MA03.06 ctDNA Mass-Adjusted bTMB as a Predictive Biomarker in NSCLC Patients Receiving PD-(L)1 Inhibitors

Abstract

High blood tumor mutational burden (bTMB) was significantly associated with progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients receiving atezolizumab. However, it failed to predict overall survival (OS). We hypothesized that ctDNA mass-adjusted bTMB (abTMB) might predict survival benefits in NSCLC patients receiving immune checkpoint inhibitors (ICIs) treatment. We collected clinical and genetic data from POPLAR and OAK trials. Genetic mutations and bTMB were determined by blood-based FoundationOne next-generation sequencing assay. Durable clinical benefit (DCB) was defined as PFS lasting ≥ 6 months. The cutoff value of abTMB for DCB prediction was calculated based on a receiver operating characteristic curve. Interaction between treatment and abTMB was assessed. National Cancer Center (NCC) cohort was used as a validation. 853 NSCLC patients from POPLAR and OAK trials were included (n=429 for atezolizumab and n=424 for docetaxel) in this study. In the atezolizumab arm, the optimized cutoff value of abTMB for predicting DCB was 8 muts/Mb*ng. Significantly higher objective response rate (ORR) and DCB were observed in high abTMB patients than low abTMB patients receiving atezolizumab (20.5% vs. 11.0% for ORR, P=0.020; 40.8% vs. 23.8% for DCB, P<0.001). The median PFS (4.2 months vs. 2.4 months; adjusted hazard ratio [HR] for disease progression or death, 0.730; 95% CI, 0.593 to 0.900; P=0.003) and OS (15.9 months vs. 9.5 months; adjusted HR for death, 0.646; 95% CI, 0.508 to 0.822; P<0.001) of patients with high abTMB were significantly longer than those of patients with low abTMB in the atezolizumab arm. Importantly, the interaction between abTMB and treatments was significant for OS (interaction P=0.019) and PFS (interaction P=0.002). In addition, the prognostic role of abTMB was validated in the NCC cohort and high abTMB was associated with improved OS (28.5 months vs. 13.0 months; adjusted HR for death, 0.210; 95% CI, 0.049 to 0.899; P=0.035), PFS (15.5 months vs. 2.9 months; adjusted HR for disease progression or death, 0.305; 95% CI, 0.120 to 0.778; P=0.013), DCB (61.5% vs. 26.5%, P=0.041), and ORR (46.2% vs. 17.6%, P=0.065). The ctDNA mass-adjusted bTMB was predictive of the PFS and OS benefits in NSCLC patients receiving ICIs treatment. The abTMB might be used to identify patients who will benefit from ICIs treatment.