crizotinib and Cardiotoxicity

Crizotinib is a multitarget tyrosine kinase inhibitor and it represents the standard of care in patients with anaplastic lymphoma kinase translocated non-small-cell lung cancer. Crizotinib is generally well tolerated and the most frequent adverse events include gastrointestinal effects, visual disorders, edema, fatigue and liver enzyme abnormalities. However, due to the increasing clinical experience with crizotinib, other toxicities are emerging, such as Q-wave T-wave interval prolongation and bradycardia. In the current review we will focus on the management of crizotinib-related cardiotoxicity.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bradycardia; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Crizotinib; Drug Interactions; Heart Rate; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Oncology clinical trials demonstrate the risk of cardiotoxicity but are not sufficient to reveal the true risk. In this article, we compared the incidence of cardiotoxicity of crizotinib and osimertinib from a real-world study to data reported by phase 3 clinical trials.. Data from an ongoing real-world lung cancer study was used as a comparator. Patients were recruited retrospectively with the criteria of being diagnosed with non-small cell lung cancer and having received at least a course of treatment of tyrosine-kinase inhibitor and/or immune check-point inhibitor. Characteristics of the patients who developed cardiotoxicity associated with osimertinib and crizotinib in the real-world lung cancer study were analysed against the inclusion criteria of the corresponding phase 3 clinical trials. Variations of cardiotoxicity incidence among the real-world lung cancer study and clinical trials were investigated.. 18%, n = 37/206, of the patients developed cardiotoxicity. QTc prolongation was the most frequently observed cardiotoxicity (n = 12/37). Osimertinib and crizotinib were the most cardiotoxic agents, each responsible for seven cases of cardiotoxicity. FLAURA, AURA3, PROFILE 1007 and PROFILE 1014 were the included clinical trials for analysis. None of the patients who developed cardiotoxicity in the real-world study would have been eligible to participate in FLAURA and PROFILE 1014 study whereas n = 4/7 and n = 5/7 patients were eligible to participate in AURA3 and PROFILE 1007 trials, respectively.. Although phase 3 clinical trials play an important role in understanding the effectiveness and give insights on side-effect profiles, real-world studies can show the real risk of cardiotoxicity more accurately and realistically.

Topics: Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Crizotinib; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies

This case report describes a pharmacokinetic drug-drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic nonsmall cell lung cancer with mesenchymal-epithelial transition exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb oedema and class III New York Heart Association dyspnoea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug-drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir, velpatasvir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

Topics: Aged; Antiviral Agents; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Crizotinib; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lung Neoplasms; Macrocyclic Compounds; Male; Sofosbuvir

We analyzed cardiac function in two Phase III studies of previously treated (PROFILE 1007) or untreated (PROFILE 1014) ALK-positive advanced non-small-cell lung cancer.. Adverse events associated with cardiac failure were compared between treatment arms in each study separately. Cardiac function was assessed prospectively by multigated acquisition scans or echocardiograms.. In PROFILE 1007 and 1014, incidence of cardiac failure adverse events was 0% (crizotinib) versus 0.6% (chemotherapy) and 2.3% versus 0.6%, respectively. In crizotinib versus chemotherapy arms, respectively, >20% left ventricular ejection fraction decreases occurred in 0/19 (0%) versus 1/16 (6.3%) patients from PROFILE 1007 and 4/150 (2.7%) versus 10/150 (6.7%) patients from PROFILE 1014.. These analyses did not reveal any clinically meaningful changes in myocardial function with crizotinib in patients with ALK-positive non-small-cell lung cancer. Clinicaltrials.gov identifier: PROFILE 1007, NCT00932893; PROFILE 1014, NCT01154140.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Clinical Trials, Phase III as Topic; Crizotinib; Follow-Up Studies; Heart Failure; Humans; Lung Neoplasms; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic

Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.

Topics: Adenocarcinoma; Antineoplastic Agents; Arrhythmias, Cardiac; Cardiotoxicity; Crizotinib; Female; Humans; Long QT Syndrome; Lung Neoplasms; Middle Aged; Pericarditis; Protein Kinase Inhibitors; Proto-Oncogene Mas