AUTHOR=Chen Yu-tong , Seeruttun Sharvesh Raj , Wu Xiang-yuan , Wang Zi-xian 

TITLE=Maximum Somatic Allele Frequency in Combination With Blood-Based Tumor Mutational Burden to Predict the Efficacy of Atezolizumab in Advanced Non-small Cell Lung Cancer: A Pooled Analysis of the Randomized POPLAR and OAK Studies

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01432

DOI=10.3389/fonc.2019.01432

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> 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], <italic>P</italic> &lt; 0.001 and HR = 0.73 [95% CI, 0.61–0.87], <italic>P</italic> &lt; 0.001, respectively). Among patients with a low MSAF (i.e., MSAF &lt; 10.3%), OS significantly favored atezolizumab (HR = 0.59 [95% CI, 0.48–0.72], <italic>P</italic> &lt; 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], <italic>P</italic> = 0.500; interaction test <italic>P</italic> = 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], <italic>P</italic> = 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], <italic>P</italic> &lt; 0.001; interaction test <italic>P</italic> &lt; 0.001). Consistent findings were obtained for progression-free survival data.</p><p><bold>Conclusions:</bold> 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.</p>