title: Factors associated with sinus bradycardia during crizotinib treatment: a retrospective analysis of two large-scale multinational trials (PROFILE 1005 and 1007).
abstract: Decreases in heart rate (HR) have been described in patients receiving crizotinib. We performed a large retrospective analysis of HR changes during crizotinib therapy. HRs from vital-sign data for patients with anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer enrolled in PROFILE 1005 and the crizotinib arm of PROFILE 1007 were analyzed. Sinus bradycardia (SB) was defined as HR <60 beats per minute (bpm). Magnitude and timing of HR changes were assessed. Potential risk factors for SB were investigated by logistic regression analysis. Progression-free survival (PFS) was evaluated according to HR decrease by <20 versus ≥ 20 bpm within the first 50 days of starting treatment. For the 1053 patients analyzed, the mean maximum postbaseline HR decrease was 25 bpm (standard deviation 15.8). Overall, 441 patients (41.9%) had at least one episode of postbaseline SB. The mean precrizotinib treatment HR was significantly lower among patients with versus without postbaseline SB (82.2 bpm vs. 92.6 bpm). The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. PFS was comparable among patients with or without HR decrease of ≥ 20 bpm within the first 50 days of starting crizotinib. Decrease in HR is very common among patients on crizotinib. The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. This is the first large-scale report investigating the association between treatment with a tyrosine kinase inhibitor and the development of bradycardia. HRs should be closely monitored during crizotinib treatment.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, California.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Pfizer Oncology, La Jolla, California.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Polli
authors.affiliation: Pfizer Oncology, La Jolla, California.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.affiliation: Pfizer Oncology, New York City, New York.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnell
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001794:Blood Pressure; D001919:Bradycardia / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002986:Clinical Trials as Topic; D000077547:Crizotinib; D005260:Female; D006339:Heart Rate; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011720:Pyrazoles / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: Anaplastic lymphoma kinase; blood pressure; bradycardia; crizotinib; heart rate; nonsmall cell lung cancer
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