B-F1RST Trial: Blood-Based TMB Shows Promise but Needs Refinement for Immunotherapy Selection
The prospective phase II B-F1RST trial evaluated blood-based tumour mutational burden as a standalone predictive biomarker for first-line atezolizumab in 152 NSCLC patients. While bTMB at the pre-defined cutoff of 16 or higher was associated with higher response rates and longer overall survival at 36-month follow-up, the co-primary PFS endpoint was not met. The results indicate that bTMB holds promise but requires further assay optimisation and combination with other biomarkers.
The original study
Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial.
- Authors
- Kim ES, Velcheti V, Mekhail T, Yun C, Shagan SM, Hu S, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase II, Journal Article
- PMID
- 35422531
Original abstract
Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.