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

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.