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

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.

Liquid First Is “Solid” in Naïve Non-Small Cell Lung Cancer Patients: Faster Turnaround Time With High Concordance to Solid Next-Generation Sequencing

“…Recent research, however, has found that VAF is related to tumor burden and corresponds with prognosis. Patients with reduced VAF, for example, reacted better to atezolizumab in the B-F1RST research ( 23 ). Furthermore, at very low VAF, some discordance between tissue and plasma NGS may be identified ( 24 ).…”

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors

“…In 2020, the FDA approved the FoundationOneCDX assay (Foundation Medicine, Inc, Cambridge, MA, USA), a next generation sequencing test, as a companion diagnostic for pembrolizumab treatment in unresectable or metastatic TMB-high (TMB ≥ 10 mutations/megabase (mut/Mb)) solid tumors, including NSCLC [ 67 ]. TMB can also be measured in blood-based assays in circulating tumor DNA; however, its clinical utility as a predictive biomarker is still under development [ 68 , 69 ]. In addition to TMB, whole exome sequencing of tumor and matched normal DNA and RNA-seq whole transcriptome analysis, as well as computational bioinformatics, can also be used to predict neoepitopes that can induce an effective anti-tumor immune response, and to develop novel strategies for cancer immunotherapy [ 70 , 71 ].…”

Comparison of real-world data (RWD) analysis on efficacy and post-progression outcomes with pembrolizumab plus chemo vs chemo alone in metastatic non-squamous non-small cell lung cancer with PD-L1 < 50%

“…In detail, sub-groups of patients benefitting the most from ICI were good performance status (PS 0-1), reduced number of metastatic sites (0-1) as well as bone or liver involvement ( 17 ). Novel predictive biomarkers are currently being investigated in this context also prospectively, such as for the blood-derived tumor mutational burden ≥16 in the B-F1RST clinical trial (NCT02848651) ( 18 ).…”