Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial

Edward S. Kim, Vamsidhar Velcheti*, Tarek Mekhail, Cindy Yun, Sarah M. Shagan, Sylvia Hu, Young Kwang Chae, Ticiana A. Leal, Jonathan E. Dowell, Michaela L. Tsai, Christopher S.R. Dakhil, Philip Stella, Yanling Jin, David S. Shames, Erica Schleifman, David A. Fabrizio, See Phan, Mark A. Socinski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)939-945
Number of pages7
JournalNature Medicine
Issue number5
StatePublished - May 2022

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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