Authors
- Clarissa Wilkins, PharmD, BCOP, Lead Outpatient Oncology Pharmacist - Specialty Pharmacy at CHRISTUS Health
- Anne DeLisa, PharmD, CCRP, Investigational Drug Service Pharmacist at Hershey Penn State Medical Center
Summary
In September 2024, the FDA approved ribociclib (Kisqali) in early-stage high risk hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer based on the results of the NATALEE trial. This open-label, phase 3 trial randomized 5,101 adults with early-stage HR–positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer to receive ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) or NSAI alone and showed a significant improvement in invasive disease-free survival (iDFS) with ribociclib.
Background
Breast cancer continues to be the most common type of cancer in women and the leading cause of cancer-related death in women. The incidence of breast cancer continues to increase by about 0.6% every year, with it being closer to 1% in younger women less than 50 years of age. Around 3 out of 4 breast cancers will be HR-positive. HR-positive, HER2 negative breast cancer has traditionally been treated with a combination of chemotherapy followed by maintenance endocrine therapy until the introduction of targeted therapy known as cyclin-dependent kinases (CDK) 4/6 inhibitors.1,2
CDK4/6 inhibitors are targeted therapy drugs that block cyclin-dependent kinases (CDKs), particularly CDK4 and CDK6. Blocking these proteins causes cell cycle arrest and slows cancer growth. There are three FDA approved CDK 4/6 inhibitors: ribociclib, palbociclib, and abemaciclib. All three CDK 4/6 inhibitors are currently approved for first line use in advanced breast cancer in combination with an aromatase inhibitor or fulvestrant (along with ovarian suppression therapy in pre-menopausal women). Ribociclib and abemaciclib are both category 1 recommendations with progression free survival and overall survival (OS) benefits in a first-line setting.3,4 For patients with early-stage breast cancer with positive lymph node involvement, and a high risk of recurrence, abemaciclib was approved on March 3rd, 2023 for adjuvant therapy along with tamoxifen or an aromatase inhibitor for 2 years based on the MonarchE Trial.5
Until this point, abemaciclib was the only CDK 4/6 inhibitor approved as adjuvant therapy in early-stage breast cancer. Patients unable to tolerate abemaciclib would need to either dose reduce or discontinue abemaciclib and remain on single agent endocrine therapy. Now, after the data from the NATALEE trial, ribociclib in combination with an aromatase inhibitor has received approval for stage II or stage III breast cancer as adjuvant therapy in patients with a high chance of reoccurrence.6,7 This not only gives patients another option, but also widens the criteria for early-stage HR-positive, HER2-negative breast cancer patients to receive treatment, as lower risk patients were included in the NATALEE trial compared to the MonarchE trial.
NATALEE
NATALEE was a randomized, open-label, phase 3 trial designed to evaluate adjuvant treatment with the CDK4/6 inhibitor, ribociclib, in a wide range of early breast cancer (EBC) patients. This multicenter, international trial included subjects with HR-positive/HER2-negative EBC, stage II (stage IIA with N1 or N0 or grade 2 or 3 disease and evidence of high genomic risk) and stage III disease (included N0 and N1). Eligible patients were randomized 1:1 to receive either ribociclib 400mg/day on days 1-21 of a 28-day cycle over 36 months with an NSAI (letrozole 2.5mg or anastrozole 1mg once daily) for 60 months or an NSAI alone. A change in NSAI was only allowed for toxicity, a medical event requiring change, or subject request.8 Men and premenopausal women were concurrently treated with goserelin 3.6mg every cycle. The primary endpoint was iDFS as defined by Standardized Definitions for Efficacy Endpoints 1.0 (STEEP). Interim analysis occurred at a predefined cutoff in January of 2023 (426 iDFS). Final efficacy was assessed once 509 iDFS events were documented. Secondary endpoints included recurrence-free survival (RFS), distant disease-free survival (DDFS), and OS.
From January 2019 to April 2021, 2,549 patients were randomized to receive ribociclib plus NSAI, and 2552 patients to receive an NSAI alone. Most patients were white and female with a small percentage of male, Asian, and Black subjects. Demographics and baseline clinical characteristics were balanced between the groups. High risk, node negative patients comprised approximately 12% of subjects enrolled. Prior endocrine therapy was allowed, but prior CDK4/6 inhibitor treatment was an exclusion criterion.9,10
In the final analysis in which 1,091 (42.8%) subjects completed 3-years of ribociclib, there was a 25.1% (HR 0.749, 95% CI 0.628-0.892; two-sided P=0.0012) reduction in the risk of iDFS events in the ribociclib arm compared to NSAI alone. Kaplan Meyer estimates of 3-year iDFS favored the ribociclib arm in several subgroups including stage II (94.2% [95% CI 92.4%-95.6%] vs 92.6% [95%CI 90.6%-94.1%]), stage III (88.1% [95% CI 86.1%-89.9%] vs 83.8% [95% CI 81.5%-85.8%]), node-positive disease (90.3% [95% CI 88.9%-91.6%] vs 87.1% [95% CI 85.5%-88.6%]), and node negative disease 93.2% ([95% CI 89.2%-95.7%] vs 90.6% [95% CI 86.5%-93.4%]). The secondary endpoints of DDFS and RFS exhibited some benefit in the ribociclib arm. OS data is not yet mature.
Treatment related adverse events (AEs) of any grades occurred in 98.0% in the ribociclib group and 87.8% in the NSAI only group. In the ribociclib arm, 44.3% of subjects experienced grade 3 or 4 neutropenia as compared to 0.9% in the NSAI only group. Grade 3 or 4 aspartate transaminase (AST)/alanine transaminase (ALT) increases occurred in 12.3% of subjects on the ribociclib arm versus 1.3% on the NSAI arm. QT interval prolongation occurred in both the ribociclib group and the NSAI arm (5.3% vs 1.4%). Other AE’s included nausea, arthralgia, headache, fatigue, hot flush, asthenia, and alopecia. Overall deaths in the ribociclib group (83 subjects [3.3%] were slightly lower than the control group 89 subjects [3.6%] since the primary analysis.
Discussion
The NATALEE trial showed a significant iDFS benefit with ribociclib plus an NSAI compared to NSAI alone in patients with HR-positive, HER2-negative stage II or III early breast cancer. iDFS was 90.4% with ribociclib + NSAI versus 87.1% with an NSAI alone. The secondary endpoints also favored the ribociclib + NSAI group with a 25.2% lower risk of invasive disease, recurrence, or death, and an absolute iDFS benefit of 3.3% at 3 years. Also of note, no new safety signals were observed for either ribociclib or the NSAIs. The top three AEs in the ribociclib + NSAI group were neutropenia (62.1%), arthralgias (36.5%), and nausea (23%) for all grades.8
Notably, ribociclib for early-stage breast cancer is given at a dose of 400 mg, administered orally once daily for 21 consecutive days, followed by 7 days off, for a complete cycle of 28 days, and administered for 36 months. This dose is lower than the dosage used in advanced HR-positive breast cancer and as such was associated with a lower incidence of dose-dependent toxicities. Along with the new indication, ribociclib storage requirements have changed. Refrigeration is now required prior to dispensing. Once dispensed to the patient, the drug can remain at room temperature for 60 days.6,11 Also of note, ribociclib is not given with tamoxifen, due to the risk of QTc prolongation; therefore, pre-menopausal women must receive ovarian function suppression along with an NSAI when receiving therapy.11
Now that we have two CDK 4/6 inhibitors indicated for early-stage high risk HR-positive, HER2-negative patients, there are some things to consider when deciding therapy. Ribociclib given with an NSAI is approved for patients with any lymph node involvement or no nodal involvement if their tumor size is >5 cm, or if the tumor size is 2-5 cm, either grade 2 or grade 3 disease. The above-mentioned AEs shown in the NATALEE trial, along with the risk of QTc prolongation with ribociclib, may exclude some patients from being able to tolerate this therapy, such as patients with an extensive cardiac history. This regimen is given for a total of 3 years in contrast to abemaciclib with endocrine therapy which is given for 2 years. Abemaciclib has narrower criteria and is approved for high-risk patients with ≥4 positive lymph nodes or 1-3 positive lymph nodes with either tumor grade 3 disease or a tumor size ≥5 cm.2,12 In the MonarchE trial, abemaciclib with endocrine therapy demonstrated significant AEs including diarrhea in 82.2% of patients, neutropenia in 44.6%, and fatigue in 38.4%.5 Patients who have a history of gastrointestinal disease or diarrhea may not tolerate this therapy. Ultimately, deciding on which therapy is best will come down to patient-specific disease state factors, medical history, and patient preference.
The results of the NATALEE trial have established ribociclib plus an NSAI as a category 1 recommendation for the adjuvant treatment of adults with HR-positive/HER2-negative stage II and III early breast cancer at high risk of recurrence for 3 years of therapy. OS data is currently immature. Additional analyses with longer follow-up are on-going to fully assess the larger clinical effect of this regimen.
References
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2.National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Breast Cancer. Version 6.2021. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf on August 13, 2021.
3.American cancer society. Targeted Drug Therapy for Breast Cancer. Accessed at http://www.cancer.org/cancer/types/breast-cancer/treatment/targested-therapy-for-breast-cancer.html on October 28, 2024.
4.Ma CX and Sparano JA. Treatment for hormone receptor-positive, HER2-negative advanced breast cancer. In Vora SR, ed. UpToDate. Waltham, Mass.: UpToDate, 2024. https://www.uptodate.com. Last updated October 2, 2021. Accessed October 30, 2024
5.Priya Rastogi et al., Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative, High-Risk Early Breast Cancer: Results from a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. JCO 42, 987-993(2024).
6.FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer | FDA
7.Dennis J. Slamon et al., Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. JCO 41, LBA500-LBA500(2023).
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9.Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390 (12):1080-1091
10.Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trail of adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR+/HER2- early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol 2024, doi:https://doi.org/10.1016/j.annonc.2024.10.015
11.Kisqali [package insert] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024
12.Verzenio [package insert] Indianapolis, IN: Eli Lilly and Company; 2024
