JCSE01.19 ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line

Abstract

Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline. Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis. Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p= 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97). This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919.