BR.36 Trial Validates ctDNA Molecular Response at Cycle 3 as Predictor of Pembrolizumab Outcome in NSCLC
In this phase 2 adaptive trial, ctDNA molecular response -- defined as maximal mutant allele fraction clearance at the third pembrolizumab cycle -- predicted RECIST response with 82% sensitivity and 75% specificity in advanced NSCLC. Patients achieving molecular response had significantly longer progression-free and overall survival. These results form the basis for the interventional second stage of BR.36, where ctDNA non-responders are randomised to treatment intensification, pioneering a ctDNA-directed adaptive trial design.
The original study
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.
- Authors
- Anagnostou V, Ho C, Nicholas G, Juergens RA, Sacher A, Fung AS, et al.
- Journal
- Nature medicine
- Type
- Randomized Controlled Trial, Multicenter Study, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Adaptive Clinical Trial
- PMID
- 37814061
Original abstract
Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (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 survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .