by Dr. C.H. Weaver M.D. ASCO 9/2021 update
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
A Kisqali ®Femara ® Co-Pack allows patients the convenience of obtaining a full 28-day cycle of the two medicines in one package with one prescription and one co-pay. The Kisqali-Femara Co-Pack is available at the same cost as Kisqali alone. The Kisqali-Femara Co-Pack will be available in the US later this month at both specialty and retail pharmacies, and does not change the indication for either medicine.15
Monaleesa-3 Clinical Trial
The 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 2022 European Society Oncology Annual Meeting.9,15,16
After a median follow-up of 56.3 months, average survival for patients taking Kisqali in combination with fulvestrant was 53.7 months vs. 41.5 months for fulvestrant alone.
The need for chemotherapy was delayed to 4 years (48.1 months) in patients taking Kisqali in combination with fulvestrant and 28.8 months in the patients taking fulvestrant alone.
Extended follow-up data showed that the estimated survival rate at five years was 56.5% for women who received the Kisqali fulvestrant combination treatment compared to 42.1% for women who received fulvestrant alone.
MONALEESA-2 - Clinical Trial
The 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
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Among patients with measurable disease the overall response rate was 53% with Kisqali and Femara compared to only 37% with Femara alone. Kisqali was associated with a significant improvement in time to cancer progression and overall survival. The average duration of survival for the Kisqali-Femara combination was 64 months compared to only 51 months for Femara alone.
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 Clinical Trial
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.
After a median of 53.5 months follow-up, patients taking Kisqali in combination with endocrine therapy survived on average 58.7 months compared to 48.0 months for for tamoxifen or an aromatase inhibitor plus goserelin.15
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.
Kisqali® Improves Survival in Advanced Breast Cancer with Aggressive Visceral Disease
Researchers presented new data on the effectiveness of Kisqali for the treatment of women with aggressive breast cancer involving the liver and other internal organs at the 2020 American Society of Clinical Oncology Annual Meeting. Kisqali plus endocrine therapy extended life compared to endocrine therapy for patients with liver metastases – showing ~47% and 37% reduction in the risk of death in M7 and M3, respectively.13
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
- 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 here. Accessed October 2017.
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- 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.
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
- Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer
- 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.
- Yardley, Denise, A. et. al. Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials. Presented at the American Society of Clinical Oncology (ASCO) meeting (Abstract #1054).
- Tripathy D, Im S-A, Colleoni M, et al, Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Presented at the San Antonio Breast Cancer Symposium, December 9, 2020. Abstract #PD2-04
- Slamon D, Neven P, Chia S, et al. Updated overall survival (OS) results from the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2− advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, June 5, 2021, (Abstract #1001).