Allele Frequency–Adjusted Blood-Based Tumor Mutational Burden as a Predictor of Overall Survival for Patients With NSCLC Treated With PD-(L)1 Inhibitors

Abstract Introduction Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. Methods Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N = 211, and OAK, N = 462) and further validated in the third National Cancer Center (NCC) cohort (N = 64). Results bTMB-H (bTMB ≥ cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF ≤ 5%) was not (Pearson r = 0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.52–0.95, p = 0.02), progression-free survival (PFS; HR = 0.62, 95% CI: 0.47–0.80, p Conclusions We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated.