether 100% of patients will benefit, or less.
MONALEESA-7 is a comparative clinical trial designed to evaluate Kisqali in combination with hormone therapy consisting of tamoxifen or a non-steroidal aromatase inhibitor plus goserelin compared to treatment with tamoxifen or an aromatase inhibitor plus goserelin alone, in premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer in women who had not previously received endocrine therapy for advanced disease.
Kisqali in combination with tamoxifen or an aromatase inhibitor plus goserelin demonstrated an improved time of survival without cancer progression of 23.8 months compared to 13.0 months for tamoxifen or an aromatase inhibitor plus goserelin. Premenopausal women treated with the Kisqali combination therapy saw a response as early as eight weeks. The researchers observed that after 42 months of follow-up, for patients receiving ribocilcib, the survival rate was 70% when given with endocrine therapy compared with 46% when given with placebo. Overall this represented a 29% relative reduction in the risk of death.
The Kisqali combination was well tolerated and women taking Kisqali also had a clinically meaningful improvement in pain symptoms as early as eight weeks; this improvement was sustained. The most significant side effect observed in patients receiving Kisqali combination therapy compared to endocrine therapy alone was neutropenia which occurred in 60.6% compared to 3.6% of endocrine only treated patients.
Premenopausal breast cancer is a biologically distinct and more aggressive disease than postmenopausal breast cancer, and it is the leading cause of cancer death in women 20-59 years old.2,3 The Kisqali combination therapy represents a new and improved treatment option for these women.
The drug was approved in the US in March last year for use in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with the disease, an indication for which it was also previously awarded breakthrough status.(4)
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- Tripathy D, Sohn J, Im S, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized Phase III MONALEESA-7 trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), December 6, 2017, San Antonio, Texas (abstract#S2-05).
- Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol. 2008;66:65-74
- World Health Organization. Women’s health fact sheet. September 2013. Available at http://www.who.int/mediacentre/factsheets/fs334/en/. Accessed October 2017.
- Siegel RL, Miller KD, et al. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. Vol. 68, No. 1. January/February 2018.
- Johnson RH, Chien FL, et al. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA. 2013;309:800–5.
- U.S. Food and Drug Administration: FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer.
- Tripathy D, Im SA, et al. Lancet Oncol. 2018;19:904-915
- LBA7_PR ‘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 + ribociclib (rib)’ will be presented by Dennis Slamon the Presidential Symposium II on Sunday, 29 September 2019, 16:30-18:00 in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
- LBA6_PR ‘Monarch 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer’ will be presented by George Sledge during the Presidential Symposium II on Sunday, 29 September 2019, 16:30-18:00 in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
- Hortobagyi B, Stemmer S, Burris H, et al. First-line Kisqali + letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC). Proceedings from the annual meeting of the 2016 European Society for Medical Oncology (ESOM). Abstract LBA1_PR. Presented October 8, 2016.