title: Heart rate decrease during crizotinib treatment and potential correlation to clinical response.
abstract: BACKGROUND
  Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB, patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and clinical response to crizotinib.
  
  
  METHODS
  A retrospective chart review was conducted of the timing and frequency of SB, patient characteristics, and clinical response of patients to crizotinib treatment.
  
  
  RESULTS
  Forty-twp patients who had ALK-rearranged or mesenchymal epithelial transition (MET)-amplified NSCLC and received treatment with oral crizotinib 250 mg twice daily who were enrolled in 2 crizotinib trials (PROFILE 1001 and PROFILE 1005) were analyzed. There was an average decrease of 26.1 beats per minute (bpm) from the pretreatment HR among all patients during crizotinib treatment. Twenty-nine patients (69%) experienced at least 1 episode of SB (HR, <60 bpm). The average time to the lowest HR recorded was 18.6 weeks (range, 5-72 weeks). Patients who experienced SB were significantly older (aged 55.8 years vs 47.8 years; P = .0336), had a lower pretreatment HR (mean, 77.9 bpm vs 100.6 bpm; P = .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P = .0050) than patients who did not experience SB. The overall response rate (P = .0195) and the maximum tumor shrinkage (P = .0205) were significantly greater in patients who experienced SB.
  
  
  CONCLUSIONS
  HR decrease is common during crizotinib treatment. It remains to be determined whether the correlation between HR decrease and clinical response to crizotinib reflects a biomarker of drug efficacy or a time/cumulative dose-dependent phenomenon.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA, USA. ignatius.ou@uci.edu
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.forename: Wilson P
authors.initials: WP
authors.lastname: Tong
authors.forename: Michele
authors.initials: M
authors.lastname: Azada
authors.forename: Christina
authors.initials: C
authors.lastname: Siwak-Tapp
authors.forename: Joni
authors.initials: J
authors.lastname: Dy
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Stiber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D001146:Arrhythmia, Sinus / Q000139:chemically induced*; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D000077547:Crizotinib; D005260:Female; D015321:Gene Rearrangement; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases