Philip Mack, Ph.D. of Mount Sinai discusses his ASCO 2020 abstract on Residual circulating tumor DNA (ctDNA) after two months of therapy to predict progression-free and overall survival in patients treated on S1403 with afatinib +/- cetuximab.
Longitudinal improvements in the occurrence of mutant alleles (MAF) have high potential to refine clinical management of targeted therapies.
S1403 was a first-line phase II analysis of afatinib w or w/o cetuximab in pts with EGFR-mutant NSCLC. 174 pts were randomized with 168 confirmed to be qualified between March 2015 and April 2018. Owing to futility, the study closed early. Plasma specimens were collected prospectively at baseline, Cycle 3 Day 1 (C3D1; 8 weeks) and at progression, and processed by next-generation sequencing (Guardant 360) for batch analysis of ctDNA. A full technique for case analysis was used. The Kaplan-Meier method has been used to estimate distributions of survival, a Cox model to estimate hazard ratios and boundaries of confidence and a log-rank test to compare distributions. For the assessment of the predictive value of ctDNA clearance at C3D1, a landmark study was used.
104 patients (62 percent) had usable analyzable baseline plasma specimens and 83 (80 percent) had EGFR mutations. For pts with EGFR ctDNA positivity at baseline (p = 0.03) (Table), PFS was significantly shorter (probably a prognostic effect) relative to those without detectable ctDNA. In 79 pts with corresponding baseline and C3D1 specimens, kinetic changes in ctDNA MAFs were analysed. 68 percent (42/62) of 62 cases with detectable ctDNA at baseline were undetectable at C3D1 ('ctDNA clearance'); ctDNA clearance was correlated with slightly longer PFS (p = 0.00001) and OS (0.003) compared to residual ctDNA (Table). To date, at-progression samples of 29 pts have matched. In 6/29 (24 percent) cases, T790 M mutations were observed during progression. A TACC3-FGFR3 and an EML4-ALK fusion, MET exon 14 skipping, several MET amplifications and NF1 frameshift mutations are other suspected emergent resistance factors.
After 60 days of therapy the clearance of EGFR ctDNA was associated with a major and statistically relevant increase in subsequent PFS and OS. The integration of ctDNA kinetics into routine clinical treatment is a promising forum for recognizing patients with inferior TKI outcomes and detecting targetable mechanisms of emerging resistance.