Abstract CT194: Exploratory subgroup analysis of atezolizumab (atezo) clinical characteristics in patients (pts) with low circulating tumor DNA (ctDNA) in B-F1RST—a Phase II trial evaluating blood-based tumor mutational burden (bTMB) in NSCLC
Authors: Socinski Mark A. , Paul Sarah M. , Yun Cindy , Hu Sylvia , Shen Vincent , Velcheti Vamsidar , Mok Tony S. , Gandara David R. , Chae Young Kwang , Schleifman Erica , Fabrizio David A. , Shames David S. , Phan See , Kim Edward S. 
Published: August 2019

Abstract
Background
B-F1RST (ITT, n = 152) was the first prospective trial to evaluate bTMB as a predictive biomarker in 1L NSCLC. In the biomarker evaluable population (BEP, ctDNA with max somatic allele frequency [MSAF] ≥ 1%), bTMB high (≥ 16) predicted a better overall response rate (ORR) to atezo vs bTMB low (&lt; 16; 28.6 vs 4.4%). In exploratory analyses, numerically higher ORR was also seen in the biomarker non-evaluable population (ORR, 34.5%), although these pts were not evaluable for bTMB due to reduced assay sensitivity at very low ctDNA levels (MSAF &lt; 1%). Here we further evaluate the ≥ 1% MSAF and &lt; 1% MSAF subgroups.
Methods
Baseline characteristics were compared across MSAF &lt; 1% (n = 29) and MSAF ≥ 1% (n = 119) subgroups. Factors with a notable difference between groups (P &lt; 0.15) were included in an inverse probability weighting (IPW) method to adjust for baseline imbalances. Clinical outcomes from unadjusted and adjusted models were compared.
Results
Baseline factors with imbalances between MSAF groups (P &lt; 0.15) were age, smoking status, PD-L1 status, no. of target lesions and SLD (Table). In the unadjusted analysis, ORR for MSAF &lt; 1% vs ≥ 1% was 34.5 vs 10.1% (odds ratio [OR], 4.69; P = 0.002). After IPW adjustment, ORR was 19.9 vs 11.1% (OR, 1.99; P = 0.43). Unadjusted mPFS for MSAF &lt; 1% vs ≥ 1% was 6.8 vs 4.0 mo (HR, 0.63; P = 0.065), and adjusted mPFS was 2.8 vs 4.0 mo (HR, 0.88; P = 0.72).
Conclusions
Consistent with previous findings regarding low levels of ctDNA, pts with MSAF &lt; 1% had better baseline prognostic factors than those with MSAF ≥ 1%, likely accounting for their better outcomes. After adjusting for baseline imbalances, ORR and mPFS did not differ significantly between subgroups. These results do not alter interpretation of high bTMB results in the BEP (MSAF ≥ 1%). Clinical validation of the bTMB assay continues in B-F1RST and BFAST.
Table.Unadjusted and Adjusted Baseline Characteristics Included in the IPW ModelUnadjustedAdjustedMSAF ≥ 1%MSAF &lt; 1%PMSAF ≥ 1%MSAF &lt; 1%Pn11929119.027.5Age &lt; 65 y, %29.448.30.0933.030.20.80Never smoker, %5.013.80.146.66.90.52PD-L1+, %a37.851.70.1340.949.20.65Number of target lesions, mean (SD)2.38 (1.23)1.79 (0.86)0.022.27 (1.20)2.26 (1.13)0.98SLD, mmmedian (range)70.0 (12.7, 257.0)42.4 (13.0, 200.0)0.00162.0 (12.7, 257.0)48.2 (13.0, 200.0)0.77HR, hazard ratio; SD, standard deviation; SLD, sum of longest diameters.a PD-L1+ defined as ≥ 1% PD-L1 on tumor cells by any commercially available assay.
Citation Format: Mark A. Socinski, Sarah M. Paul, Cindy Yun, Sylvia Hu, Vincent Shen, Vamsidar Velcheti, Tony S. Mok, David R. Gandara, Young Kwang Chae, Erica Schleifman, David A. Fabrizio, David S. Shames, See Phan, Edward S. Kim. Exploratory subgroup analysis of atezolizumab (atezo) clinical characteristics in patients (pts) with low circulating tumor DNA (ctDNA) in B-F1RST—a Phase II trial evaluating blood-based tumor mutational burden (bTMB) in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT194.