Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann-Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5-9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer.

PURPOSE: PD-(L)1-blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade. RESULTS: We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10-2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction. CONCLUSIONS: We identified an association of the KIR3DS1 allelic variant with response to PD-1-targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1-targeted immunotherapy.

Fulminant pulmonary embolism with fatal outcome in a patient with low clinical prediction scores.

We present a case of a 72-year-old man with submassive acute pulmonary thromboembolism. Pulmonary embolism severity index Score and common clinical risk stratification recommended systemic anticoagulation and a clinical course without complications was expected. A primary reperfusion strategy was not indicated by the current guidelines. Under established anticoagulation, the patient was found in cardiac arrest immediately after mobilisation from the bed the next morning. Right heart catheterisation under ongoing resuscitation revealed a complete obstruction of the right pulmonary artery by a big thrombus. Catheter-directed intervention trying to bypass the thrombus with interventional guidewires failed. Ultimately, the patient died from acute right heart failure. The current case raises concern that the prediction scores available for pulmonary embolism may insufficiently predict short-term outcome in isolated patients.