KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:...for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Plasma samples from patients with NSCLC treated with pembrolizumab were collected immediately before and after one or two cycles of treatment....Mutations were detected in ctDNA in 83.93% of patients before treatment initiation. High blood tumor mutational burden (bTMB), measured as the number of different mutations per Mb panel, correlated to longer progression-free survival (PFS) (10.45 vs. 2.30 months) and overall survival (OS) (21.80 vs. 12.20 months)....

At the data cutoff (January 11, 2021), 208 patients were treated (pembrolizumab+lenvatinib, n=72; pembrolizumab+quavonlimab, n=72; pembrolizumab+favezelimab 200mg, n=30; pembrolizumab+favezelimab 800mg, n=34). The overall assay success rate for testing and determining TcellinfGEP and TMB was 94%. In patients treated with pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, or pembrolizumab+favezelimab, ORRs were generally highest in the TcellinfGEPhighTMBhigh subgroup (table 1); response rates were similar across combinations within this subgroup...These data demonstrate the feasibility and clinical usefulness of prospective TcellinfGEP and TMB assessment to study the clinical activity of three first-line pembrolizumab-based combination therapies in patients with advanced NSCLC. Although sample sizes were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the biomarker subgroups for all three combination therapies.

This observational retrospective study involved 73 patients with advanced NSCLC who received either anti-PD-1 (pembrolizumab, nivolumab, or camrelizumab) or anti-PD-L1 (atezolizumab) therapy….Our results showed that the variables of male sex, smoking history, and high TMB were associated with a significantly longer PFS....Patients with high TMB and low TMB had an mPFS of 3.7 and 2.1 months (log-rank P=0.004), respectively....In univariate analysis of PFS, TMB was found to be a significant determinant of PFS (HR, 0.46; 95% CI, 0.23–0.92; P=0.027)....In multivariable analysis, TMB was identified as an independent determinant factor of PFS (HR, 0.41; 95% CI, 0.23–0.73; P=0.002)...

TMB high status was significant for OS benefit with pembrolizumab...Data comparing pembrolizumab treatments with chemotherapy and independent marker associations suggest TMB has predictive power for determining overall survival benefit from pembrolizumab...

We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab....When assessed as a continuous variable, TMB showed a trend towards improved PFS (HR =1; 95% CI, 0.99–1.00; P = 0.065). When assessed by quartiles, increasing TMB correlated with improved PFS...

When testing anti-PD-1 agents, such as dostarlimab and pembrolizumab, in a cohort of NSCLC explants from stage I-III treatment-naïve patients...Interestingly, responsive tumors presented with a high level of PD-L1 expression (high TPS), had elevated TMB...