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A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer.
Zheng, X, Xu, Z, Ji, Q, Ge, M, Shi, F, Qin, J, Wang, F, Chen, G, Zhang, Y, Huang, R, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(20):5502-5509
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Abstract
PURPOSE Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
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NS1643 enhances ionic currents in a G604S-WT hERG co-expression system associated with long QT syndrome 2.
Huo, J, Guo, X, Lu, Q, Qiang, H, Liu, P, Bai, L, Huang, CL, Zhang, Y, Ma, A
Clinical and experimental pharmacology & physiology. 2017;(11):1125-1133
Abstract
Loss of function mutations in the human ether-a-go-go-related gene (hERG) cause long QT syndrome type 2 (LQT2). Most LQT2 patients are heterozygous mutation carriers in which the mutant hERG exerts potent dominant-negative effects. 1, 3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) is known to enhance IKr in WT-hERG. We investigated its actions following lipofectamine-induced expression of both mutant G604S- and WT-hERG in the heterologous HEK293 expression system. Cells transfected with pcDNA3-G604S-hERG did not lead to any expression of detectable currents whether before or following NS1643 challenge. Cells transfected with both pcDNA3-WT-hERG and pcDNA3-G604S-hERG showed reduced hERG currents compared to those transfected with pcDNA3-G604S-hERG consistent with the reduced trafficking and formation of modified heteromeric WT-G604S channels reported on earlier occasions. Nevertheless, NS1643 then continued to produce concentration- and voltage-dependent increases in hERG current amplitude. It did not affect the voltage dependence of activation, recovery from inactivation and deactivation. However, NS1643 (30 μmol/L) slowed steady state inactivation and shifted the steady state half maximal activation voltage (V1/2 ) of the inactivation curve by +10 mV, and significantly increased the time constants of inactivation. Our present experimental results suggest that NS1643 significantly increases ion current and attenuates its inactivation in cells co-expressing G604S-hERG and WT-hERG. These findings raise the possibility that hERG channel activators offer potential treatment strategies for inherited LQT2.