Real-World Findings Support the Safety of Frontline Ribociclib Plus ET for HR+/HER2-Negative Metastatic Breast Cancer

The safety of ribociclib (Kisqali) plus endocrine therapy in the frontline hormone receptor (HR)–positive/HER2-negative metastatic breast cancer setting was reaffirmed according to findings from 2 observational, retrospective database studies presented at the 42nd Annual Miami Breast Cancer Conference® from an encore presentation given at the 2024 San Antonio Breast Cancer Symposium.1,2

“This analysis of frontline real-world use of ribociclib in HR-positive HER2-negative metastatic breast cancer from 2018 to 2022 from the electronic health record [EHR] and the Komoda Research Database [KRD] reflects an increase in use starting in 2022 in the KRD. In the real-world setting, rates of adverse effects [AEs] of special interest for ribociclib are comparable with published randomized controlled trial data among the overall cohorts as well as patients 65 years and older,” Sarah Sammons, MD, wrote in a poster presentation of the data.

Additionally, dose patterns in the real-world typically followed the label of ribociclib. Most patients (84.72%) received 600 mg of the CDK4/6 inhibitor once daily, which is the recommended on-label dose of the agent for those with advanced or metastatic disease,3 and some patients received 400 mg (7.24%) once daily or 200 mg (4.56%) once daily.1 Among patients who received the 600 mg dose, 34% had a dose reduction to 400 mg, with 27% of those whose dose was reduced mentioning an AE of therapy as a reason at the end of the last treatment episode.

Per the EHR and KRD, which the real-world study was conducted with, patients in overall cohorts at risk of developing neutropenia (n = 367 and n = 333, respectively), elevated liver enzyme/transaminases levels (n = 366; n = 349), and QT interval prolongation (n = 373; n = 346) experienced new onset of said events at rates of 53.4% and 21.3%; 9.0% and 4.6%; and 4.0% and 2.0%, respectively.

Furthermore, the EHR examined the new onset of tolerability-related medical conditions in patients at least 65 years of age (n = 183) and in those 75 years of age and greater (n = 65). These patients experienced new onset of neutropenia (50.8%; 47.7%, respectively), elevated liver enzyme/transaminases levels (10.9%; 13.8%), and QT interval prolongation (5.5%; 3.1%). According to the KRD, those aged 65 years and older who were at risk of developing neutropenia (n = 56), elevated liver enzyme/transaminases levels (n = 57), and QT interval prolongation (n = 57) experienced new onsets of the events at respective rates of 14.3%, 3.5%, and 1.8%.

Rates of ribociclib treatment in the frontline setting by index year also generally increased with each year and were as follows in 2018 (12.6%), 2019 (16.3%), 2020 (14.6%), 2021 (16.0%), and 2022 (40.6%).

Study Criteria and Methods

The 2 observational, retrospective national cohort studies were conducted using the nationwide, longitudinal, EHR-derived Flatiron Health database and the deidentified KRD. The EHR was comprised of deidentified patient-level data from approximately 280 US cancer clinics, including approximately 800 sites of care primarily in the community setting, and it was curated via technology-enabled abstraction. The KRD had US census-level representation of all ages, incomes, races, and ethnicities to capture diverse as well as large cohorts of patients and was comprised of closed medical and pharmacy claims in the US for more than 150 payers; members had commercial managed Medicare, excluding fee-for-service, and Medicaid insurance.

“The datasets complement each other in depth and breadth, patient types (e.g., health insurance-wise, such as Medicare fee-for-service, commercial insurance, etc.), patient age, and inclusion of community/academic settings. This highlights the importance of querying each separately. They are presented side by side for complementarity, without direct comparisons,” Sammons wrote.

The index date for the EHR was date of frontline initiation of ribociclib plus endocrine therapy between March 2017 and August 2022 and was date of first paid pharmacy claim for the therapy between February 2018 and December 2022 for the KRD. Baseline/pre-index periods were the period before index date for the EHR and at least 12-month period of continuous enrollment prior to the index date for the KRD. The protentional follow-up period went from the index date to the data cutoff; cutoffs were November 2022 for the EHR and June 2023 for the KRD. Notably, the KRD only included patients who were adults as of the index date and they must have had at least 1 ribociclib paid pharmacy claim in the index period and at least 2 medical service claims with a code for breast cancer separated by at least 30 days.

Patients included in the EHR and KRD populations were a mean age of 62.6 years (SD, 12.6) and 56.5 years (SD, 10.5), respectively. Patients were female (98.9%; 99.7%, respectively), White (63.5%; 40.3%), received an aromatase inhibitor (76.1%; 80.6%) or fulvestrant (Faslodex; 23.9%; 19.4%) as an endocrine therapy partner, and were from the South (39.9%; 30.6%), Midwest (14.7%; 23.1%), Northeast (11.5%; 16.3%), West (24.9%; 29.7%), or other/missing (8.8%; 0.3%) regions, respectively.

Regarding cardiovascular disease (CVD)-related conditions, data were only available in the KRD and were reported in administrative claims data. CVD-related conditions were also described based on the presence of at least 2 medical claims on different days in any setting with a diagnosis code for the condition of interest in any position. Further, a sensitivity analysis was conducted based on the presence of at least 1 medical claim. Investigators also noted that counts and proportions for categorical variables and means, medians, SD, and IQR for continuous variables were used to report descriptive statistics.

Examining CVD-Related Medical Conditions of Interest

The amount of patients at risk who received ribociclib plus endocrine therapy in this setting and the percent of those who experienced new-onset CVD-related medical conditions were as follows: cardiomyopathy (n = 348; 0.0%), congestive heart failure (n = 336; 1.5%), cardiac arrhythmias (n = 324; 3.1%), hypertension (n = 183; 8.2%), ischemic heart disease (n = 327; 0.9%), and pericardial heart disease (n = 341; 0.0%), respectively.

“Evidence of newly diagnosed CVD-related medical conditions (e.g., cardiomyopathy, congestive heart failure, cardiac arrhythmias, hypertension, ischemic heart disease, and pericardial disease), regardless of causality, was relatively low. These conditions were available only in the KRD, as evidenced by the presence of at least 2 diagnosis codes indicative of the specific condition…. A sensitivity analysis based on the presence of at least 1 diagnosis code of a newly diagnosed or suspected CVD-related medical condition was consistent with the main analysis (available only in the KRD),” Sammons added in the poster.

Sammons is associate director of the Metastatic Breast Cancer Program and a senior physician at Dana-Farber Cancer Institute as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

Furthermore, data showed that the new onset of these CVD-related medical conditions in patients at least 65 years of age was consistent with that in the overall cohort. No patients in this population who were at risk experienced a new onset of cardiomyopathy (n = 56), ischemic heart disease (n = 50), or pericardial heart disease (n = 57). Among patients at risk of developing congestive heart failure (n = 54), 1.9% developed the condition. Those at risk of developing cardiac arrhythmias (n = 50) and hypertension (n = 11) had new onset of such events at rates of 2.0% and 18.2%, respectively.

Real-World Study Limitations and More

Limitations of the real-world data included that the 2 studies had different designs and data sources and thus could not be compared. Further, the KRD administrative health care database assessed of AE- and CVD-related medical conditions based on the identification of medical claims with primary or secondary diagnoses codes which may have allowed for underreporting for mild AE-related conditions that did not result in reimbursement requests for healthcare services. “Given the nature of the data in both datasets, no causality can be inferred between a frontline ribociclib regimen and the reported tolerability-related and CVD-related medical conditions,” Sammons added.

“Ribociclib plus endocrine therapy is recommended by the National Comprehensive Cancer Network [NCCN] as [an] NCCN category 1 preferred CDK4/6 inhibitor for [the] first-line treatment of HR-positive/HER2-negative metastatic breast cancer with no visceral crisis in postmenopausal patients or premenopausal patients with ovarian ablation/suppression,” Sammons wrote. “In addition to progression-free survival and overall survival benefits, first-line ribociclib plus endocrine therapy demonstrated a tolerable and manageable safety profile across all phase 3 MONALEESA (MONALEESA-2, -3, and -7) randomized controlled trials.”1

References

1. Sammons S, Sharma P, Abdou Y, et al. Tolerability of first-line treatment with ribociclib for metastatic breast cancer using 2 large US data sources. Presented at: 42nd Annual Miami Breast Cancer Conference; March 6-9, 2025; Miami, Florida. Poster 18.
2. Sammons S, Sharma P, Abdou Y, et al. Tolerability of first-line (1L) treatment (tx) with ribociclib (rib) for metastatic breast cancer (MBC) using 2 large US data sources.Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract P3-10-14.
3. Kisqali. Prescribing information. Novartis; 2024. Accessed March 7, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf