Early ctDNA molecular response captures therapeutic response in the first stage of CCTG BR.36 ctDNA-directed, multi-center phase II study of molecular response adaptive immunotherapy in non-small cell lung cancer

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase II trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer (NCT04093167). Consisting of 2 independent stages, the primary objectives of stage 1 were to ascertain ctDNA response, determine optimal timing and concordance with radiologic RECIST response. Liquid biopsy analyses utilized a validated tumor-agnostic white blood cell DNA-informed next-generation sequencing approach. Maximal mutant allele fraction clearance on C3D1 signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% CI:52%-97%) and a specificity of 75% (90% CI:56.5%-88.5%). Median time to ctDNA response was 2.1 months (90% CI:1.5-2.6) and patients with mR attained longer progression-free (5.03 vs 2.6 months) and overall survival (not reached vs 7.23 months). These findings are incorporated into the ctDNA-interventional randomized second stage of the trial.EGA study EGAS00001007298