Journal Article

ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results

Ding, Keyue, Sacher, Adrian, Brahmer, Julie R., Laurie, Scott A., Dancey, Janet, Avrutin, Egor, Zhu, Liting, Wheatley-Price, Paul, Ho, Cheryl, Levy, Benjamin, O’Donnell-Tormey, Jill, Nicholas, Garth, Balan, Archana, Anagnostou, Valsamo, Niknafs, Noushin, Sausen, Mark, Juergens, Rosalyn Anne, Fung, Andrea S., Bradbury, Penelope A., Gaudreau, Pierre Olivier

2023

Overview

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 . In the first stage of the BR.36 adaptive trial in patients with non-small cell lung cancer receiving anti-PD1 immunnotherapy, the primary endpoint of concordance between circulating tumor DNA (ctDNA) molecular response and RECIST response was met. The results will inform the second, ctDNA-directed stage.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212/2301 / 631/67/1612/1350 / 692/308/575 / 692/53/2423 / Antibodies, Monoclonal, Humanized / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Chemotherapy / Deoxyribonucleic acid / DNA / Humans / Immunotherapy / Infectious Diseases / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Neurosciences / Non-small cell lung carcinoma / PD-1 protein / Pembrolizumab / Progression-Free Survival / Small cell lung carcinoma / Solid tumors / Survival / Targeted cancer therapy / Tumors