Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial

Xing-Sheng Hu, Xiao-Hong Han, Sheng Yang, Ning Li, Lin Wang, Yuan-Yuan Song, Hua Mu, Yuan-Kai Shi, Xing-Sheng Hu, Xiao-Hong Han, Sheng Yang, Ning Li, Lin Wang, Yuan-Yuan Song, Hua Mu, Yuan-Kai Shi

Abstract

Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.

Keywords: EGFR; non-small cell lung cancer; pharmacokinetics; simotinib; toxicity.

Conflict of interest statement

Dr Xing-Sheng Hu, Dr Sheng Yang, Dr Ning Li, Dr Lin Wang, Dr Yuan-Yuan Song and Dr Yuan-Kai Shi report non-financial support from Jiangsu Simcere Pharmaceutical Co. Ltd and grants from the Chinese National Major Project for New Drug Innovation during the conduct of the study. Hua Mu is employee of Jiangsu Simcere Pharmaceutical Co. Ltd. Dr Xiao-Hong Han reports grants from Chinese National Major Project for New Drug Innovation, during the conduct of the study; Dr Hua Mu reports nothing from Simcere Pharmaceutical Group, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Waterfall plot of best percent change from baseline in sum of target lesion dimensions from baseline. (A) Full analysis population and (B) per protocol population (n=40).

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