Phase Ib Study Of Safety, Tolerability And Pharmacokinetics Of Simotinib In Patients With Advanced Non-Small Cell Lung Cancer

e20642 Background: Simotinib is a novel small molecule agent specifically inhibits EGFR and its downstream signaling pathway. Phase Ia study in healthy volunteers demonstrated that simotinib was well-tolerated at doses up to 500 mg. Here, we report a phase Ib study in NSCLC patients with EGFR sensitive mutations to investigate the safety, tolerability and pharmacokinetics of simotinib (ClinicalTrials.gov identifier: NCT01772732). Methods: Patients with histologically confirmed advanced or metastatic NSCLC with EGFR sensitive mutations, relapsed after first-line platinum-contained chemotherapies were eligible. Patients were orally administered with simotinib twice daily continuously, with assessment of dose-limiting toxicities (DLTs) during the first cycle (28 days). Dose escalation was carried out to determine maximum tolerated dose (MTD) using a 3+3 design and 100 mg as starting dose. Pharmacokinetics of simotinib was assessed on Days 1 and 15, respectively. Tumor response was assessed on Day 29 and every 8 weeks afterwards. Results: Fourty-one patients were enrolled and 40 patients were evaluable for response. Simotinib was well tolerated without DLTs, and MTD was not reached up to dose 650 mg. Thirty-nine (95.1%) 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 frequent AEs. Within the doses examined, simotinib was rapidly absorbed (Tmax ranged 1-4 hours), and the elimination T1/2 ranged 6.2-13.0 hours. Exposure to simotinib was approximately proportional with a single dose from 200 mg to 650 mg, but was less than dose proportional after multiple doses. Sixteen (40%) patients achieved partial response (PR). Median progress free survival (PFS) and overall survival (OS) were 9.9 months and 14.6 months, respectively. Notably, 5 of 8 (62.5%) patients with brain metastasis (BM) in dose cohorts of 500 mg and 650 mg achieved PR. Conclusions: Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM. Further study of simotinib in treatment of NSCLC patients with BM is warranted and on-going. Clinical trial information: NCT01772732.