Abstract

Background: Blood-based tumor mutational burden (bTMB) was recently found to be suboptimal in predicting overall survival (OS) benefits of atezolizumab over docetaxel among patients with advanced non-small cell lung cancer (NSCLC). The maximum somatic allele frequency (MSAF) is an indicator of the proportion of tumor-derived plasma DNA, which could affect the concordance between bTMB and tissue-based TMB. Therefore, we aimed to evaluate the utility of MSAF, alone or in combination with bTMB, to identify NSCLC patients with or without survival benefit from atezolizumab over docetaxel.Methods: We analyzed the individual patient-level data from the randomized POPLAR and OAK studies. The bTMB and MSAF were derived from the pre-treatment blood-based genomic data.Results: In both the bTMB-high (i.e., bTMB ≥ 13) and bTMB-low subgroups, atezolizumab significantly improved OS compared with docetaxel (hazard ratio [HR] = 0.43 [95% CI, 0.29–0.65], P < 0.001 and HR = 0.73 [95% CI, 0.61–0.87], P < 0.001, respectively). Among patients with a low MSAF (i.e., MSAF < 10.3%), OS significantly favored atezolizumab (HR = 0.59 [95% CI, 0.48–0.72], P < 0.001), whereas OS with atezolizumab was similar to that with docetaxel in the MSAF-high subgroup (HR = 0.91 [95% CI, 0.68–1.20], P = 0.500; interaction test P = 0.017). Among patients from the bTMB-low and MSAF-high subgroup, OS was numerically worse with atezolizumab than with docetaxel (HR = 1.06 [95% CI, 0.78–1.45], P = 0.710); in contrast, OS was significantly improved with atezolizumab compared with docetaxel in those with either a high bTMB or low MSAF (HR = 0.57 [95% CI, 0.47–0.69], P < 0.001; interaction test P < 0.001). Consistent findings were obtained for progression-free survival data.Conclusions: MSAF alone or in combination with bTMB can effectively distinguish patients with or without survival benefit from atezolizumab compared with docetaxel. MSAF and the combined bTMB-MSAF classification may become practical predictive markers for atezolizumab in advanced NSCLC.

Highlights

  • MATERIALS AND METHODSTumor mutational burden (TMB) is being extensively studied as a promising biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) [1,2,3]

  • We hypothesized that incorporating maximum somatic allele frequency (MSAF) with based TMB (bTMB) can partially lower the risk of misclassifying tissue-based TMB (tTMB)-high cases as bTMB-low, and mitigate the discordance between bTMB and tTMB and improve the differentiation between patients with or without survival benefits from ICIs. In this pooled analysis of the randomized POPLAR (NCT01903993) and OAK (NCT02008227) studies [13, 14], we comprehensively investigated the performance of MSAF alone or in combination with bTMB in predicting the comparative efficacy of atezolizumab and docetaxel among patients with advanced non-small cell lung cancer (NSCLC)

  • Atezolizumab significantly improved overall survival (OS) compared with docetaxel in both the bTMB-high (HR, 0.43 [95% confidence intervals (CIs), 0.29– 0.65], P < 0.001; Figure 1B) and bTMB-low (HR, 0.73 [95% CI, 0.61–0.87], P < 0.001; interaction test P = 0.023; Figure 1C) subgroups

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Summary

Introduction

MATERIALS AND METHODSTumor mutational burden (TMB) is being extensively studied as a promising biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) [1,2,3]. Mounting data have found that a high tissue-based TMB (tTMB) was associated with greater clinical benefit from anti-PD-1 therapies in patients with advanced non-small cell lung cancer (NSCLC) [4,5,6,7]. The maximum somatic allele frequency (MSAF) is a useful bioinformatics tool for estimating the amount of tumor fraction of cell-free DNA in peripheral blood samples [10]. Blood-based tumor mutational burden (bTMB) was recently found to be suboptimal in predicting overall survival (OS) benefits of atezolizumab over docetaxel among patients with advanced non-small cell lung cancer (NSCLC). The maximum somatic allele frequency (MSAF) is an indicator of the proportion of tumor-derived plasma DNA, which could affect the concordance between bTMB and tissue-based TMB. We aimed to evaluate the utility of MSAF, alone or in combination with bTMB, to identify NSCLC patients with or without survival benefit from atezolizumab over docetaxel

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