Study On Anlotinib Combined With Docetaxel In The Treatment Of Advanced Non-small Cell Lung Cance

BACKGROUND:Advanced non-small-cell lung cancer(NSCLC)is an incurable disease.Docetaxel is the standard second-line chemotherapy choice for advanced NSCLC patients with progression after first-line chemotherapy,targeted therapy or immunotherapy.Anlotinib,a novel oral multi-targeted receptor tyrosine kinase inhibitor with highly effective,is designed to primarily inhibit endothelial growth receptors(VFGFR),fibroblast growth factor receptors(FGFR),platelet-derived growth factor receptors(PDGFR),etc.Thus has a broad spectrum of inhibitory effect on tumor angiogenesis and growth.This study aimed to explore the efficacy and safety of anlotinib combined with docetaxel for advanced NSCLC.At the same time,Animal models will be constructed for researching benefit and mechanism from the combination therapy.METHOD:This study enrolled patients with stage Ⅲb and Ⅳ NSCLC who failed to improve platinum-based doublet chemotherapy.Therapy:oral anlotinib 12 mg,once a day for 14 days,stop for 7 days,21 days as a cycle;inject docetaxel 60mg/m2,on the first day of the 21-days’cycle.RECIST 1.1 assessments were performed at baseline and the end of every second treatment cycle until progression.The primary study endpoint was progression-free survival(PFS).Secondary endpoints were objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety.A549 xenograft model and patient-derived tumor xenograft(PDX)model were successfully constructed and treated with anlotinib(0.8-1 mg/kg)combined with docetaxel(10-15mg/kg).Observe the tumor volume changes for evaluating the efficacy,and perform proteomics approach to find out the target of combination therapy.RESULT:As of the last follow-up(February 10,2020),a total of 19 patients had been recruited and treated in combined treatment with anlotinib and docetaxel,with a median age of 61 years old.The median follow-up time was 5.5 months,the median PFS was 4.5 months,and the median OS was not reached.The ORR was 26.3%(5/19)and the DCR was 94.7%(18/19).The common adverse events were fatigue(21.1%,4/19),hand and foot skin reaction(21.1%,4/19),bleeding(15.8%,3/19)and hypertension(15.8%,3/19).In the xenograft model,anlotinib significantly enhanced the antitumor effect of docetaxel and cause little damage in main organs(heart,liver,kidney).By iTRAQ technology,207 differential proteins were screened between the PDX samples of the combined group and the docetaxel group.The GO/KEGG enrichment analysis found highly differential proteins enriched in collagen,involving in extracellular matrix(ECM)metabolic pathway.CONCLUSION:combined treatment with anlotinib and docetaxel has considerable efficacy and acceptable toxicity in patients with advanced NSCLC who have failed platinum-based doublet chemotherapy.This study successfully constructed a PDX model and verified the synergistic antitumor effect of combination.Furthermore,in the proteomics of the A549 xenograft model,the combination is beneficial to collagen synthesis in the extracellular matrix.