Background: CRZ is an oral tyrosine kinase inhibitor approved for the treatment of ALK-positive NSCLC at a starting dose of 250 mg BID. An ECG substudy was conducted to evaluate and quantitate any potential impact of CRZ on corrected QT interval (QTc). This ECG substudy enrolled patients with ALK-positive advanced NSCLC at selected sites from the phase III trial PROFILE 1007 and the phase II trial PROFILE 1005.

Methods: All patients enrolled in the ECG substudy received CRZ 250 mg BID orally on a continuous basis. Triplicate 12-lead ECG measurements, approximately 2 minutes apart, were collected after a fast of at least 1 hour at predose, 4 and 8 hours following morning CRZ dosing on Day 1 of Cycle 1, and predose, 2, 4, 6 and 8 hours following morning CRZ dosing on Day 1 of Cycle 2 (1 Cycle = 21 days). All ECG tracings from this substudy were sent to an independent ECG laboratory for blinded manual interval measurements. Plasma PK samples for CRZ and its metabolite, PF-06260182, were collected at respective times immediately following each ECG measurement. ECG endpoints included QT interval corrected for heart rate (HR) using Fridericia's (QTcF) (primary endpoint) and Bazett's (QTcB) formulas and a model-based study-specific correction factor (QTcS), PR interval, RR interval, and QRS complex. Categorical analysis was conducted for all QTc endpoints. ANOVA was performed for QTcF and QTcS, the QTc with the most appropriate HR correction. These analyses were performed using the ECG Evaluable Population (EEP), defined as all treated patients with an adequate baseline assessment and at least 1 adequate ECG measurement on Cycle 2 Day 1 (at CRZ steady state). A pharmacokinetic/pharmacodynamic analysis was performed using the ECG-PK matched dataset.

Results: A total of 65 patients were enrolled in the ECG study, and 52 were in the EEP. ANOVA revealed that all upper limits of the 90% confidence intervals for the least squares mean changes from baseline in QTcF at all Cycle 2 Day 1 time points were <20 ms. The largest LS mean change from baseline was an increase of 12.3 ms, reported at 6 hours post morning dose on Cycle 2 Day 1. No patients had a maximum QTc ≥500 ms and 1 (1.9%) patient had a QTc increase from baseline of ≥60 ms. Consistently with previous findings, mean steady state predose (Ctrough) and maximum plasma concentrations (Cmax) of CRZ were 271 ng/mL and 345 ng/mL, respectively, and mean steady state Ctrough and Cmax of metabolite PF-06260812 were 86.7 ng/mL and 107 ng/mL, respectively. A relationship was observed between CRZ plasma concentration and QTc. HR decreased with increasing CRZ plasma concentration, as reported previously in other studies.

Conclusions: Based on ANOVA results from this substudy, a large QTc effect (≥ 20 ms) by CRZ can be excluded however a smaller increase in QTc cannot be ruled out. Periodic ECGs monitoring should be considered for patients who have a history of QTc prolongation or who are taking medications that prolong QT.

Citation Format: Weiwei Tan, Keith D. Wilner, Silvana Lanzalone, Anna Polli, Matthew L. Zierhut, Dana Nickens, Kenneth J. O'Byrne, Fiona H. Blackhall, Alice T. Shaw, Ravi Salgia, Jesus Correl Jaime, Dong-Wan Kim. Evaluation of the effect of crizotinib (CRZ) on the QT interval in patients with ALK-positive non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT117. doi:10.1158/1538-7445.AM2015-CT117