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 ¼ .0336), had a lower pretreatment HR (mean, 77.9 bpm vs 100.6 bpm; P ¼ .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P ¼ .0050) than patients who did not experience SB. The overall response rate (P ¼ .0195) and the maximum tumor shrinkage (P ¼ .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. Cancer 2013;119:1969-75. V C 2013 American Cancer Society.KEYWORDS: crizotinib, sinus bradycardia, heart rate decrease, pharmacodynamic, receptor tyrosine kinase inhibitor, anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer. INTRODUCTIONCrizotinib is a first-in-class, orally available anaplastic kinase (ALK) inhibitor that has exhibited impressive clinical activity in ALK-rearranged nonsmall cell lung cancer (NSCLC) in 2 phase 2, single-arm clinical trials. [1][2][3] It has also demonstrated significantly improved progression-free survival (PFS) over single-agent chemotherapy as second-line treatment for patients with ALK-rearranged NSCLC in a randomized phase 3 trial. 4 Crizotinib has been approved in many countries for the treatment of ALK-rearranged NSCLC. In addition, as a multitargeted receptor tyrosine kinase (RTK) inhibitor that also can inhibit both the mesenchymal epithelial transition (MET) and ROS1 receptor tyrosine kinases, crizotinib has demonstrated clinical activity in MET-amplified NSCLC and ROS1-rearranged NSCLC. 5,6 Thus, crizotinib will likely play an expanding role in targeted therapy for NSCLC.Crizotinib is generally well tolerated, and most of its side effects are in the grade 1 and 2 ...

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12. QTc prolongation was infrequent or absent with afatinib, crizotinib, ceritinib, dovitinib, imatinib, lapatinib, lenvatinib, nintedanib, pazopanib, and ponatinib 9, 14, 16, 17, 19, 24, 26, 27, 29, 30, 31, 32, 33, 35, 36, 38, 39, 72, 78, 81, 161, 162, 163, 164…”

Managing Treatment–Related Adverse Events Associated with Alk Inhibitors

“…Although QT prolongation was observed in patients on crizotinib, no associated arrhythmias were observed 25 . Crizotinib should be used with caution in patients with a predisposition to QT prolongation or in those on concomitant QT-prolonging medications.…”

“…The exact mechanism of this phenomenon is not known. Some hypothesize that it might be related to c-Met inhibition 25 . Concurrent heart-rate-lowering medications such as beta-blockers or non-dihydropyridine calcium channel blockers should be used with caution in patients receiving crizotinib.…”

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

“…Rare fatal interstitial lung disease/pneumonitis has been reported [119]. Bradycardia and Q-T prolongation can occur in about 5 % of patients taking crizotinib [120]. [124,125].…”