Cardiac Safety of Ribociclib Evaluated with 24-hour- Rhythm Holter Electrocardiogram

doi:10.21203/rs.3.rs-3911390/v1

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Cardiac Safety of Ribociclib Evaluated with 24-hour- Rhythm Holter Electrocardiogram

https://doi.org/10.21203/rs.3.rs-3911390/v1

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Objective

We aimed to evaluate cardiac safety profile of ribociclib with 24-hour-rhythm holter ECG.

Material-Method:

42 female metastatic breast cancer patients were included in the study. Rhythm holter ECG was performed before starting treatment with ribociclib and after 3 months of the treatment initiation.

Results

The mean age of the patients was 56.36 ± 12.73. 52.4%(n = 22) of the patients were using ribociclib in combination with fulvestrant and 47.6% (n = 20) with aromatase inhibitors.None of the patients developed cardiotoxicity. When the rhythm holter results before and in third month of the treatment were compared, there was no statistically significant difference.

Conclusion

This is the first study evaluating effects of ribociclib treatment on cardiac rhythm with holter ECG. The study highlighted cardiac safety profile of ribociclib.

Breast cancer is the most common cancer in women worldwide. It is known that about three-quarters of all breast cancers are hormone receptor-positive, which is a prognostic and predictive factor for endocrine treatment response(1). Hormonotherapies in breast cancer aim to prevent tumor growth by reducing circulating estrogen or antagonizing the effect of estrogen at the tissue level(2).

Current therapeutic options for metastatic hormone receptor-positive HER2- breast cancer patients without visceral crisis include selective ER modulators (SERMs), selective ER degraders (SERDs), aromatase inhibitors (AIs), and Cyclin-dependent kinase (CDK) 4/6 inhibitors (3).

There are three CDK 4/6 inhibitors approved by the FDA: abemaciclib, palbociclib, and ribociclib. CDK inhibitors which are selective for CDK 4 and 6; arrest the cell cycle in the G1 phase by inhibiting retinoblastoma protein phosphorylation. It is known that this effect is further increased when used in combination with endocrine agents (4, 5, 6, 7). Ribociclib from this group of drugs, which contributes significantly to PFS in hormone-sensitive metastatic breast cancer, is the only CDK4/6 inhibitor with overall survival (OS) contribution in addition to PFS (8). Furthermore, interim analyses of the NATALEE study showed longer iDFS in the high-risk stage 2–3 hormone-positive breast cancer patients treated with ribociclib in the adjuvant setting(9).Despite remarkable efficacy, potential cardiac toxicities remain a concern. Advanced breast cancer patients may have cardiac dysfunction due to prior cardiotoxic chemotherapies. In a recent meta-analysis, ribociclib was found to be associated with a significantly higher risk of QTc prolongation and the resultant dosing inconsistencies and discontinuation (10).

Ribociclib is the only CDK 4/6 inhibitor with a warning for QT prolongation in the FDA label(11). Therefore, it is recommended to monitor ECG before treatment initiation and not to start ribociclib on patients with QTcF ≥ 450 ms. The ECG should be repeated on day 14 of the first cycle and at the beginning of the second cycle. If QTcF is > 500 msec on ECG treatment should be interrupted until QTcF resolves to < 481 msec. The treatment may resume at the next lower dose level. The QTcF values greater than 500 msec or any increase greater than 60 msec or serious cardiac adverse effects are indications of permanent discontinuation of ribociclib (12).

A recent real-world study showed a higher frequency of CVAEs than previous phase 3 trials among breast cancer patients using CDK4/6 inhibitors. Furthermore, they found that cardiac adverse effects of CDK4/6 inhibitors are not limited to QT prolongation and the median time was 2.3 months for developing CVAEs (13).

In this study, we aimed to investigate whether a more detailed rhythm evaluation is required to address concerns about the cardiotoxicity that ribociclib may cause. While instantaneous rhythm disturbances are detected by ECG, 24-hour rhythm Holter can provide more accurate information about the effect of the drug on rhythm. We evaluated the effect of the drug on cardiac rhythm in more detail by recording the changes in rhythm holter at the beginning of treatment and the third month of treatment in patients using ribociclib.

Patients followed up in Bezmialem Vakif University Medical Oncology clinic between June 2021 and June 2022 were screened. 42 female metastatic breast cancer patients using ribociclib combined with any endocrine therapy were enrolled in the study. Patient characteristics, clinical features, and comorbidities of the patients were recorded. An echocardiogram and rhythm Holter ECG were performed before starting treatment with ribociclib and after 3 months of the treatment initiation. QTc was calculated according to Framingham Formula(14). QTc values were recorded before treatment initiation; on day 14 of cycle 1, at the beginning of cycles 2 and 3. Electrolyte abnormalities, hemoglobin levels, and thyroid functions of the patients were checked, to exclude other factors causing cardiac arrhythmia. Patients with known cardiac arrhythmia, ischemic heart disease, diseases causing QT prolongation, or using QT prolonging drugs were excluded. Patients signed an informed consent form before enrollment. The study was complied according to the Helsinki Declaration and approved by the local ethics committee (2020/7–30)

Statistical analysis was performed using the IBM® SPSS 24.0 program. for continuous variables were taken mean values, and for categorical variables number and percentage ratios were used.Kolmogorov–Smirnov test was used for normal distribution. Qualitative variables were compared using the Pearson χ² test. Repeated measures were compared with ANOVA analysis of variance. The characteristics of patients were evaluated with descriptive analysis. Statistical significance was accepted as p < 0.05.

The mean age of the patients was 56.36 ± 12.73, and 50%(n = 21) of them had de novo metastatic disease. 52.4%(n = 22) of the patients were using ribociclib in combination with fulvestrant and 47.6% (n = 20) with aromatase inhibitors. 26.2%(n = 11) of the patients were using tobacco, 14.3%(n = 6) had diabetes mellitus and 31%(n = 13) had hypertension. 61.9% (n = 26) of the patients experienced grade 1–2 neutropenia, and 28.5% (n = 12) had grade 3 neutropenia requiring dose reduction. 9.5% (n = 4) of the patients had grade 1 hepatotoxicity, 2.4% (n = 1) had grade 3 hepatoxicity requiring dose reduction, and 2.4% (n = 1) required permanent discontinuation of the treatment due to severe hepatotoxicity. Patient characteristics are shown in Table 1. None of the patients developed cardiotoxicity. EF (Ejection Fraction) of each patient was within normal limits, both at the beginning and in the third month. When the QTc values of the patients were compared there was no significant difference at the beginning of day 14, and on the first day of the second and third cycle. The QTc values of the patients and their comparison are shown in Table 2. The abnormalities in 24-hour ECG rhythm holter results before and in the third month of the treatment are shown in Table 3. None of the abnormalities were clinically meaningful or resulted in contraindications to ribociclib treatment. There was no statistically significant difference in rhythm holter results before and after the treatment.

Table 1

Patient characteristics
Age (mean ± SD)	56.36 ± 12.74
De Novo metastatic n (%)	21 (50%)
BMI (mean ± SD)	28.36 ± 6.96
Smoking n (%)	11( 26.2%)
Endocrine Therapy
Fulvestrant n (%)	22
Aromatase Inhibitors n (%)	20
Comorbidities
DM n (%)	6 (14.3%)
HT n (%)	13 (31%)
Neutropenia
Grade 1 n (%)	4 (9.5%)
Grade 2 n (%)	22 (52.4%)
Grade 3 n (%)	13 (31.0%)
Grade 4 n (%)	0
Hepatotoxicity
Grade 1 n (%)	4 (9.5%)
Grade 2 n (%)	0
Grade 3 n (%)	1 (2.4%)
Grade 4 n (%)	1 (2.4%)
Dose reduction	17 (40.5%)
Drug discontinuation	1 (2.4%)
DM:Diabetes Mellitus HT: Hypertension BMI :Body Mass Index SD: Standard Deviation

Table 2

Comparison of QTc results during the first 3 cycles
	QTc 1 (mean ± SD)	QTc 14 (mean ± SD)	QTc 2 (mean ± SD)	QTc 3 (mean ± SD)	p
mSec(mean ± SD)	404.68 ± 26.56	412.45 ± 33.01	405.64 ± 23.27	405.96 ± 27.21	0.583
SD: Standard Deviation P < 0.05: significant

Table 3

24-Hour-Rythym Holter Results
	NORMAL	Rare PVC	Rare AES	PAF	Non-Sustained VT
Holter 1	18	12	4	8	0
Holter 2	18	12	3	8	1
PVC : Ventriculary extracystoles AES: Atrial extracystoles PAF: Paroxismal atrial fibrillation VT: Ventriculary tachycardia

CDK 4/6 inhibitors have become the new standard in the first-line treatment of hormone-positive HER2-negative metastatic breast cancer with their contribution to progression-free and overall survival(7, 15, 16).

Moreover, CDK 4/6 inhibitors have also been approved for use in adjuvant settings, showing a contribution to disease-free survival in the treatment of high-risk early and locally advanced breast cancer(17).Although the general toxicity profile of CDK 4/6 inhibitors is manageable, the most common side effects have been reported as myelosuppression, gastrointestinal, and skin toxicities(7, 15, 16).When CDK 4/6 inhibitors were evaluated in terms of cardiac safety, it was observed that Cardiovascular adverse events (CVAEs) were rare, but the most common events were QTc prolongation and venous thromboembolism. Furthermore, it was determined that only ribociclib caused QT prolongation, while other drugs in the group did not have such an effect.

The safety and tolerability of various endocrine therapy combinations with ribociclib have been evaluated in recent years. MONALEESA-3 study reported QTcF prolongation resulted in discontinuation of the drug in 0.6% of patients receiving ribociclib + fulvestrant(18). Furthermore, in the MONALEESA-2 study QTcF interval was longer than 480 msec in 3.3% of the patients treated with ribociclib. An increase greater than 60 msec of QTcF interval was observed in 1.8% of the patients. Most of the patients were able to receive their treatment without dose escalation and interruption(15). The total percent of the patients with dose interruption, reduction, or discontinuation was 1.4% in phase 3 trials of ribociclib(19).

Recently, Fradley et al found that 24% of breast cancer patients using CDK4/6 inhibitors developed CVAEs, most commonly hypertension, heart failure, and atrial fibrillation(13). The median time was 2.3 months for developing CVAEs. CVAE incidence was not different among the CDK4/6 inhibitors. Also, they showed that there was a slightly higher incidence of CVAEs among patients treated with CKD4/6 inhibitors compared with anthracyclines (P = 0.063). The real-world data of 1376 patients receiving CDK4/6 inhibitors highlighted that the frequency of cardiac adverse effects of CDK4/6 inhibitors was more than reported in previous studies and not limited to QT prolongation, but there were various cardiac adverse effects(13).

It is of great importance that the safety of the drug and the easily manageable side-effect profile of the drug are as important as its effectiveness for the continuation of the treatment. Ribociclib, which stands out with its survival contribution among CDK 4/6 inhibitors and is preferred in NCCN 2023 guidelines, requires close ECG monitoring, especially in the first 3 months, due to its effect on QTc, unlike other drugs in this group.

According to the guidelines, it is recommended to calculate QTc by taking a baseline ECG before starting ribociclib treatment and to check QTc with ECG on the 14th day of treatment, and at the beginning of the second cycle. In general, it is not recommended to start treatment for those whose QTc is above 450 msec. In addition, if QTc rises above 480 msec during the treatment process, it is recommended to interrupt the treatment until it drops below 480 msec and then continue the treatment with the next lower dose. To detect electrolyte disorders that may cause QTC prolongation, blood tests should be performed at the beginning of treatment and regular intervals, and electrolyte levels should be adjusted if necessary. In addition, it should be checked whether patients are using other medications that may cause QTC prolongation.Closer monitoring is recommended in the presence of underlying cardiac arrhythmia or in patients using concomitant drugs that may cause QTc prolongation(2).

In this study, we wanted to further examine the possible cardiac side effects of ribociclib. For this purpose, in addition to routine ECG monitoring, rhythm holter and echocardiography were performed at the beginning of treatment and in the 3rd month of ribociclib treatment. We aimed to detect clinical or subclinical rhythm changes by performing rhythm holter in this way. In our study including 42 patients, the changes in rhythm holters and echocardiography at the beginning of treatment and the third month were recorded, and no significant difference was observed between the results at the beginning of treatment and the third month. Although the lack of change in cardiac rhythm holter and echocardiography after 3 months of ribociclib use indicates the cardiac safety of ribociclib, it is a limitation of our study that it followed only a 3-month period. The 3-month follow-up period for echocardiographic change may be short, but since the median time until AF/AFL developed in the Fradley study was 2.3 months (13), we find it important for the cardiac safety of ribociclib that the rhythm holter results at the 3-month showed no significant difference in our study.

CDK4/6 inhibitors have shown promise in cancer treatment but may have cardiotoxic effects. In the present study, we could not detect any evidence of cardiotoxicity in addition to routine ECG monitoring with echocardiography and rhythm holter test at the beginning and the end of 3 months. Therefore, we agree that routine ECG monitoring is sufficient in patients using ribociclib. We may recommend further cardiac monitoring in patients with underlying cardiac disease and elderly patients.

It is of great importance for patients to be evaluated by a multidisciplinary team including oncologists, cardiologists, and pharmacologists, for protecting patients from possible CDK4/6 inhibitor cardiotoxicity and improving patients’ quality of life, while receiving the best possible cancer treatment.

Author Contribution

A.I.Y. ,,A.T. and M.S.designed the study and wrote the main manucscript text, Z.S.I., Y.E.E and M.U collected the data , A.T. ,M.S. and , M.B have done the statistics. All authors reviewed the manuscript

Human Ethics and Consent to Participate declarations: All participants signed an informed consent form before enrollment. The study was complied according to the Helsinki Declaration and approved by the local ethics committee (2020/7-30)

Funding Declaration: No funding

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No competing interests reported.

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You are reading this latest preprint version

Cardiac Safety of Ribociclib Evaluated with 24-hour- Rhythm Holter Electrocardiogram

Status:

Version 1

Abstract

Objective

Material-Method:

Results

Conclusion

1.INTRODUCTION

2.MATERIAL- METHOD

3.STATISTICAL ANALYSIS

4.RESULTS

5.DISCUSSION

6. CONCLUSION

Declarations

Author Contribution

References

Additional Declarations

Status:

Version 1