Cardiac Event Management Is a Key Aspect of Safely Treating Patients With Ribociclib in Advanced Breast Cancer

Rita Deimler, MSN, ANP-BC

Managing QTcF prolongation is a key aspect in caring for patients who receive ribociclib (Kisqali), according to Rita Deimler, MSN, ANP-BC, a nurse practitioner at Duke Cancer Institute.¹

“Current guidelines emphasize the monitoring and management of QTcF prolongation in patients receiving ribociclib,” Deimler said during a presentation at the 48th Annual Oncology Nursing Society Congress. “Cardiac monitoring may also be beneficial with other CDK4/6 inhibitors prescribed to patients at a high risk of QTcF prolongation.”

Ribociclib was first approved in combination with an aromatase inhibitor for patients with hormone receptor–positive, HER2-negative breast cancer in March of 2017. It was later approved in combination with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men with hormone receptor–positive/HER2-negative advanced or metastatic breast cancer. Of note, the prescribing label comes with a warning for QT interval prolongation.²

Therefore, nurse investigators sought to define best practices in QTcF prolongation monitoring and management by conducting an analysis of the pivotal trials supporting the agents use in clinical practice.¹

QTcF prolongation occurred at low rates in the phase 3 MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120) trials and in the phase 3b CompLEEment-1 trial (NCT02941926).

In a pooled analysis of the pooled MONALEESA studies (n = 1065), 5.2% of patients exhibited postbaseline QTcF values greater than 480 ms, and 1.4% had postbaseline values greater than 500 ms. Overall, 5.8% had a 60 ms or greater increase in QTcF prolongation since their baseline assessment.

In the CompLEEment-1 trial (n = 3246), the rate of patients with postbaseline rates greater than 480 ms or 500 ms were 3.1% and 1.3%, respectively; 5.9% had a 60 ms or greater increase in QTcF prolongation since their baseline assessment.

In MONALEESA, QTcF values did not lead to dose interruption, reduction, or withdrawal, but they did in the CompLEEment-1 trial. These rates were 1.2%, 0.6%, and 0.2%, respectively. Time to the first occurrence of a grade 2 or higher QTcF prolongation was 15 days for patients in the MONALEESA studies and was not reached in CompLEEment-1. The median duration of QTcF prolongation was 15 days and not reached, respectively.

Recommendations for Electrocardiogram Monitoring

The study authors noted that serum electrolytes should be monitored for patients undergoing treatment with ribociclib at screening, the beginning of the first 6 cycles, and as clinically indicated as electrolyte abnormalities can lead to a prolonged QTcF interval.

Patients are at a higher risk of QTcF prolongation if they are 65 years or older, have acute myocardial ischemia, baseline QTcF interval prolongation, bradyarrhythmia, a family history of congenital long QT syndrome, history of syncope or drug-induced torsades de pointes (TdP), impaired renal function, and liver disease. Further, having preexisting cardiovascular diseases such as coronary artery disease, heart failure, and left ventricular hypertrophy are also associated with having a higher risk of QTcF prolongation.

To monitor for QTcF prolongation, electrocardiogram assessments should be used prior to beginning treatment, at cycle 1 day 14, at cycle 2 day 1, and as clinically indicated. The study authors noted that emerging mobile electrocardiogram monitoring device may be useful in gathering these assessments.

Recommendations released by the European Society of Cardiology for patients undergoing treatment with a CDK4/6 inhibitor (such as ribociclib) state that in class I level A patients receiving ribociclib should have QT interval monitored at baseline, cycle 1 day 14, and cycle 2 day 1. In class I level B, when increasing the dose of ribociclib, QT should continue to be monitored. In the class IIa level C setting, clinicians may consider monitoring QT interval for patients who are at an increased risk for QT prolongation and who are receiving palbociclib (Ibrance) or abemaciclib (Verzenio).

On day 1 in the pretreatment phase, nurses should ensure the patient is at rest, electrolytes are in a normal range, that there are no QTcF-prolonging concomitant medications, and that the patient’s past medical history does not include QT prolongation risk factors.

After obtaining an electrocardiogram assessment and calculation QTcF, those over 450 ms may move forward to treatment with ribociclib. Patients with QTcF values of 450 ms or more should not receive treatment.

During treatment, if a patient’s values remain under 480 ms, they may continue as normal with no dose modifications. However, if their values rise above 480 ms, they will require treatment interruption. Dose reductions may be used to get the QTcF value below 481 ms; however, if the problem keeps recurring, and a dose reduction below 200 mg/day is required, treatment will need to be discontinued.

If, during treatment a QTcF value greater than 500 ms or a change from baseline of 60 ms and an associated cardiac event are observed, treatment must be discontinued.

Concomitant Medicines to Avoid

The study authors advised nurses to consider the pharmacokinetic/pharmacodynamic interactions with ribociclib and concomitant medications, herbal supplements, and foods that may affect therapy.

“Ribociclib levels in patients can be affected by some drugs and dietary supplements because of their effects on ribociclib’s metabolism,” Deimler, noted. “Ribociclib is metabolized by CYP3A; CYP3A inhibitors raise ribociclib levels, increasing concentration and toxicities. CYP3A inducers reduce ribociclib levels. As such, administering ribociclib with CYP3A inhibitors must be avoided and, if [this is] unavoidable, the ribociclib dose may be modified.”

CYP3A inhibitors to avoid using with ribociclib include boceprevir (Victrelis), clarithromycin, conivaptan (Vaprisol), grapefruit juice, indinavir (Crixivan), itraconazole (Sporanox), ketoconazole (Nizoral), lopinavir/ritonavir (Kaletra), nefazodone (Serzone), nelfinavir (Viracept), posaconazole (Noxafil), ritonavir (Norvir), saquinavir (Invirase), and voriconazole.

The CYP3A inducers that should not be used in conjugation with ribociclib are phenytoin, rifampin, carbamazepine, and St John wort (hypericum perforatum). Further, the dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced when given during treatment including the substrates alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus (Rapamune), and tacrolimus.

Drugs that prolong the QT interval such as the antiarrhythmics amiodarone (Pacerone), disopyramide (Norpace), procainamide, quinidine, and sotalol (Sotacor) should not be used while undergoing treatment with ribociclib. Ribociclib is not indicated for concomitant use with tamoxifen.

Further, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil (Vascor), pimozide (Orap), and ondansetron (Zofran) should be avoided.

Additional AEs

Nurses should know that ribociclib has shown a consistent safety profile across the 3 MONALEESA trials, and that there have been no new safety signals after 6.5 years of follow-up.

Pooled data from the MONALEESA studies demonstrated that following treatment with ribociclib and endocrine therapy patients experienced grade 3 and grade 4 AEs at rates of 66% and 15%, respectively. Neutropenia, which was the most common any-grade AE (74%), was also the most common grade 3 (52%) and grade 4 (9%) AE.

Nausea followed neutropenia in incidence rate. The rate of any-grade, grade 3, and grade 4 nausea, respectively, was 45%, 1%, and 0%. Leukopenia occurred at rates of 31%, 17%, and 1%, respectively. Anemia also was common. The incidence rate of anemia at any grade was 19%, at grade 3 was 3%, and at grade 4 was less than 1%.

Other commonly reported AEs (reported by greater than 20% of patients) included fatigue, diarrhea, arthralgia, vomiting, alopecia, constipation, headache, hot flush, cough, and backpain.
References

1. Deimler R, Moore H, and Dent S. Ribociclib safety, monitoring, and management strategies in advanced breast cancer. Poster Presented at: 48th Annual Oncology Nursing Society Congress; April 26-30, 2023; San Antonio, Texas. Accessed April 14, 2023.
2. Kisqali. Prescribing information. Novartis; 2022. Accessed April 20, 2023. https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf