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 ...

e18140 Background: Crizotinib can result in SB as a part of its dose-dependent pharmacodynamic property. We analyzed the correlation between SB and tumor response in ALK or MET+ NSCLC patients (pts). Methods: Single institution retrospectively analysis of SB incidence (HR < 55) of ALK or MET+ NSCLC patients enrolled in 2 phase II crizotinib trials. Comparison performed between pt characteristics, HR changes, treatment duration, tumor response and shrinkage according to SB status. Results: 42 ALK or MET+ NSCLC pts (30 from A8081001, 12 from PROFILE1005) rx’d with crizotinib 250 mg po bid were analyzed. 90% of pts had a HR decrease of > 10 beats per minutes (bpm). 19 (45%) patients developed at least 1 SB episode at anytime during crizotinib treatment including 8 (19%) pts with profound SB (HR =< 45). All pts with SB were asymptomatic. There was no difference in the median age of diagnosis between pts (57.6 yrs [SB] vs. 49.7 yrs [no SB]; p = 0.073) by SB status. Median time to SB was 3 wks (mean: 7.2 wks, range 2-32 wks). There was significant difference in the mean pre-Rx baseline HR by SB status (74.5 bpm [SB] vs. 92.6 bpm [no SB]; p = 0.005), Rx duration (57.3 wks [SB] vs. 33.3 wks [no SB]; p = 0.021). The average maximum HR decrease (MHRD) from baseline for all pts were 26.3 bpm. There was no significant difference in the mean MHRD from baseline according to SB status (28.2 bpm [SB] vs. 24.7 bpm [no SB]; p = 0.598). 68% (13/19) of SB pts compared to 35% (8/23) of pts without SB achieved a CR/PR (p = 0.030). The mean maximum decrease in tumor measurements (MDTM) (RECIST) was 46.2% for pts with SB compared to 32.0% for pts without SB (p = 0.095). There was no difference in the mean MDTM in pts who achieved CR/PR without SB (62.5%) and with SB (63.5%) (p = 0.913) nor the mean response duration (RD) in CR/PR pts by SB status (43.3 wks [SB] vs. 51.5 wks [no SB]; p = 0.426). Conclusions: HR decrease is common in pts treated with crizotinib. Pts who developed asymptomatic SB had significantly lower pre-Rx baseline HR, longer Rx duration, higher response rates. However there was no difference in the mean MDTM or RD between pts who achieved CR/PR by SB status.