Prolonged QTc Interval in Cancer Therapeutic Drug Development: Defining Arrhythmic Risk in Malignancy
Section snippets
What is the incidence of drug-induced TdP?
Defining the risk of TdP is challenging. In one study of consecutive patients on continuous monitoring receiving any proarrhythmic drug in Sweden, the incidence of TdP was estimated at approximately 4 cases per 100,000 patients.3 Other estimates, especially for noncardiac medications, have ranged from <1 in 10,000 to 1 in 100,000 cases.4, 5 When adjusted for TdP risk factors, the range could be as frequent as 1 in 2000 to >20,000.6 It is necessary to know that the risk of TdP for cisapride was
The importance of the Qt interval and measurement problems
The QTc interval is monitored meticulously by drug regulatory agencies, and its prolongation is the most common reason for FDA withdrawal, nonapprovals, or delayed approval for all categories of noncardiology drugs.8 The QTc interval is at this time the best, although very imprecise, way to measure cardiac repolarization. It is considered a marker for the risk of TdP,4, 9 even though the actual clinical relationship between drug-induced QTc interval prolongation and TdP is likely only with very
Oncology patients present a high risk for pQTc interval
Appraising QTc intervals in oncology patients is confounded by several factors, including preexisting cardiac perturbations. In a compilation of 4 early-phase cancer trials, 36% of patients displayed some type of ECG abnormality at screening.19 A prolonged or borderline pQTc interval was seen in 14% to 15%.19, 20 Cancer patients possess many of the risk factors for cardiac disease and pQTc interval, such as older age, underlying coronary disease, or previous myocardial infarction. Even without
Current international recommendations for general QTc interval testing
Even with the limitations of QTc measurement, monitoring QT is an essential component of the drug development process. Essentially, every drug is initially considered to be proarrhythmic. To form consensus on best practices and improve communication as industry moves drugs forward, the ICHTR published guidelines in 2005 on the “Clinical Evaluation of QT/QTc Prolongation and Proarrhythmic Potential.”2, 25 A preclinical document, ICH S7B, focuses on repolarization capacities of new drugs before
Issues in testing the QTc interval in oncology patients
Anticancer agents form a large category of drugs whose testing must deviate from the regular ICH E14 guidelines.2 Most importantly, complex advanced cancer patients must be used as the subjects in anticancer drug trials assessing pQTc interval; administering more than limited dosing of an anticancer agent in subjects without malignancy would expose these healthy volunteers to unnecessary genetic and other adverse effects. Traditionally, phase 1 clinical trials are designed to find the maximally
Proceeding with a pQTc interval
QTc prolongation approximately >500 milliseconds or a change from baseline of >60 milliseconds are of clinical concern2 and are common criteria to indicate potential cardiotoxicity and impede further development. If the QTc interval is discovered to be prolonged from baseline to just below those values, further drug development does not have to be necessarily discontinued, with the caveat that these numbers are biomarkers that do not always correspond with clinical outcomes. More credence can
Summary
There are several key points regarding the investigation of the QTc interval in anticancer drug development:
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QTc interval is imprecisely measured because of wide diurnal variations; the incidence of drug-induced pQTc leading to TdP is estimated as small, but would be unacceptable for a healthy population.
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Oncology patients have multiple risk factors for pQTc at presentation, so the incidence of TdP is theoretically higher, but may not be attributable to drug alone, confounding assessment new
Current state
The FDA has convened a “QT interdisciplinary review team” with the expertise to assess QT interval studies and discuss plans for modified TQTSs.27 Published lists of medications associated with pQTc interval steer healthcare providers from possible additive risks of pQTc interval, especially after drug approval.32 In this way, much-needed cancer therapeutics such as romidepsin (ISTODAX; Gloucester Pharmaceuticals Inc., Cambridge, MA)33 for cutaneous T-cell lymphoma are being approved (November
Future directions
The development of new powerful cancer drugs that do not cause TdP will proceed on many fronts:
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expanding knowledge of multiple ion channels and pathways involved with repolarization, aiming for improved preclinical models, such that only a small fraction of QTc prolonging drugs progress to human studies;
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discovering genetic changes such as polymorphisms involved in drug-induced QT prolongation, such that future testing, can be tailored to a patient's unique susceptibility,36 avoiding drug
Statement of Conflict of Interest
The author declares that there are no conflicts of interest.
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2021, JTO Clinical and Research ReportsCitation Excerpt :QTc prolongation, a biomarker for increased risk of cardiac complications, is particularly important in safety assessments of TKIs owing to its association with potentially lethal arrhythmias, such as torsades de pointes, ventricular tachycardia, ventricular fibrillation, and sudden cardiac death.7–9 A QTc value of more than 500 msec or more than 60 msec increase in QTc value from baseline is considered a grade 3 AE and a clinically meaningful indicator of cardiac safety concern and possible cardiotoxicity.1,10,11 Decreased LVEF is a widely recognized risk factor for congestive heart failure and death.12–14
Turning liabilities into opportunities: Off-target based drug repurposing in cancer
2021, Seminars in Cancer BiologyOnco-cardiology: Drug-drug interactions of antineoplastic and cardiovascular drugs
2020, Critical Reviews in Oncology/HematologyCitation Excerpt :Since most of the TKIs are substrates of CYP3A4, significant DDIs are possible. Felodipine interacts with sorafenib via CYP3A4 that increases the risk of sorafenib related adverse events, including hypertension (Kruzliak et al., 2014; Brell, 2010). Abnormally prolonged QT interval could occur during treatment with CCBs, BBs, and other antiarrhythmic drugs.
QTc Interval-Prolonging Medications Among Patients With Lung Cancer: Implications for Clinical Trial Eligibility and Clinical Care
2020, Clinical Lung CancerCitation Excerpt :Given the increasing rates of polypharmacy across populations and the increasing number of cancer therapies—in particular, molecularly targeted therapies such as tyrosine kinase inhibitors—that convey a potential risk of QTc prolongation, these pharmacologic considerations could have considerable effects on patient selection. Tyrosine kinase inhibitors targeting all the common genomic alterations in lung cancer (EGFR, ALK, ROS1, BRAF, MET, HER2, RET) have been associated with potential QTc prolongation.19-21 The results from our present study have confirmed these suspicions.
Statement of Conflict of Interest: see page 171.
Address reprint requests to Joanna Brell, MD, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd. EPN 2017, Bethesda, MD 20892.