text: The use of ribociclib (Kisqali), in combination with an aromatase inhibitor, has grown since its approval in early 2017 for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (See Original Ribociclib Spotlight). In the summer of July 2018, the U.S. Food and Drug Administration expanded the indication for ribociclib in combination with an aromatase inhibitor to include pre/perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. Ribociclib is also approved in combination with fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or after disease progression on previous endocrine therapy.
  MONALEESA-7 Trial: Overall Survival Benefit
  Some 2 years later, in 2019, ongoing research with ribociclib has yielded impressive new data. According to the results of the phase III MONALEESA-7 trial, adding ribociclib to endocrine therapy significantly improved overall survival in premenopausal and perimenopausal patients with advanced HR-positive breast cancer as compared with endocrine therapy alone.1,2 The combination resulted in a 70.2% overall survival rate at 42 months of follow-up compared with 46% in patients receiving endocrine therapy plus placebo—a 29% lower risk of death in patients receiving the ribociclib combination.
  According to the lead study author of MONALEESA-7, Sara A. Hurvitz, MD, of the University of California, Los Angeles Jonsson Comprehensive Cancer Center, who presented these data at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, “This is the first study to show improved survival for any targeted therapy when used with endocrine therapy as a first-line treatment for advanced breast cancer.” Study coauthor Debu Tripathy, MD, of The University of Texas MD Anderson Cancer Center, underscored the importance of their study findings: “Breast cancer in younger women is known to be more aggressive and have distinct genetic changes compared to postmenopausal patients, so this provides a much-needed therapeutic option for these patients.”3
  Next Step: Clinical Trials in Earlier-Stage Breast Cancer
  In light of the survival benefit reported with ribociclib in this patient population, naturally the MONALEESA-7 investigators are studying whether it also will be of benefit in patients with earlier-stage HR-positive/HER2-negative breast cancer. “Because overall survival and postprogression outcomes are key factors in clinical decision-making, the results of adding biologic treatments to endocrine therapies in early lines of therapy are highly relevant in this patient population,” they commented.1
  For instance, the phase III NATALEE trial (ClinicalTrials.gov identifier NCT03701334) is currently examining ribociclib as an adjuvant therapy option in combination with endocrine therapy for patients with early breast cancer. The primary endpoint of the study is invasive disease–free survival, and the estimated primary completion date is December 2025.
  “In an era when we are thinking about value in oncology care, the demonstration of a robust survival benefit adds to the value proposition for products such as ribociclib,” said Harold J. Burstein, MD, PhD, Associate Professor of Medicine, Breast Oncology Program, Harvard Medical School, in an ASCO statement released before the presentation of the MONALEESA-7 data.4 “Hopefully, these data will enable access to this product to more women around the world, particularly in health-care systems that assess value more rigorously as part of their decisions for national access to their drugs.”
  [Editor’s Note: At the end of this update, see Commentary by William J. Gradishar, MD, JNCCN 360 Site Editor in Breast Cancer, about the use of ribociclib in the treatment of breast cancer in 2019.]
  References
  1. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med 2019;381:307–316.
  2. Hurvitz SA, Im SA, Lu YS, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer treated with endocrine therapy ± ribociclib: Overall survival results. J Clin Oncol. 2019;37 (suppl; abstr LBA1008).
  3. The University of Texas MD Anderson Cancer Center. Ribociclib plus hormone therapy extends survival for patients with premenopausal advanced hormone receptor-positive breast cancer. Press release. June 1, 2019.
  Commentary by Breast Cancer Site Editor for JNCCN 360
  William J. Gradishar, MD
  Director, Clinical Network; Chief, Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
  The introduction of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has altered the approach to treatment for most patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer. Before the availability of CDK4/6 inhibitors, single-agent endocrine agents had been used in sequence for as long as patients remained appropriate candidates for endocrine therapy. Now, with three FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) for treatment of advanced HR-positive/HER2-negative metastatic breast cancer, clinicians treat most of such patients with combination endocrine therapy comprising an aromatase inhibitor or fulvestrant along with a CDK4/6 inhibitor as first-line therapy or as a second-line choice for those who did not receive a CDK4/6 inhibitor in the first-line setting. The remarkable consistency of results from the registration trials of all three available agents, particularly with regard to significantly improving progression-free survival, is reassuring, but the question of impact on overall survival was less clear.
  Now, with the report of a significant overall survival benefit in the MONALEESA-7 study for ribociclib in combination with endocrine therapy for the first-line treatment of premenopausal women with HR-positive/HER2-negative breast cancer, the ultimate goal of adding targeted therapy to endocrine therapy has been realized. It is anticipated by many that with longer follow-up, a similar overall survival benefit will be observed in trials of other CDK4/6 inhibitors.
  The next logical step for these agents is evaluation as a component of adjuvant endocrine therapy in large randomized clinical trials involving thousands of patients, with results due to be reported in the next few years. Many questions remain, including whether a different CDK4/6 inhibitor can be used after disease progression or whether switching out the endocrine therapy and continuing the CDK4/6 inhibitor is an option. The use of CDK4/6 inhibitors has had a meaningful impact on how clinicians treat HR-positive breast cancer, with ribociclib now associated with a significant survival benefit.
  DISCLOSURES
  Dr. Gradishar has served on a scientific advisory board or as a consultant or expert witness for Genentech, Inc; has served on a promotional advisory board or speakers’ bureau for Genomic Health; and has received patent, equity, or royalty from Biotheranostics and MGI Pharma, Inc.
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  Managing Neutropenia Associated with CDK Inhibitors
  Spotlight
  Fast Facts
  Drug Class/Description
  Oral kinase inhibitor
  FDA Indication/Patient Eligibility
  In combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy
  In combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy
  Dosage and Administration
  Ribociclib tablets are taken orally with or without food in combination with an aromatase inhibitor or fulvestrant.
  Recommended starting dose: 600 mg orally (three 200-mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days
  When given with ribociclib, the recommended dose of fulvestrant is 500 mg administered on days 1, 15, 29, and once monthly thereafter.
  When given with ribociclib, the recommended dose of the specific aromatase inhibitor being used may be found in the prescribing information for that aromatase inhibitor.
  Dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability.
  Common Adverse Events (Reported in ≥ 20% of Patients)
  Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain
  Warnings and Precautions
  QT interval prolongation: Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with ribociclib. Repeat ECGs at approximately day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated.
  QTcF interval prolongation: Avoid using ribociclib with drugs known to prolong QT interval and/or strong CYP3A inhibitors, as this may lead to prolongation of the QTcF interval.
  Hepatobiliary toxicity: Increases in serum transaminase levels have been observed with ribociclib. Liver function tests (LFTs) should be performed before initiating treatment with ribociclib. LFTs should be monitored every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
  Adapted from ribociclib (Kisqali®) prescribing information.
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