crizotinib and Heart-Failure

Crizotinib shows antitumor activity against C-ros oncogene 1-rearranged non-small-cell lung cancer (NSCLC). While corrected QT interval (QTc) prolongation and bradycardia are known as cardiac adverse effects, little is known about crizotinib-related heart failure. Our patient with C-ros oncogene 1-rearranged NSCLC on a reduced dose of crizotinib (200 mg twice daily) after initially experiencing bradycardia and QTc prolongation developed crizotinib-induced heart failure. With further dose reduction (250 mg once daily), there was no recurrence of any cardiac adverse effects, and the patient achieved a long-term response. Although crizotinib can cause heart failure, continuation of crizotinib at a low dose may be an effective treatment option.

Topics: Bradycardia; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Heart Failure; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Reactive Oxygen Species

Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF.. Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias.. Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis.. The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.

Topics: Crizotinib; Dasatinib; Everolimus; Heart Failure; Humans; Incidence; Protein Kinase Inhibitors; Vemurafenib

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

Topics: Crizotinib; Heart Failure; Humans; Protein Kinase Inhibitors; Pyrazoles; Pyridines