At what QTc interval should I withhold ribociclib (cyclin-dependent kinase 4/6 inhibitor)?

From the Guidelines

Ribociclib should be withheld if the QTc interval exceeds 500 milliseconds or if there is an increase of more than 60 milliseconds from baseline along with torsades de pointes or polymorphic ventricular tachycardia. This is based on the most recent and highest quality study, which suggests that a QTc interval greater than 500 milliseconds or a prolongation of more than 60 milliseconds from baseline is associated with an increased risk of torsades de pointes and other serious arrhythmias 1.

When managing patients on ribociclib, it is essential to monitor their QTc interval regularly, especially at baseline, after initiation or changes in dose, and periodically during treatment. The QTc interval should be calculated using either Bazett's or Fridericia's formula, and the same method should be used for all measurements 1.

Some key points to consider when managing patients on ribociclib include:

• Monitoring ECGs at baseline, day 14 of the first cycle, beginning of the second cycle, and as clinically indicated
• Checking electrolytes before treatment and correcting any abnormalities, as imbalances can further increase QT prolongation risk
• Avoiding concomitant use of medications known to prolong the QT interval when possible
• Considering treatment discontinuation or alternative regimens if the QTc is greater than 500 milliseconds, QTc prolongation is more than 60 milliseconds, or dysrhythmias are encountered 1

It is also crucial to be aware of the conditions that can provoke torsades de pointes, such as hypokalaemia and extreme bradycardia, and to minimize exposure to other QT-prolonging drugs in patients treated with potentially QT-prolonging chemotherapy 1.

In cases where the QTc interval exceeds 500 milliseconds or there is an increase of more than 60 milliseconds from baseline along with torsades de pointes or polymorphic ventricular tachycardia, treatment with ribociclib should be interrupted until the QTc returns to less than 481 milliseconds, and then resumed at a reduced dose 1.

From the FDA Drug Label

Table 4: Dose Modification and Management for QT Prolongation

QTcF* prolongation	Early breast cancer	Advanced or metastatic breast cancer

480 ms and ≤ 500 ms | Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms Resume at the same dose | Reduce to the next lower dose level 500 ms | Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level | If QTcF > 500 ms recurs, discontinue KISQALI.

Withhold ribociclib if the QTc interval is:

• > 480 ms and ≤ 500 ms in patients with early breast cancer
• > 500 ms in patients with early or advanced/metastatic breast cancer 2

From the Research

QTc Interval and Ribociclib

• The decision to withhold ribociclib due to QTc interval prolongation is critical in patients with advanced breast cancer, as ribociclib is associated with QT prolongation, a surrogate marker for Torsades de Pointes (TdP) and sudden cardiac death 3.
• According to the study by 3, 19 out of 82 patients (23%) were initially excluded from receiving ribociclib due to a prolonged QTc >450ms, but 17 of these patients successfully received treatment without arrhythmogenic effects after manual measurement and recalculation of QTc interval using Fridericia and Framingham formulae.
• The Fridericia formula is preferred in the cancer population as it is often more accurate at heart rate extremes, and the FDA has adopted this formula for submitting QT data for review 3.
• A systematic review and meta-analysis of randomized controlled trials found that ribociclib was associated with a higher risk of QTc prolongation compared to other CDK4/6 inhibitors, with a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001) 4.
• The study by 5 found that ribociclib, but not palbociclib, could act by down-regulating the expression of KCNH2 and up-regulating SCN5A and SNTA1, three genes associated with long QT syndrome.
• The MONALEESA-3 trial suggested that ribociclib's efficacy in combination with fulvestrant is effective for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC, but ribociclib may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions) 6.
• There is no specific QTc interval value mentioned in the studies as a threshold for withholding ribociclib, but the studies suggest that a QTc interval >450ms may be a concern, and patients with cardiac morbidities or other risk factors for QTc prolongation should be carefully monitored 3, 6.

Key Considerations

• Patients with a QTc interval >450ms may be at increased risk of QTc prolongation and should be carefully monitored 3.
• The Fridericia formula is preferred for measuring QTc interval in cancer patients, and the FDA has adopted this formula for submitting QT data for review 3.
• Ribociclib is associated with a higher risk of QTc prolongation compared to other CDK4/6 inhibitors, and patients with cardiac morbidities or other risk factors for QTc prolongation should be carefully monitored 4, 6.