Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors

Abstract

BackgroundAnlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors.MethodsAnlotinib (5–16 mg) was orally administered in patients with solid tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2) 2-week on/1-week off (2/1). Pharmacokinetic sampling was performed in all patients. Twenty-one patients were further enrolled in an expanded cohort study on the recommended dose and schedule. Preliminary tumor response was also assessed.ResultsOn the 4/0 schedule, dose-limiting toxicity (DLT) was grade 3 hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib had long elimination half-lives and significant accumulation during multiple oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum tolerated dose for the expanding study. Twenty of the 21 patients (with colon adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary thyroid carcinoma, and soft tissue sarcoma) were assessable for antitumor activity of anlotinib: 3 patients had partial response, 14 patients had stable disease including 12 tumor burden shrinkage, and 3 had disease progression. The main serious adverse effects were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation.ConclusionsAt the dose of 12 mg once daily at the 2/1 schedule, anlotinib displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential, justifying the conduct of further studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0332-8) contains supplementary material, which is available to authorized users.

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

“…Anlotinib (AL3818), a new antitumor drug, was developed by Jiangsu Chia-Tai Tianqing Pharmaceutical Co., Ltd [1, 2]. It has been approved by State Food and Drug Administration (SFDA) and China Food and Drug Administration (CFDA) and is in phase II or III clinical trial for the treatment of patients with renal cancer, non-small cell lung cancer, and gastric cancer.…”

“…A previous study has mentioned that anlotinib is primarily metabolized by cytochrome P450-mediated biotransformation reactions in vitro [1]. However, the impact of anlotinib on CYP450 enzyme activities in vivo has not been reported.…”

Self‐Assembled/Drug‐Composed Nanomedicine for Synergistic Photonic Hyperthermia and Targeted Therapy of Breast Cancer by Inhibiting ERK, AKT, and STAT3 Signaling Cascades

“…Anlotinib is a novel member of the tyrosine kinase inhibitors (TKIs) family, which has shown a potential inhibitory efficacy on numerous receptor tyrosine kinases implicated in cancer progression, such as VEGFR‐2 and ‐3 (vascular endothelial growth factor receptor types 2 and 3), FGF (fibroblast growth factor), and PDGF‐α/β (platelet‐derived growth factor‐α/β) . The outcomes of preclinical trials demonstrated that Anlotinib exhibited efficacy in a host of solid tumors, including non‐small‐cell lung cancer (NSCLC), hepatocarcinoma, gastric cancer, renal carcinoma, and soft tissue sarcoma . Besides, Anlotinib has been approved by the China Food and Drug Administration (CFDA) for indication of NSCLC in 2018.…”

CD31‐labeled circulating endothelial cells as predictor in anlotinib‐treated non‐small‐cell lung cancer: Analysis on ALTER‐0303 study

“…Anlotinib is a multitarget receptor tyrosine kinase inhibitor which inhibits vascular endothelial growth factor receptor (VEGFR) 1‐3, fibroblast growth factor receptor (FGFR) 1‐4, platelet‐derived growth factor receptors (PDGFR) α/β, c‐Kit, and Met, that is, has a broad spectrum of inhibitory action on angiogenesis and malignancies growth. In addition, anlotinib showed antitumor activity on tumor cells carrying mutations in epidermal growth factor receptor (EGFR) . Phase I clinical trial has established the safety profile of anlotinib and identified commended dose of 12 mg once daily at the 2 weeks on treatment followed by 1 week off treatment schedule .…”

“…In addition, anlotinib showed antitumor activity on tumor cells carrying mutations in epidermal growth factor receptor (EGFR) . Phase I clinical trial has established the safety profile of anlotinib and identified commended dose of 12 mg once daily at the 2 weeks on treatment followed by 1 week off treatment schedule . In phase II, as a third‐line and above treatment for patients with advanced non‐small‐cell lung cancer (NSCLC), anlotinib has got an affirmatory efficacy on patients with advanced NSCLC, in ALTER0302 double‐blind, controlled trial …”