Tumor mutational burden (TMB) as a predictive biomarker of immune checkpoint blockade (ICB) in metastatic solid tumors.

Abstract

80 Background: TMB is a promising predictive biomarker for ICB, but recent studies have shown that TMB varies substantially between tumor types. We examined the association between TMB and clinical response to ICB in metastatic urothelial carcinoma (mUC), renal cell carcinoma (mRCC), and non-small cell lung cancer (mNSCLC). Methods: We conducted a single center retrospective study inclusive of 1444 consecutive patients (pts) initiating ICB prior to 1/2019, cross-referenced with pts with Foundation One testing with TMB (mut/Mb), resulting in 17 mUC, 10 mRCC, and 60 mNSCLC. PD-L1 status was determined by the Dako 22C3 antibody. Pts were divided into clinical responders (R) and non-responders (NR) based on clinical assessment per their oncologist. The primary outcome of the study was to describe the relationship between TMB and clinical benefit, including duration of clinical response and overall survival (OS). A t-test was performed between R groups. Kaplan Meier (KM) curves and Cox-Mantel log rank tests were performed for PFS/OS comparing high TMB (≥ median) to low TMB pts. Results: For mUC, 8/17 (47%) were R with median TMB 7.74 (Interquartile range or IQR 6.04-9.78) compared to 9 NR, median TMB 7.57 (IQR 3.78-11.41) [p = 0.36]. For mRCC, 4/10 (40%) were R with median TMB 1.75 (IQR 1.75-1.97), versus 6 NR with median TMB 5.79 (IQR 3.07-7.48) [p = 0.02]. For mNSCLC, 30/60 (50%) were R with median TMB 11.38 (IQR 9.65-16.24), significantly higher than 30 NR with median TMB 9.46 (IQR 7.65-13.87) [p = 0.05]. For mNSCLC, no difference in PD-L1 positivity was found between R (17/30, 56%) and NR (16/30, 53%), and concurrent chemotherapy with ICB was the same in both R (10/30 (33%)) and NR (10/30 (33%)). KM analysis showed equivocal results for duration of clinical response and OS between high TMB vs low TMB in the three solid tumors, except OS in mUC which favored high TMB (p = 0.03) [cutoff TMB: mUC 7.57, mRCC 2.63, mNSCLC 11.35]. Conclusions: Higher TMB was associated with a greater likelihood of clinical benefit to ICB in our cohort of NSCLC patients and mUC. This correlation was not detected among mRCC patients, although these data are limited by relatively small number of cases.