Blood-based TMB fails primary endpoint as biomarker for atezolizumab in NSCLC
The BFAST phase 3 cohort C trial tested blood-based tumour mutational burden (bTMB) as a predictive biomarker for first-line atezolizumab versus chemotherapy in advanced NSCLC. The trial narrowly missed its primary PFS endpoint at the bTMB-16 cutoff (HR 0.77, p=0.053). However, exploratory analysis showed high concordance between the clinical trial assay and the FoundationOne Liquid CDx. The results temper enthusiasm for bTMB as a standalone selection biomarker and call for further optimisation of cutoffs and cooperative biomarkers.
The original study
Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial.
- Authors
- Peters S, Dziadziuszko R, Morabito A, Felip E, Gadgeel SM, Cheema P, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
- PMID
- 35995953
Original abstract
Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.